Chemicals and Drugs Forming Reactive Quinone and Quinone Imine

Review Cite This: Chem. Res. Toxicol. 2019, 32, 1−34

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Chemicals and Drugs Forming Reactive Quinone and Quinone Imine Metabolites Ivana Klopcǐ č and Marija Sollner Dolenc*

Chem. Res. Toxicol. 2019.32:1-34. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/22/19. For personal use only.

University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia ABSTRACT: Quinones and quinone imines are highly reactive metabolites (RMs) able to induce dangerous effects in vivo. They are responsible for all kinds of toxicity, for example, cytotoxicity, immunotoxicity, and carcinogenesis. Furthermore, hepatotoxicity of chemicals/drugs in particular can be induced by quinone and quinone imine metabolites. According to their reactivity, quinones and quinone imines react as Michael’s acceptors with cell proteins or DNA and, in this way, cause damage to the cells. Quinones and quinone imines also have high redox potential and, due to their semiquinone radicals, are capable of redox cycling and forming reactive oxygen species (ROS). However, the presence of quinones and quinone imines structures in compounds is not always responsible for a toxic effect. The main question, therefore, is what are the main factors responsible for the toxicity of the chemicals and drugs that form RMs. For this reason, the presence of structural alerts and evidence for the formation of reactive quinones and quinone imines metabolites and their mechanisms of toxicity through cellular effects are discussed in this review, together with examples.

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CONTENTS

1. Introduction 2. Selected Chemicals and Drugs-Involvement of Reactive Quinone and Quinone Imine Metabolites in Their Toxicity 3. Chemicals and Toxins That Form Quinone Reactive Metabolites 3.1. Benzene and Role of Its Quinones Metabolites in Hematotoxicity and Leukemogenicity 3.1.1. Benzene-Reactive Metabolites 3.2. Naphthalene 3.2.1. Bioactivation of Naphthalene by P450 3.3. CR-6 3.3.1. Metabolic Activation of CR-6 3.4. Ochratoxin A 3.4.1. Chemical Structure of Ochratoxins 3.4.2. Oxidative Stress and Disruption of Mitosis Caused by OTA 3.4.3. Direct Genotoxicity of OTA 3.4.4. DNA Adducts 3.5. Pentachlorophenol (PCP) 3.5.1. Metabolic Activation of Pentachlorophenol to Quinones and Conseqences 4. Drugs That Form Quinone Imine Reactive Metabolites 4.1. Lumiracoxib 4.2. Diclofenac 4.3. Bioactivaton of Drugs Used for Parkinson’s Disease © 2018 American Chemical Society

4.4. Paracetamol 4.5. Amodiaquine 4.6. Nomifensine 4.7. Tyrosine Kinase Inhibitors 4.7.1. Lapatinib 4.7.2. Dasatinib, Gefitinib, and Erlotinib 4.8. Nefazodone 4.9. Carbamazepine 4.10. Atorvastatin 4.11. Aripiprazole 4.12. Trazodone 5. Presence of Methylene Dioxyphenyl Functional Group in Chemical: Structural Alert or Not for Forming Quinones? 5.1. Paroxetine 5.2. Tadalafil 5.3. Carvedilol 5.4. Raloxifene 5.5. Estradiol 5.6. Bisphenol A 5.7. Dopamine 5.8. Doxorubicin 6. Conclusion and Future Directions Author Information Corresponding Author ORCID Funding

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Received: August 7, 2018 Published: November 30, 2018

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DOI: 10.1021/acs.chemrestox.8b00213 Chem. Res. Toxicol. 2019, 32, 1−34

Chemical Research in Toxicology Notes Biographies Acknowledgments References

Review

Being Michael acceptors, they can alkylate proteins or DNA, thereby being responsible for damaging cells. Thus, they can react with sulfur nucleophiles, such as GSH or cysteine residues on proteins, or with nucleophilic amino groups of proteins or DNA. Further, their activity can damage proteins, DNA, lipids, and other cellular macromolecules through the formation of ROS that are responsible for oxidative stress by oxidizing these macromolecules. Further, it has been shown that the formation of 8-oxodeoxyguanosine is associated with aging and carcinogenesis. In addition, protein kinase C and RAS can be activated by ROS.16 Regulatory proteins, such as protein tyrosine phosphatases, kelch-like ECH-associated protein 1, the regulatory protein for NF-E2-related factor 2, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, are also possible targets for this type of reaction. Quinones and quinone imines also affect the pathways involved in cell signaling that protect against inflammatory responses and cell damage. These actions vary depending on the specific quinone and its concentration.17 Aromatic compounds such as phenols, hydroquinones, and catechols can be transformed to quinones by monooxygenase or peroxidase enzymes, metal ions, and, in some cases, directly by molecular oxygen.14,18 Quinones are derivatives of their parent aromatic system; for example, benzoquinones are derived from substituted benzene. For the effects of quinones on biological systems, two chemical properties are important that enable their reactivity, and their relative contribution to toxicity is influenced by substituent effects.14 They are considered as chemically reactive species because they are electrophilic compounds, but they can also undergo redox cycling and cause oxidative stress in cells (2, Figure 3).19 As a result of redox cycling, they can generate superoxide anion radicals.20 Oxygen intermediates (including the superoxide anion radical, hydrogen peroxide, and hydroxyl radical) are termed reactive oxygen species (ROS). ROS can be generated by ultraviolet (UV) radiation or enzymatically. Free radicals have the potential of damaging every biological molecule present in the body. Molecules damaged in such a way can impair the functions of cells or even provoke their death, ultimately leading to different pathologies.21−23 For example, oxidation of proteins, caused by ROS, can generate protein hydroperoxides, which can generate additional radicals and may produce certain additional radicals, mainly on interaction with transition metal ions. Gradual accumulation of some oxidized proteins, which can occur with time, may contribute to the damages associated with age as well as to different pathological conditions.16 Lipids may be oxidized by ROS through generation of lipid peroxidederived malondialdehyde DNA adducts.24 DNA is highly susceptible to damage by free radicals such as HO• since HO• very effectively attacks susceptible purines, which generates 8hydroxydeoxyguanosine (8-OHdG), 8-hydroxydeoxyadenosine, formamidopyrimidines, and other less well characterized purine oxidative products. In addition, the reactivity of free radicals can also lead to the activation of poly(ADP-ribose) synthetase, which may result in fragmentation of DNA and programmed cell death.21,23 From these data, it can be concluded that the compounds that form quinone and quinone imine metabolites may cause serious toxic effects. The main question is which factors affect the degree of toxicity of the chemicals and drugs that form quinones and quinone imines metabolites. The aim of this review is therefore to represent the involvement of these metabolites in the toxicity of a variety of selected chemicals and drugs.

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1. INTRODUCTION Drug metabolism is associated with conversion of a xenobiotic to a less reactive hydrophilic metabolite that can be removed from the body. However, drug metabolism can lead, by another path, to chemically more reactive species, that is, reactive metabolites (RMs).1 This process is, therefore, termed metabolic activation or bioactivation; it is known to have detrimental effects.1−3 Chemically, RMs are electrophiles (molecules that contain positive centers) or free radicals, and their toxicity can be mediated by covalent or noncovalent binding mechanisms.2 Electrophiles, which are inherently reactive, can be generated by the metabolism of chemically inert compounds. “Hard electrophiles” (e.g., alkyl carbocation, carbonyl carbocation, and nitrenium ion) and “soft” electrophiles (e.g., Michael acceptors, quinone methide, and quinone imine) are known. Factors such as the presence of a good leaving group, ring strain, polarization of a double bond by a Michael acceptor, and the presence of electron withdrawing groups are crucial for the reactivity of electrophiles.4 Free radicals have an unpaired electron and form a covalent bond by reacting with another free radical, abstracting a hydrogen atom to form a new radical or abstracting an electron to generate a radical cation. Free radicals comprise those known as reactive oxygen species (ROS) and those that contain an additional nitrogen atom (e.g., nitric oxide (NO)). Despite their high reactivity, their function is important in the vasculature, the nervous and immune systems, regulation of cell growth, and in gene expression.5,6 Formation of RMs is also linked with an idiosyncratic adverse drug reaction (IDR), which is linked to life-threatening effects. The high reactivity of RMs may occasionally result in irreversible inhibition of the enzyme involved in their formation.7,8 Such toxicities cannot be disregarded by the pharmaceutical industry, and a standard battery of toxicological assays must be used routinely in a drug-discovery paradigm. RMs can react with nucleophilic centers of endogenous macromolecules to modify them covalently, causing toxicity. Metabolites can react with proteins leading to cell toxicity and immunogenicity.4,9 Reaction with nucleic acids can lead to changes in DNA and mutagenicity, teratogenicity, or carcinogenicity (see Figure 1).10−13 Quinones and quinone imines are highly redox active molecules and electrophiles, both these properties being crucial for their reactivity in biological systems. Furthermore, differences in chemical structure, in particular substituent effects, influence quinone toxicology.14 These compounds have a fully conjugated cyclic dione structure, such as that of benzoquinone (1, Figure 2), the prototypical member of the quinones.15 Quinones as well as quinone imines are highly reactive organic chemicals and comprise a class of toxicological intermediates16 that interact alone or by generating ROS in biological systems to promote inflammatory reactions, reactivate immune cells, oxidize DNA, and in a such a way, induce toxicity. They can be responsible for effects in vivo including immunotoxicity, cytotoxicity, and carcinogenesis.16 Two reactions of quinones and quinone imines are crucial for their activity: they reduce oxygen to reactive oxygen species, acting as prooxidants, and, as electrophiles, they form covalent bonds with tissue nucleophiles. 2


Chemical Research in Toxicology

Review

Figure 1. Metabolic fate of xenobiotics in mammals.1

2. SELECTED CHEMICALS AND DRUGS-INVOLVEMENT OF REACTIVE QUINONE AND QUINONE IMINE METABOLITES IN THEIR TOXICITY We focus on compounds with alerts in their chemical structure that have been associated with the formation quinone or quinonimine metabolites and with their role in compound

Figure 2. 1, p-Benzoquinone.

Figure 3. Nucleophilic substitution of DNA and proteins and redox cycling of quinones. 2, Quinone; 3, Hydroquinone; 4, Semiquinone radical.16 3



Review

Table 1. Chemicals and Drugs, Their Source, Toxicity, and Nature of Reactive Intermediates

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Table 1. continued

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Table 1. continued

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Table 1. continued

biotransformed, through both phases I and II, in the liver.27,30,120 It has been shown that the toxicity of benzene can be reduced by partial hepatectomy and inhibition of benzene metabolism by toluene.121 The latter finding led to the suggestion that metabolism in the liver plays an important role in creating the toxic effect.122 Biotransformation involves the cytochrome P450, yielding benzene oxide in the first step, followed by converted into phenol, catechol, hydroquinone, and 1,2,4-trihydroxybenzene.19 This process requires the participation of the specific isoform of P450- P450 2E1.123 Mice without P450 2E1 do not exhibit benzene-induced hematotoxicity.124 In humans, monohydroxylated benzene (phenol) is the major metabolite. There are other biotransformation pathways, such as ring opening, that lead to mucondialdehyde and muconic acid. It is assumed that the transformation of benzene to benzene oxide or its oxepin precedes the opening of the benzene ring.125 The hematotoxicity of benzene is mediated by its metabolites such as phenol, catechol, and hydroquinone. These are produced in liver 121,127 and transported to the bone marrow128,129 where they are converted to biologically reactive intermediates such as p-benzoquinone by peroxidase-mediated oxidation. The bone marrow of humans, as well as of other animals, is therefore the primary target organ where toxic effects are expressed due to, among other factors, its high myeloperoxidase activity and relatively low expression of NAD(P)H-quinone oxidoreductase (NQO). This combination results in rendering the two-electron transfer and inactivation of the p-benzoquinone back to the p-hydroquinone, and to a large number of rapidly dividing cells, in which cell damage is readily manifested.130−132 Further, bone marrow exhibits much lower levels of glutathione that is involved in xenobiotic protection.19,133 Reactive species are catechol, hydroquinone (HQ),

toxicity (Table 1). In addition, not all RM-free compounds have guaranteed safety. Further, it is also well-known that rare lifethreatening reactions (such as hepatotoxicity, skin rashes, and blood dyscracias) can be multifactorial in nature. The presence of structural alerts, evidence for quinone and quinone imine formation, and their toxicity mechanisms through cellular effects will be discussed in this review.

3. CHEMICALS AND TOXINS THAT FORM QUINONE REACTIVE METABOLITES 3.1. Benzene and Role of Its Quinones Metabolites in Hematotoxicity and Leukemogenicity. Benzene is a ubitiquous human environmental carcinogen.113−116 It is widely used as an industrial chemical as a solvent and reagent for synthesis. It is a constituent of gasoline and cigarette smoke.19,25 The different ways of exposure to benzene affect a large proportion of the world population.117 Health concerns about benzene exposure arose when a recent study on shoe workers in China revealed that exposed people had lower numbers of granulocytes, lymphocytes, and platelets in the peripheral blood than those in nonexposed people.19 Shorter exposure to benzene leads to early, reversible hematotoxicity, while longer exposure to high doses induces irreversible damage of bone marrow. The exposure to high-levels of benzene results in either the development of irreversible bone marrow aplasia (aplastic anemia) or, in case of patients who survive aplasia, in the appearance of dysplastic marrow (myelogenous leukemia).26,27,118 Although the current U.S. occupational exposure limit is 1 ppm (parts per milion),19 there is still concern that prolonged/chronic exposure to low levels of benzene, due to environmental conditions, may be damaging.119 3.1.1. Benzene-Reactive Metabolites. Exposure to benzene occurs primarily via inhalation. After absorption, it is 7



Review

Figure 4. Metabolism of benzene. 5, Benzene; 6, Benzene oxide; 7, Dihydrodiol; 8, Phenol; 9, Catechol; 10, 1,2-Benzoquinone; 11, Hydroquinone; 12, 1,4-Benzoquinone; NQO1, NAD (P) H quinone oxidoreductase; MPO, myeloperoxidase; P450 2E1, cytochrome P450 2E1; EH, epoxide hydrolase.126

is GSH, which can react directly with BQ. Mutation of the gene for NQO1 leads to increased risk of benzene poisoning.145,146 GSH and NQO1 play roles in preventing hydroquinoneinduced toxicity that vary according to the state of cell differentiation, cell type, and the species from which the bone marrow cells are derived.147 The in vivo method in mice of Lee et al.148 demonstrated the relative potency with which benzene and its metabolites inhibit erythropoiesis. Combining the hydroquinone plus muconaldehyde produces the greatest potency, while benzene has the lowest potential for toxicity. Also, all the benzene metabolites were highly effective when given in combination. Many of the benzene metabolites, except for phenol, were effective at lower iron uptake. The specific benzene metabolites that influence several cell-types and their different functions are responsible for overall benzene toxicity. The effect of 1,2,4-benzenetriol needs more experiments on circulating blood cells and other hematopoietic tissue and further proofs of its toxicity since it was ineffective in preliminary studies. 1,2,4Benzenetriol can be isolated from mouse hepatocytes, suggesting a correlation with susceptibility to toxicity.120,149 The biological interactions of benzene are rather complex (5, Figure 4). Biotransformation of a structurally simple chemical is the main element in its hepato- and hemato-toxicity. Furthermore, benzene is one of the cases where strong evidence exists for RMs being responsible for its toxicity. The importance of understanding its toxicological actions in target cells underlies strategies for reducing and preventing them. 3.2. Naphthalene. Naphthalene (NAP) has commonly been used in moth repellent products150 both as a solvent and a component of industrial products and waste materials.151 As a nonredox xenobiotic, it can damage marine organisms and freshwater fish by producing ROS.151−153 NAP is genotoxic and is an endocrine disruptor for fish,154−156 a carcinogen in rats157 and, probably, in humans.158,159 Primary exposure of the general human population is through the environmental sources (indoor and outdoor air, water, soil, food) and in various work places (creosote impregnation, distillation of coal tar and naphthalene production, manufacture of refractories, graphite electrodes, aluminum, and mothballs).157 Of the several human sites sensitive to the toxicity of naphthalene (e.g., eyes, lungs, liver, brain), the most prominent tissues associated with toxicity include the lens of the eye and the lungs.160

and benzoquinone (BQ). Their toxicity is a result of either direct interaction with proteins (e.g., P450) and DNA30,32,33 or via oxygen activation.29,134 BQ thus affects tubulin by reacting with its thiol groups that are strong nucleophiles. The consequence is the myelotoxicity of benzene that is caused by damage of the mitotic spindle. BQ can also react spontaneously with DNA, creating DNA adducts. The damaging effect of HQ on DNA is indirect, through the formation of ROS, specifically, hydroxyl radicals, that result from the dissociation of hydrogen peroxide and which is involved in 8-hydroxydeoxyguanosine formation.29,30 Oxidized forms of HQ damage P450 directly, rather than via oxygen activation of P450. Benzene metabolites destroy P450 in vitro, their ability decreasing in the order BQ > HQ > catechol > phenol. BQ or HQ damage P450 directly; this is not mediated by hydroxyl radical formation or by lipid peroxidation.31 In contrast, HQ and BQ protect P450 from destruction by radicals or the ROS that originate during the futile P450 cycle.32,135−137 HQ reacts spontaneously with oxygen, forming semiquinone radical and superoxide anion radical; O2•− may dismutate to H2O2. Furthermore, these two oxygen species form hydroxyl (HO•) radicals (the ironcatalyzed Haber-Weiss reaction generates HO• from H2O2 and O2•−) that are thought to be the most effective ROS in damaging DNA.134 Various benzene metabolites exhibit a variety of mechanisms of toxicity in hydroquinone-treated cells in which DNA adduct formation plays a role in the inhibition of cell differentiation but not in 1,2,4-benzenetriol-treated cells.120 Myeloperoxidases convert hydroquinone to benzoquinone, requiring hydrogen peroxide to be catalytically active. Hydrogen peroxide is present at high concentrations in differentiated myeloid cells (polymorphonuclear leukocytes and monocytes) as well as in their progenitors.138−140 Oxidation of hydroquinone by molecular oxygen or by copper ions results in the formation of benzoquinone and hydrogen peroxide; this reaction is a potential source of hydrogen peroxide.141−144 Myeloperoxidase is located in azurophilic granules; Cu/Zn SOD is cytoplasmic, and copper is found associated with DNA. Benzene metabolites, especially HQ and BQ, can react with tubulin, topoisomerase II, histone, and DNA.138 BQ can be reduced- by NAD(P)H:quinone oxidoreductase (NQO1)- back to hydroquinone, which can be glucuronidated or sulfated for cell excretion. The alternative way to remove BQ 8



Review

Figure 5. Main pathways and metabolites of naphthalene in mammals. 13, Naphthalene-1,2-epoxide; 14, 1-naphthol; 15, 2-naphthol; 16, 1naphthylglucuronide/sulfate; 17, 2-naphthylglucuronide/sulfate; 18, 1,4-dihydroxynaphthalene; 19, 1,4-naphthoquinone; 20, trans-1,2-dihydro-1,2dihydroxynaphthalene; 21, 1,2-dihydroxynaphthalene; 22, 1,2-naphthoquinone; 23, 2-hydroxynaphthyl-1-glucuronide/sulfate; 24, trans-1,2-dihydro2-hydroxynaphthyl-1-glucuronide/sulfate; 25, naphthylmercapuric acids. UGT/ST, UDP-glucuronyltransferase/sulphotransferase; GSH, glutathione-SH; R1, glucuronic acid/sulfate residue; R2, N-acetyl-L-cysteine residue, EH, epoxide hydrolase, AKR, aldo-keto-reductase.157

3.2.1. Bioactivation of Naphthalene by P450. Metabolic activation of naphthalene starts by oxygene reduced nicotinic acid amide dinucleotide phosphate (NADPH)/P450-dependent mono-oxygenase enzymes (P450), which form very reactive, unstable stereoisomeric arene oxides, 1R,2S-epoxide and 1S,2Repoxide (13, Figure 5).161,162 Epoxides can either be conjugated and excreted by kidneys or form 1-naphthol and 2-naphthol (14 and 15, Figure 5), which can be eliminated directly as conjugates (16 and 17, Figure 5). Furthermore, the third metabolic pathway of epoxides is hydroxylation by epoxide hydrolase (EH) to form trans-1,2-dihydro-1,2-dihydroxynaphthalene (20, Figure 5). There are three metabolic pathways for dihydrodiol: in the first, it becomes dehydrated, forming 2-naphthol (15, Figure 5); in the second, it is oxidized to 1,2-dihydroxynaphthalene (21, Figure 5) by dihydrodiol dehydrogenases (aldo-ketoreductase (AKR)). Further, 1,2-naphthalenediol (21, Figure 5) can be metabolized to form 1,2-naphthoquinone (22, Figure 5) or the glucuronide/sulfate conjugate (23, Figure 5). The third metabolic pathway for the dihydrodiol (20, Figure 5) is glucuronic acid/sulfate conjugation (24, Figure 5) with potential subsequent dehydration (16, Figure 5). One more option for the metabolism of naphthalene is the formation of premercapturic acids and mercapturic acids (resulting from the glutathione conjugation) (25, Figure 5).163−168 1-Naphthol can be further oxidized to 1,4-dihydroxynaphthalene (18, Figure 5), which is oxidized to form 1,4-naphthoquinone (19, Figure 5). Reactive species (naphthoquinones) that are involved in naphthalene toxicity could lead to increased production of ROS, such as superoxide anion and hydroxyl radical,16,160,169−171

depleting glutathione and resulting in the formation of oxidative stress or in increased covalent adduct formation with proteins and DNA bases.172−176 3.3. CR-6. The 3,4-dihydro-6-hydroxy-2,2-dimethyl-7-methoxy-1-(2H)-benzopyran is a free radical scavenger and αtocopherol analogue with potent inhibitory activity against lipid peroxidation in rat liver microsomes. It is neuro-protective in the disease where oxidative stress is a causative factor.37,177 CR-6 contains a nonsubstituted, activated aromatic position (C5), which explains its ability to act as a scavenger of nitric oxide and peroxynitrite by forming the corresponding 5-nitroderivative and 1,4-benzoquinone.178 Upon oral administration, antioxidant CR-6 reaches the rat brain tissue and, after transient ischemia, protects the brain from reperfusion injury.179 Furthermore, it may reduce infarct size caused by cerebral ischemia by preventing vessel hypertrophy and normalization of wall stress.180 As an NO scavenger and the protectant, CR-6 prevents glutamate neurotoxicity in cultures of cerebellar neurons.181 Antioxidants can be useful in a supportive therapy in diabetes: for example, CR-6, which is able to protect glutathione peroxidase (GPx) activity from glucose-induced hyperglycemia, effectively quenches nitrogen reactive species in Alloxan-induced experimental diabetes in mice.182 Reactive oxygen species (ROS) play a critical role in photoreceptor apoptosis, while, on the other hand, CR-6 acts as a scavenger of ROS and reduces 661W photoreceptor apoptosis induced by nitric oxide donor sodium nitroprusside (SNP) by preventing activation of a pathway in which calpains play a key role.183 Sanvicens et al. highlight the relevance of CR-6, alone or in 9



Review

Figure 6. P450 mediated metabolic activation of CR-6. 26, CR-6 (3,4-Dihydro-6-hydroxy-2,2-dimethyl-7-methoxy-1-(2H)-benzopyran); 27a, 2-(3′hydroxy-3′-methylbutyl-5-methoxy-1,4-benzoquinone; 27b, oxaspiro[4.5]-2,2-dimethyl-8-methoxy-dec-8-ene-7,10-dione; 28, hydroquinone 2-(3′hydroxy-3′-methylbutyl)-5-methoxyhydroquinone; 29, hydroxylated metabolite 3,4-dihydro-4,6-dihydroxy-2,2-dimethyl-7-methoxy-1(2H)-benzopyran; 30, catechol 3,4-dihydro-6,7-dihydroxy-2,2-dimethyl-1(2H)-benzopyran; 31, 3,4-dihydro-2,2-dimethyl-1(2H)-benzopyran-6,7-dione.37

Figure 7. 32, Ochratoxins.

corresponding o-quinone derivative has also been identified by high-performance liquid chromotography (HPLC) (31, Figure 6).37 CR-6 antioxidant is an inhibitor of P450 isoenzyme activity. It showed inhibition of the 7-ethoxyresorufin O-dealkylation activity of P450 1A and the 7-pentoxy-resorufin O-dealkylation activity of P450 2B in treated microsomes. The reactive metabolites, formed after CR-6 biotransformation, were stronger inhibitors of P450 2B than of P450 1A isoform. The stronger inhibition could be attributed either to the higher formation of potentially reactive metabolites for the P450 2B or the metabolites generated by P450 2B could bind more efficiently to this isoenzyme. Inactivation of P450-activities most probably occurs at the level of the P450 isoenzymes rather than at the level of the reductase. It is known that the activation of microsomal glutathione-S-transferases can be used to detect the thiol-reactive and potentially toxic chemicals that are formed,36 which happens as the result of oxidative and electrophilic compounds that react through a regulatory cysteine residue.185−188 CR-6 metabolites activate microsomal GSH transferases since protein-thiol reactive metabolites are formed during P450-mediated biotransformation of CR-6.37 The reactive metabolites formed are not mutagenic but are cytotoxic reactive intermediates. 3.4. Ochratoxin A. Ochratoxin A (OTA) (N-{[(3R)-5chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl] carbonyl}3-phenyl-L-alanine) is a mycotoxine produced by some

combination with other drugs, as a potential therapeutic strategy for the treatment of neurodegenerative diseases.184 Together, all the studies suggest that not only could CR-6 be a significant adjuvant therapy for retinal conditions, it could also be applied in other oxidative stress-induced disorders or neuropathies.177 3.3.1. Metabolic Activation of CR-6. CR-6 is biotransformed in vitro via three different metabolic pathways in which the five metabolites (with the exception of o-quinone) are formed (Figure 6). In the first pathway, oxidative ring opening of the chromanol moiety initially produces benzoquinone (27a, Figure 6), which can undergo a nonenzymatically promoted cyclization to give the spiro compound (27b, Figure 6). Alternatively, it can be reduced by P450 and NADP(H) to the corresponding hydroquinone (28, Figure 6). At the same time, the hydroquinone (28, Figure 6) could be reoxidized by P450 to benzoquinone (27a, Figure 6). The reactive oxygen species may also contribute to this reoxidation. Reactive oxygen species can be generated by redox cycling or by uncoupling of P450. In future work, it will be important to delineate whether the enzyme NAD(P)H quinone oxidoreductase (NQO1) plays a role in the reduction of CR-6 metabolite, 27a-benzoquinone, since it was postulated that individuals lacking NQO1 may have a decreased capacity for protecting against cellular oxidative damage. The second oxidative pathway of CR-6 is via benzylic hydroxylation to compound 29 (Figure 6) by P450. The third is associated with the activity of P450 and generates catechol (30, Figure 6) through dealkylation. The formation of the 10



Review

toxicogenic species of Aspergillus and Penicillium.189 Benzoquinone metabolites are also formed. It is a contaminant of moldy cereals, oats, and has been extracted from some beans (coffee beans, peas, etc).38,39 OTA is a strong nephrotoxicant, neurotoxicant, immunotoxicant, mutagenic, and teratogenic agent.190 There is evidence that in rodents it causes kidney tumor.40 For humans, it is a possible carcinogen (group B) based on sufficient evidence for carcinogenicity in animals but inadequate evidence on humans.41 Because of OTA-mediated genotoxicity and its mechanism of carcinogenesis, the joint FAO/WHO Expert Committee has set a provisional tolerable weekly intake of OTA at 100 ng/kg body weight.191 There are two mechanisms of genotoxic activation: by forming a reactive oxygen species (ROS) that reacts with DNA to generate damage and promotes oxidative stress, the second by bioactivation and formation of covalent DNA adducts.192 Available data suggest that, for genotoxic effects, OTA must also have an indirect mechanism of action.193 3.4.1. Chemical Structure of Ochratoxins. The chemical structures of ochratoxin A, B, and C (32, Figure 7). Ochratoxin B is less toxic than ochratoxin A and does not inhibit protein biosynthesis in hepatoma cells.194 Ochratoxin A possesses a chlorine atom on C5 of the dihydromethyl-isocoumarin ring system,195 and a phenolic OH group, which increases toxicity.196 This OH group can influence the secondary structure of ochratoxins by forming hydrogen bonds,197 and the C5−Cl atom of OTA plays an inportant role in OTB-dG formation.192 OTA consists of phenylalanine and dihydroisocumarin fragments, which are coupled via an amide linkage. Splitting of this bond results in the formation of phenylalanine and ochratoxin α, which is not toxic.196,198 OTA is a weak acid (pKa = 7.1) that, under culture conditions, can form acid amides with tyrosine, glutamic acid, methionine, tryptophan, valine, serine, alanine, and proline in place of phenylalanine. Some of them are very strong inhibitors of protein biosynthesis (for example, alanine-ochratoxin A), while others are nonfunctional (for example, proline-ochratoxin A).194 3.4.2. Oxidative Stress and Disruption of Mitosis Caused by OTA. Oxidative stress plays a critical role in OTA carcinogenicity. The ROS formed cause oxidative damage to DNA.199−206 The latter has been detected indirectly by comet assay by detecting the oxidized DNA bases207 and DNA fragmentation that are produced by the enzyme formamido-pyrimidine-DNAglycosylase (Fpg).200−206 Furthermore, OTA exposure is a source of both ROS and RNS199 since it increases expression of nitric oxide synthase (iNOs) and stimulates protein nitration.208 ROS/RNA production increases levels of oxidative DNA, lipid, and protein damage. OTA contains a phenolic ring system, and oxidative stress is mediated by phenols,209,210 which is responsible for thiol oxidation and antioxidant depletion and reduces GSH levels in mammalian cell lines.204 The second mechanism of indirect genotoxicity is disruption of mitosis for OTA-mediated renal carcinogenesis. This is also the basis for making an additional validation for risk assessment.211 The group of researchers categorize the toxin as a nonmutagenic and propose that the mechanism of action (MOA) for indirect gentotoxicity is disruption of mitosis and chromosomal instability.211−214 OTA blocks the transition between metaphase/anaphase and leads to the formation of aberrant mitotic figures,212,213 inhibits microtubule assembly, and blocks histone acetyltransferase (HAT) activity,214 which is a driving force in tumorigenesis. Furthermore, it is unlikely that disruption of

mitosis plays a critical role in OTA-induced tumor formation, especially if karyomegaly is indicative of disruption.215,216 3.4.3. Direct Genotoxicity of OTA. Bioactivation of OTA generates reactive oxygen species (ROS) that attach covalently to DNA, generating DNA adducts that stimulate mutagenicity and renal carcinogenesis. In the presence of P450, OTA forms electrophilic tetrachlorobenzoquinone (TCBQ) that reacts covalently with sulfhydryl groups, 42 2′-deoxyguanosine (dG),43 and other DNA bases44 to form benzetheno type adducts. Because it is well-known that TCBQ forms covalent DNA adducts in rat liver, it is expected to play a key role in carcinogenesis.217 In the presence of peroxidase, the electrophilic phenoxyl radical is formed by the oxidative pathway.218 The phenolic radical can react with the C8 site of dG to generate an oxygen−oxygen linked C8-OTA adduct,219 which is also formed when phenolic radical reacts with DNA (Figure 8).220 In

Figure 8. Proposed pathways for the bioactivation of OTA. 33, OTA; 34, OTQ; 35, OTHQ; 36, OTA-GSH; 37, Phenoxyl radical; 38, Carbon-centered radical.192

the presence of the glutathione (GSH), the phenolic radical generates GS• that reacts with O2 to produce O2•−. This is converted with SOD to H2O2. Further, H2O2 reacts in the Fenton reaction formed HO•, which causes oxidative DNA damage. This pathway is important in the toxicity of all phenolic xenobiotics.209,210 Furthermore, OTA, in the presence of P450, generates the electrophilic quinone OTQ that reacts covalently with GSH to form the GSH conjugate (oxidative dechlorination). The formed metabolite (OTQ) reacts with reducing agent (e.g., ascorbate) and it is reduced to hydroquinone N-{[(3R, S)-5,8dihydroxy-3-methyl-1-oxo-3,4 dihydro-1H-isochromen-7-yl]carbonyl}-L-phenylalanine (OTHQ, 35).45,46 However, the reductive dehalogenation process leads to the formation of reactive aryl radicals, which intereact at the C8 site of purine bases to yield carbon (C)-linked DNA-adducts.221−223 On the basis of the OTA chemistry, we can suggest that the aryl radical can react with an H-donor to form OTB metabolite. Furthermore, this structure is appropriate for generating both reactive radical species (phenolic and aryl radicals) and an electrophilic quinone OTQ. 11



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3.4.4. DNA Adducts. OTA forms guanine−DNA adducts shown in Figure 8. The first DNA-adduct was initially derived from the photoreactions of OTA in the presence of excess dG.224 They were also produced in the presence of Fe2+, Cu2+, and horseradish peroxidase.224 Furthermore, another theory was that the OTB−dG adduct was generated from attachment of the OTA with a phenoxyl radical.224 In fact, it was derived from direct aryl radical attachment to the dG, most likely with C8 site of dG,192 where Fe2+ acted as a reducing agent to cause reductive dehalogenation of OTA to afford the aryl radical species. Photolysis of OTA in the presence of dG gave a second adduct with the UV spectrum exposed suggesting loss of the phenolic H-atom. It is well known that photolysis of OTA generates the phenolic radical225 that reacts at the C8 site of dG (Figure 9).226,227

confirmed that OTA acts as a classical genotoxic carcinogen by bioactivation and covalent DNA addition. 3.5. Pentachlorophenol (PCP). Pentachlorophenol (PCP) has been used as a pesticide, herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and moluscicide.48 PCP is a procarcinogen in rodents,50,229 and evidence suggests that it is an endocrine disruptor and probably carcinogen in humans,51−57 absorbed by the skin, lungs, and gastrointestinal lining.230 Liver is the target organ of toxicity and carcinogenicity.49,229,231 Primary exposure is for the general human population, through the air and the food chain.47,48 Exposure to PCP has been reported in several studies including various age groups.232−236 High levels of PCP can lead to extremely high body temperature,237 which can cause a different kind of tissue injury and even death. PCP could have an immunotoxic function. High levels of PCP have, for a long time, been associated with malignant lymphoma and leukemia.238 Peripheral neuropathy and nerve damage are also described in people exposed to PCP.239 PCP induces oxidative stress and apoptosis, cell cycle arrest because of DNA damage (p53), mitogenic response (cyclin D1), and apoptosis (caspase 3).240 3.5.1. Metabolic Activation of Pentachlorophenol to Quinones and Conseqences. One of the reasons why PCP induces liver tumor is its metabolism to chlorinated quinones in the liver59,241 by two proposed different pathways. The first is P450-mediated dechlorination, which gives tetrachlorohydroquinone (Cl4HQ) and tetrachlorocatechol (Cl4CAT),63 the latter being less prone to auto-oxidation than Cl4HQ.242 This auto-oxidation leads to subsequent oxidation of the hydroquinone to semiquinones, which could also proceed via an enzymatic pathway. Furthermore, these two metabolites are oxidized to semiquinones (i.e., tetrachloro-1,4-benzosemiquinone (Cl4-1,4-SQ) and tetrachloro-1,2-benzosemiquinone (Cl41,2-SQ)), which are then oxidized to the respective quinones (i.e., tetrachloro-1,4-benzoquinone (Cl4-1,4-BQ) and tetrachloro-1,2-benzoquinone (Cl4-1,2-BQ)).42,58 The second path-

Figure 9. Chemical structures of OTA-DNA adducts produced photochemically from the reaction of OTA or OTHQ with dG. 39, OTA-dG; 40, C-OTA-3′-dGMP; 41, O-OTA-3′-dGMP.192

The final adduct was formed from the photoreaction of OTHQ in the presence of excess dG.228 There is a tendency of quinone electrophiles to react with dG to form benzetheno type adducts. The proposed structure for OTHQ-dG is confirmed by its mass observed by LC−MS.43,44,220 In conclusion, it is

Figure 10. Proposed pathways for the PCP bioactivation to quinones and semiquinones. 42, PCP; 43, Cl4−HQ; 44, Cl4−CAT; 45, Cl4-1,4-SG; 46, Cl4-1,2-SG; 47, Cl4-1,4-BQ; 48, Cl4-1,2-BQ.242 12



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In humans, it is metabolized primarly via P450 enzymes.246 The major circulating metabolite of lumiracoxib in human is 4hydroxylumiracoxib.64,65 It has recently been shown that 4hydroxylumiracoxib is bioactivated to a proposed quinone imine. N-acetylcysteine (NAC) trapped this quinine-imine metabolite by forming two NAC adducts (Figure 12).65 Furthermore, P450 and peroxidases bioactivated 4-hydroxylumiracoxib to a quinine-imine and several GSH-conjugated quinine-imine intermediates.64 In summary, bioactivation of lumiracoxib to quinine-imines may result in GSH-depletion because it could interact up to four GSH molecules, bind covalently to proteins, and trigger oxidative stress. Altogether, these risk factors lead to hepatotoxicity.64 Structurally, lumiracoxib is related to diclofenac (54, Figure 13), the only differences being a methyl substituent on the 5-

way is direct cytochrome P450/peroxidase-mediated oxidation of PCP to (Cl4-1, 4-BQ) and includes loss of the chlorine anion (Figure 10).218,243,244 Since quinones and semiquinones are electrophiles, they form adducts with nucleophilic parts of macromolecules.42,58−61,245 Experiments on rats and mice show that Cl4-1, 4-BQ reacts with the sulfhydryl groups of cysteinyl residues in blood42 and with liver proteins245 to give mono-S- and multi-S-substituted adducts. Furthermore, Cl4-1,4,-SQ hydroxyl radicals, produced via metal-independent Fenton reactions,62 induce DNA damage. Furthermore, lipid peroxidation is an important factor in PCP-induced hepatic toxicity in mice because, under conditions of oxidative stress, lipid hydroperoxides can mediate the bioactivation of PCP to quinones or semiquinones, but much more than those associated with microsomal P450/ NADPH. 242 This is why lipid hydroperoxides may be predominantly important for the ultimate carcinogenicity of PCP.

4. DRUGS THAT FORM QUINONE IMINE REACTIVE METABOLITES 4.1. Lumiracoxib. Lumiracoxib is an arylacetic acid derivative used in the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. It is a carboxylic acid with weak acidic properties, which may be the reason for its pharmacokinetic and pharmacodynamic profile.246

Figure 13. Structure of 54, Diclofenac.

position and replacement of the dichloroaniline moiety of diclofenac by a fluorochloroaniline ring system (49, Figure 11).65 4.2. Diclofenac. Diclofenac is a nonsteroidal anti-inflammatory drug that has the same indications as selective COX-2 inhibitors. The reason for rare but potentially severe liver injury is metabolic activation of the drug.66 Diclofenac undergoes P450 2C9 and P450 3A4-catalyzed oxidation in humans, resulting in the formation of 4-hydroxydiclofenac and 5-hydroxydiclofenac, the products of which are also oxidized to reactive quinone imine intermediates. These react further with glutathione or microsomal proteins.67,68 Furthermore, glutathione adducts

Figure 11. Structure of 49, 2-[(2-fluoro-6-chlorophenyl) amino]-5methyl-benzene acetic acid.

Figure 12. Bioactivation of lumiracoxib in humans. 50, Lumiracoxib; 51, 4-Hydroxylumiracoxib; 52, Quinone imine; 53, GSH.64 13



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Figure 14. Scheme for the P450-mediated bioactivation of diclofenac to quinone imines. 55, Diclofenac; 56, 4-Hydroxydiclofenac; 57, 5Hydroxydiclofenac; 58, Diclofenac-2,5-quinone imine; 59, 5-OH-4-GS-diclofenac; 60, 5-OH-4-NAC-diclofenac; 61, Diclofenac-1,4- quinone imine; 62, 4-OH-3-GS-diclofenac; 63, 4-OH-3-NAC-diclofenac.66

undergo sequential hydrolysis by γ-glutamyltranspeptidase and dipeptidases to give cysteinyl-glycine and cysteine derivatives.66 Ultimately, N-acetylation leads to the formation of the mercapturic acids, which are detected in the urine.66 We can conclude from this information that oxidative bioactivation of diclofenac in humans proceeds via bezoquinone imine intermediates (55, Figure 14). 4.3. Bioactivaton of Drugs Used for Parkinson’s Disease. Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor that is used in treating patients with Parkinson’s disease. It has been associated with several cases of liver injuries and, also, of fulminant hepatic failure.69,247 Catechol glucuronidation in position 3 is the major step for tolcapone metabolism in humans.247 The product of reduction of the 5-nitro group, namely the amine, can be excreted directly or after glucuronidation, sulphation, or N-acetylation. Both the aniline and the N-acetylaniline derivatives are minor metabolites in human excreta.247 The next pathway is the oxidative hydroxylation of the methyl group to a primary alcohol and following oxidation to the carboxylic acid.247 The last step is 3-O methylation via COMT to the long-lived metabolite 3-OMT (73, Figure 15).247 The hepatotoxicity of tolcapone may be explained by the formation of reactive species (o-quinone or quinone imine species) through oxidation of the aniline and N-

acetylaniline derivatives, which can form protein adducts with hepatic proteins.69 Bioactivation of tolcapone is thus the reason for its hepatotoxicity. Individuals who are carriers of mutations for the UDP-glucuronosyltransferase (UGT) 1A9 gene may exhibit more RM formation through the redox bioactivation pathway.248 Tolcapone is also a potent uncoupler of oxidative phosphorylation and an inhibitor of mitochondrial respiration.249 4.4. Paracetamol. Paracetamol (PAR) is widely used as an over the counter remedy to treat fever and pain. Some studies have reported PAR toxicity in reproduction and development and proposed that they are linked to low sperm parameters and testicular germ cell cancer in humans.250,251 On the other hand, PAR has been shown to be an endocrine disruptor.252−254 It is a potentially genotoxic drug according to International Agency for Research on Cancer (IARC).255 Bioactivation of PAR by P450 enzymes (P450 1A1, 1A2, and 3A4) occurs at less than 5% of the oral dose (74, Figure 16).256,257 Paracetamol is metabolized, to the fullest extent, to reactive N-acetyl-p-benzoquinone imine (NAPQI) by P450 2E1, leading to the formation of reactive Nacetyl-p-benzoquinone imine (NAPQI) metabolite, which can react with DNA, nucleophilic groups of proteins, and glutathione (GSH).70,258−260 Furthermore, increased levels of ROS lead to decreased levels of GSH or redox cycling of an 14



Review

metabolized by P450 and myeloperoxidase (MPO) to reactive quinine-imine species that can react covalently to cell proteins or GSH (80, Figure 17).72,73 Introduction of a fluorine group instead of hydroxyl into the antimalarial amodiaquine could prevent the process of oxidative bioactivation; this is evident for deOH-4-FAQ, which has antimalarial activity similar to that of amodiaquine but does not form a reactive metabolite in vivo.264 Furthermore, interchanging the 3- and 4-substituents in amodiaquine would lead to analogues 81, 82, and 83 (Figure 17), which are incapable of forming the quinone imine. These strategies have been used to modify 4-aminoquinoline amodiaquine by replacing the 4-hydroxy group with a hydrogen, fluorine, or chlorine atom to give candidates with good safety profiles for further studies.265 4.6. Nomifensine. Nomifensine, a tetrahydroisoquinoline derivative, is an antidepressant drug that was been withdrawn from market because of adverse side effects like hemolytic anemia and liver and kidney toxicity.74 In one study, antibodies or autoantibodies directed against the drug or metabolite−red blood cell conjugates were detected in patients who developed immune hemolytic anemia while receiving the drug. All the antibodies belonged to the IgG or IgM class or to both and were capable of activating complement.74 Bioactivation of aniline involves N-hydroxylation of the primary amine nitrogen, leading to formation of the N-hydroxylamine intermediate, which is converted nonenzymatically to the nitroso derivative, which reacts with GSH to form an unstable mercaptal derivative that rearranges to a GSH-based sulfinamide conjugate.75 The sulfonyloxy group in the N−O sulfate conjugates of Nhydroxylamines is a very good leaving group that can be eliminated to generate a highly reactive nitrenium ion, which may lead to toxicity.75 The next step is N-glucuronidation, by which metabolites (N-glucuronides) can be hydrolyzed to the N-hydroxylamines, which cause bladder and colon cancer. The second step involves the arene oxidation pathways, resulting in the formation quinone imine species that can be trapped by GSH (86, Figure 18).75 From these data, it is again evident that the aniline and the arene groups are potential toxicophores, being capable of generating reactive quinone and quinone imine metabolites.75 4.7. Tyrosine Kinase Inhibitors. 4.7.1. Lapatinib. Lapatinib is the first oral dual tyrosine kinase inhibitor of ErbB-1 and ErbB-2, approved by the US Food and Drug Administration in 2007 as a promising alternative and orally available drug for advanced metastatic breast cancer. However, a black-boxed

Figure 15. Metabolism of tolcapone in humans. 64, Tolcapone; 65, 3O-β, D-glucuronide; 66, Amine derivative; 67, Quinone-imine; 68, Amine glucuronide; 69, Amine sulfate; 70, Quinone-imine; 71, Primary alcohol metabolite; 72, Carboxylic acid; 73, 3-O-methyltolcapone.247

electrophilic intermediate (NAPQI).261 QIs react, by a 1,4Michael addition, with nucleophiles such as reduced GSH, protein thiols, and nucleic bases.70 4.5. Amodiaquine. Amodiaquine (AQ) is a 4-aminoquinoline derivative used for treating malaria and rheumatoid diseases. Because of serious adverse side effects (agranulocytosis and liver damage), it is no longer used in frontline therapy for malaria. The detection of IgG antibodies to AQ in patients exposed to amodiaquine has shown that it is antigenic.71 The basis of the immune-mediated toxicity is a chemically reactive metabolite of AQ. Amodiaquine and its N-de-ethylated metabolite263 are

Figure 16. Paracetamol bioactivation to reactive species (quinone imine). 74, Paracetamol; 75, Paracetamol-o-glucironide; 76, Paracetamol sulfate; 77, N-acetyl-p-quinone imine (NAPQI); 78, Paracetamol 3-glutathione.262 15



Review

Figure 17. RM formation pathway for the basic drug (amodiaquine) and analogues (81, 82, and 83) incapable of forming RMs. 79, Amodiaquine; 80, Amodiaquine quinon imine.264

Figure 18. Bioactivation of the nomifensine; 84, Nomifensine; 85, Nomifensine nitrosoamine; 86, Quinone imine.

Figure 19. Formation of reactive metabolites by P450 3A4. 87, Lapatinib; 88, O-dealkylated lapatinib; 89, Quinone imine; 90, LAPA-G1; 91, LAPAG2.76

16



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Figure 20. Cytochrome P450 mediated bioactivation of the desatinib, gefitinib and erlotinib. 92, Dasatinib; 93, Imine methide; 94, Quinone imine; 95, Gefitinib; 96, Quinone imine; 97, Erlotinib; 98, Quinone imine.

4.7.2. Dasatinib, Gefitinib, and Erlotinib. All these three drugs have been approved for the treatment of various type of cancer and all are P450 3A4 mechanism-based inactivators acting through a reactive intermediate, quinine imine.78−80 Hepatotoxicity is as a possible side effect of treatment. Gefitinib and erlotinib are metabolized, through oxidative defluorination, to a hydroxyaniline metabolite that may undergo P450mediated two-electron oxidation to form a reactive quinineimine intermediate (96 and 98, Figure 20).79,80 Dasatinib inactivation proceeds through hydroxylation at the paraposition of the 2-chloro-6-methylphenyl ring, by further oxidation giving the reactive quinine imine intermediates. A minor pathway is formation of a reactive imine methide.78 Furthermore, gefitinib exhibits BSEP inhibition with strong potency.77 4.8. Nefazodone. After nefazodone was approved as an antidepressant, it has been linked, since 1994, with idiosyncratic adverse reactions including hepatobiliary dysfunction and cholestasis. We can find reports that nefazodonehepatotoxicity has even been associated with liver transplantation or death at therapeutic doses in the range of 200−400 mg/day. Signs of liver failure appear 1 to 8 months after starting treatment with this drug. Nefazodone has been withdrawn in many countries in the European Union and Canada. The exact mechanism of nefazodone toxicity is not known but there is evidence for

warning for lapatinib was released after postmarketing surveillance and clinical trial reports of elevated liver enzymes and hepatotoxicity that developed several days to months after commencement of therapy. The exact mechanism by which lapatinib causes hepatotoxicity is unknown, but it has been shown to form reactive metabolites by P450-mediated oxidation.76 The drug is bioactivated by P450 3A4/5 to form O- and N-dealkylated metabolites that have the potential to be further oxidized in reactive quinine imine. Furthermore, these metabolites are trapped by GSH (89, Figure 19). Quinone imines are electrophilic and have a tendency to react with nucleophilic groups of cellular proteins, leading to toxicity.76 These electrophilic species may cause hepatotoxicity in two ways: the first is direct covalent modification of hepatic proteins, causing cell dysfunction, and the second is to form haptens, which, in turn, trigger an immune response. It has been shown that the drug undergoes biotransformation to form quinine imine species that inhibit P450 3A4 irreversibly through mechanism-based inactivation, most probably through oxidation of its O-dealkylated metabolite.76 Lapatinib is also shown to be hepatotoxic through the inhibition of the bile salt export pump (BSEP).77 The HLA-DQA1*02:01 allele carriers may also have an increased genetic risk associated with hepatotoxicity.266 17



Review

formation of reactive metabolite.81,82 The drug undergoes a P450 3A4 catalyzed aromatic hydroxylation that occurs para to the piperazinyl nitrogen. It leads to p-hydroxynefazodone, a major circulating metabolite, para-hydroxyaniline analog and well-established toxicophore. Furthermore, metabolites are oxidatively bioactivated in human liver microsomes to electrophilic quinonoid intermediates that may play a role in nefazodone-induced hepatic necrosis (100 and 101, Figure 21)81,82 Nefazodone is a weak inhibitor of cytochrome P450

4.9. Carbamazepine. Since 1960, the aromatic anticonvulsant carbamazepine has been used for treating epileptic patients. Adverse hypersensitivity reactions have been described for carbamazepine, especially skin rash (including toxic epidermal necrolysis (Lyell’s syndrome)). Among the undesirable effects that may be associated with hypersensitivity reactions are also fever, hepatitis, bone marrow toxicity, pneumonitis, and pseudolymphoma. These symptoms has been validated to shown in 1 of 5000 patients.86 Although the exact mechanism of carbamazepine-mediated hypersensitivity is not known, the structures of metabolites show that multiple epoxides and cyclic peroxide are involved in the in vivo metabolism and formation of RM by man.267 Thirty-two metabolites of carbamazepine have been detected in epileptic patient urine.268 An in vitro study has shown bioactivation of carbamazepine with the formation of cytotoxic, protein-reactive, and stable metabolites in human liver microsomes (HLM). The major bioactivation pathways are Nglucuronidation with formation of the active carbamazepine10,11-epoxide metabolite, and hydroxylation on the aromatic rings that lead to 2- and 3-hydroxycarbamazepine derivatives.269,270 Several of these metabolites of the drug have been proposed as reactive species. They could lead to cell death by covalent binding to cell macromolecules or by acting as haptens, causing idiosyncratic toxicity. Reactive species are formed through 10,11-epoxidation and 2,3-arene oxidation, including epoxides (carbamazepine-2,3-epoxide and carbamazepine10,11-epoxide),87,88 a quinone imine metabolite derived from metabolism of major metabolite 2-hydroxycarbamazepine,89 and an ortho-quinone metabolite that is formed from catechol 2,3-dihydroxy carbamazepine (Figure 23).90 In vivo studies that include hapten formation are compatible with the known fact that sera from carbamazepine-hypersensitive patients often contain antibodies that recognize P450 3A proteins.271,272 4.10. Atorvastatin. Atorvastatin is the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and so well-established drug for treating hypercholesterolemia. Although such treatment reduces cardiovascular events and mortality rates, it also shows adverse effects, such as myopathy, that can progress to rhabdomyolysis and asymptomatic increase in hepatic transaminases.273 A major bioactivation pathway is P450 3A4-mediated monohydroxylation on the acetanilide structural alert with formation of the ortho- and parahydroxyacetanilide metabolites, which are oxidized to reactive quinone imine species.92 These reactive metabolites have been shown to bind covalently to HLM and are responsible for idiosyncratic drug toxicity.91 This type of toxicity is often very serious and appears as severe hepatotoxicity, agranulocytosis, neutropenia, Stevens-Johnsons syndrome, but has also been found late in drug development or in the postmarketing phase. 4.11. Aripiprazole. Since its introduction in 2003, aripiprazole has been used as an atypical antipsychotic. As with nefazodone, P450-mediated metabolism on the 2,3dichlorophenyl ring in aripiprazole resulted in the formation of the corresponding circulating para-hydroxyaniline metabolite, which may have a causal role for the formation of reactive quinone imines, similar to that of nephazodone (116 and 117, Figure 24). However, this circulating metabolite does not form GSH conjugates, suggesting that the bioactivation pathway does not end in a manner analogous to that of nefazodone.82 Despite liability to bioactivation and chronic use of aripiprazole, there have been no reports of idiosyncratic hepatotoxicity associated with this drug. The explanation lies in the dose levels and pharmacokinetics of the drug. The daily dose of aripiprazole is

Figure 21. Bioactivation pathways for the antidepressant nefazodone. 99, Nefazodone; 100, Quinone imine; 101, Benzoquinone; 102, GSH.82

2D6, does not inhibit P450 1A2 but inhibits P450 3A4.83 Inactivation of mentioned isoenzymes occurs by covalent adduct formation with reactive species (quinone imine or pbenzoquinone intermediates) on the enzyme.81 Nefazodone’s nonlinear pharmacokinetics and clinical drug−drug interactions with P450 3A4 substrates also indicate in vivo mechanism-based inactivation of the isoenzyme.81,83 The drug also exhibits mitochondrial toxicity and is a potent inhibitor of bile transport, most likely through these reactive metabolites. .84,85 The hepatotoxicity of nefazodone is based on the particular chemical substructure so that chemicals with the same mechanism of action, but different chemical structure, are not hepatotoxic (e.g., buspirone) (103, Figure 22).84

Figure 22. Structure of 103, Buspirone. 18



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Figure 23. Bioactivation of the anticonvulsant drug carbamazepine to reactive species. 104, Carbamazepine; 105, Carbamazepine-10,11-epoxide; 106 and 107, 1:1 ratio; 108, Carbamazepine-2,3-epoxide; 109, 2-Hydroxycarbamazepine; 110, 3-Hydroxycarbamazepine; 111, 2-Hydroxyiminostilbene; 112, Quinone imine; 113, 2,3-dihydroxycarbamazepine; 114, o-Quinone.90

Figure 24. Reactive metabolites of antipsychotic drug aripiprazole in HLM. 115, Aripiprazole; 116, Quinone imine; 117, Quinone imine.

frontline therapy since it may cause rare hepatotoxicity274 that has been associated with RM formation (120 and 121, Figure 25).93,94 As in nefazodone, the 3-chlorophenylpiperazine ring in trazodone is P450 3A4-hydroxylated to give corresponding para-hydroxytrazodone metabolite. It has been detected in human urine as a major metabolite of the drug.95 The parahydroxy-m-chlorophenylpiperazine portion, through two electron oxidation, produced a reactive quinone imine species, which was trapped with GSH in HLM incubations of trazodone.94 Furthermore, N-dealkylation of trazodone to form m-chlorophenylpiperazine was mediated by P450 3A4,

10−30-fold lower (5−20 mg once per day) than that for nefazodone (200−400 mg once per day), which may reduce the total body burden to reactive metabolite exposure upon aripiprazole administration. There are several examples of structurally similar drugs with different safety profiles, and drugs dosed at greater levels are associated with idiosyncratic adverse drug reactions (ADRs). 4.12. Trazodone. Trazodone has been in use as a secondgeneration nontricyclic antidepressant. It is coprescribed with other antidepressants because of its less anticholinergic and sedative side effects. In cases of CNS disorders, it is not used as a 19



Review

Figure 25. Bioactivation of the trazodone. 118, Trazodone; 119, 4-Hydroxytrazodone; 120, Quinone imine; 121, Quinone imine; 122, Epoxide; 123, Dihydrodiol.

Figure 26. Bioactivation/detoxication pathways of paroxetine in human hepatic tissue. 124, Paroxetine; 125, Paroxetine-catechol; 126, o-Quinone; 127, Human metabolites of paroxetine.

which, like trazodone, was also bioactivated.94 The second step of trazodone bioactivation is the formation of epoxide, which has

been confirmed by detection of a dihydrodiol metabolite of trazodone in human urine.95 Trazodone can thus form stable 20



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Figure 27. Oxidation of raloxifene to reactive species in human hepatic tissue. 128, Raloxifene; 129, 7-Hydroxyraloxifene; 130, Raloxifene-6,7-oquinone; 131, Raloxifene diquinone methide. (Modif.101).

5.2. Tadalafil. The next example of drug that forms the benzoquinone metabolites and has also the 1,3-benzidioxole alert is tadalafil, a potent reversible phosphodiesterase-5 (PDE5) inhibitor used for the treatment of erectile dysfunction. Tadalafil, like paroxetine, undergoes P450 3A4-catalyzed bioactivation, generating an electrophilic catechol/ortho-quinone species and causing inactivation of the enzyme. However, therapeutic concentrations of tadalafil (10−20 mg) do not produce idiosyncratic toxicity or DDIs in erectile dysfunction treatment.98 5.3. Carvedilol. Carvedilol, a new antihypertensive drug with combined α- and β-adrenergic receptor antagonism, is administered as a racemic mixture of the (R)-(+) and (S)-(−) enantiomers. Quinone imine metabolites are reactive species of carvedilol that are formed through N-glucuronidation and P450 2D6-mediated oxidative biotransformation pathways. The formation of reactive metabolites is expected due to presence of an aniline and a dialkoxyaromatic structural alerts in the drug.99,275 Over 50 metabolites have been confirmed in the studies of carvedilol metabolism, including among themcatechol/ortho-quinone species and GSH conjugates.99 Carvedilol is thus biotransformed also by aromatic hydroxylation on the carbazole ring to hydroxyaniline type metabolites.275 In the treatment of hypertension, it is used from 6.25 mg to the maximum recommended daily dose of 100 mg without side effects, despite the fact that it forms so many reactive metabolites. 5.4. Raloxifene. Raloxifene is a selective ER modulator that is prescribed in the treatment of osteoporosis in postmenopausal women and for the chemoprevention of breast cancer. In vitro studies have shown that the drug undergoes P450 3A4-catalyzed bioactivation, forming reactive metabolites that can be trapped by GSH. These reactive species have the potential to alkylate cell macromolecules, triggering toxicity. The major alkylating species was the relatively stable raloxifene 6,7-o-quinone (130, Figure 27).7,100,101 At the same time, the reactive species are

dihydrodiol or a GSH-conjugate derived from epoxide ring opening.81 It has been shown that trazodone collapses the mitochondrial membrane potential and imposes oxidative stress leading to cell death to which could also contribute the abovedescribed reactive metabolites.85

5. PRESENCE OF METHYLENE DIOXYPHENYL FUNCTIONAL GROUP IN CHEMICAL: STRUCTURAL ALERT OR NOT FOR FORMING QUINONES? 5.1. Paroxetine. Paroxetine is a selective inhibitor of serotonin reuptake and antidepressant that contains the 1,3benzidioxole (methylenedioxyphenyl) structural alert and has been used for treating various CNS disorders. Drugs that are metabolized by cytochrome P450 2D6 enter into drug−drug interactions (DDIs) when coadministrated with paroxetine because of its potent inhibition of human liver microsomal P450 2D6 activity via, apparently, a competitive mechanism. Furthermore, paroxetine is metabolized through P450 2D6 mediated 1,3-benzidioxole ring cleavage to a catechol intermediate. This process is also a mechanism-based inactivation of the P450 isoenzyme.96 In vitro studies with [3H] paroxetine have shown covalent binding to human liver microsomes and to S-9 proteins, and characterization of glucuronide and sulfate metabolites of reactive quinone species (126, Figure 26).97 One of the most important detoxification pathways is nucleophilic substitution of reactive intermediates with GSH or S-adenosyl methionine. As in Figure 26, the paroxetine-catechol can be O-methylated by COMT or oxidized to the reactive o-quinone metabolite, which is scavenged by GSH. Both pathways lead to a significant reduction in covalent binding to the cell macromolecules. Furthermore, in vitro covalent binding cannot necessarily be assumed to be predictive of toxicity. The latter is also dependent on the total the dose of the drug, the amount of chemically reactive intermediate, and knowledge of the contribution of metabolism that would detoxify the reactive metabolite.97 21



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Figure 28. Major metabolic pathways of the estradiol. 132, Estradiol; 133, Estrone; 134, 2-Hydroxyestradiol; 135, Estradiol-2,3-semiquinone; 136, Estradiol-2,3-quinone; 137, 4-Hydroxyestradiol; 138, Estradiol-3,4-semiquinone; 139, Estradiol-3,4-quinone. 17α-Hydroxysteroid dehydrogenase, 17α-HSD.279

Figure 29. Metabolic pathways of the bisphenol A. 140, Bisphenol A; 141, Bisphenol A catechol; 142, Bisphenol A quinone; 143, Bisphenol A ol; 144, Bisphenol A carboxylic acid; 145, 4-Methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene; 146, Bisphenol A glucuronide; 147, Bisphenol A sulfate.280

suicide inhibitors of P450 3A4.100 However, in vivo studies have shown that the main pathway to detoxification of the phenolic groups is glucuronidation in the gut. This kind of mechanism is primarily responsible for the lack of side effects of the drug administered in the low daily dose.276

5.5. Estradiol. Metabolic activation of estrogens plays an important role in the etiology of breast and ovarian cancer through adducts and oxidized bases that form mutations of genes or via expression of specific genes that normally control cell growth and proliferation.277,278 The International Agency 22



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Figure 30. Metabolic pathways of dopamine. 148, Dopamine; 149, Dopamine o-semiquinone; 150, Dopamine quinone; 151, 3,4dihydroxyphenylacetic acid (DOPAC), which also forms quinones upon oxidation; MAO, Monoamine oxidase; DBH, Dopamine beta-hydroxylase; NE, Norepinephrine; PNMT, Phenylethanolamine N-methyltransferase; EPI, Epinephrine.299

Figure 31. Bioactivation of the doxorubicin. 152, Doxorubicin; 153, Semiquinone; 154, C7−Free radical; 155, C7-Quinone methide; 156, DNA adduct; R, CH2−OH.311

5.6. Bisphenol A. Bisphenol A (BPA) is industrial raw material and thus also an environmental contaminant, widely used as a monomer in polycarbonate plastic and epoxy resins.104,280,281 Humans are exposed to BPA through various products such as packaging for food and water, cans, thermal paper, and dental sealants.282−284 BPA is an endocrine disruptor and may causes DNA damage as the result of its reactive metabolites that can form covalent adducts with nucleophilic macromolecules or produce oxidative stress (140, Figure 29).106 Exposure is also associated with inflammation or oxidative damage in brain, testes, kidney, and sperm, and peroxidation

for Research on Cancer has classified estradiol as a carcinogenfor humans. Bioactivation of estradiol (E2) begins by P450 1A1 and P450 1B1 that give two hydroxylated metabolites 2-hydroxyestradiol (2-OH-E2) and 4-hydroxyestradiol (4-OH-E2), respectively (134 and 137, Figure 28). Furthermore, the catechols 2-OH-E2 and 4-OH-E2, with help of peroxidases, form semiquinones, and these can be further oxidized to quinones. The catechol-O-methyltransferase (COMT) defends organisms against genotoxic metabolites by methylation of catechol estrogens.279 23



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reactions generated by BPA.285−288 Furthermore, it can produce harmful effects in liver of rats and mice, and adverse effects in pregnancy.104,289 The main way for decreasing toxicity is conjugation reactions that result in two main products, glucuronide and sulfate.290−296 The oxidized product of BPA is catechol analogue, which may act via semiquinone or quinone products to produce ROS and oxidative stress (141, Figure 29). BPA o-quinone metabolite could be also generated by polyphenol oxidase and tyrosinase, indicating that BPA is a substrate for many enzymes that allow the oxidation of both endogenous and exogenous compounds in organisms.297,298 5.7. Dopamine. Dopamine (DA), a central nervous system neurotransmitter, present in high concentrations in the hypothalamus is also an intermediate in the synthesis of both norepinephrine and epinephrine. It exhibits inherent toxic potential. Metabolic activation of DA may play a role in pathological processes related with schizophrenia, addiction, and Parkinson’s disease.299 DA can form reactive species via two pathways. One is production of ROS, partially by the enzyme monoamine oxidase (151, Figure 30).300 The second is spontaneous or, in the presence of transition metal ions (iron or manganese), oxidation to the reactive DA quinone.301,302 Additionally, a quinone moiety can be formed enzymatically by tyrosinase, prostaglandin H synthase, and xanthine oxidase (150, Figure 30).303−307 Once the quinone is formed, it has cytotoxic and genotoxic potential in generating ROS, which play an important role in degenerative brain diseases. 5.8. Doxorubicin. Doxorubicin, a clinically active anticancer drug for treating solid and hematological malignancies, is used for inhibition or interference with topoisomerase II. However, the use of doxorubicin is limited by its accumulation in the heart, primarily in mitochondria, and dose-dependent irreversible cardiomyopathy. Since it has a quinone fragment in its structure, it can interact with complex I in the respiratory chain and generate ROS. As a result, reduced ATP production and the activation of oxidative stress in the cell occur. Furthermore, doxorubicin can cause DNA cleavage and form double strand breaks that lead to cell death.308−310 Besides the noted mechanisms of action, bioactivation of doxorubicin may be important for its mode of action, as it produces reactive species that bind covalently, or induce damage, to various macromolecules.311 Doxorubicin contains a quinone-hydroquinone moiety, which is mainly reduced by P450 reductase,312 via one-electron reduction, to form a semiquinone radical (153, Figure 31). This unstable semiquinone radical, in the presence of molecular oxygen, undergoes an oxidation−reduction cycle to form superoxide radical and the hydroxyl radical (via further Fenton reaction, Figure 31), a highly reactive oxidant.312−316 However, one-electron reduction is followed by generation of highly reactive covalent binding species 154 and 155 that can alkylate cell macromolecules.317−320 A few studies have also confirmed DNA adduct formation.321−325 We can conclude that both the bioactivation and the quinone structure of doxorubicin cause the formation of ROS and the interaction of doxorubicin intermediates with macromolecules in the cell-mechanisms of its pharmacological as well as toxicological action.

were not toxic in therapeutical doses, although they produce reactive species. The target organ toxicity is often driven by the tissue-specific expression of the P450 enzymes and peroxidases responsible for the bioactivation of the drug or chemical (example: bone marrow is the target organ of benzene toxicity because of the high myeloperoxidase activity responsible for the oxidation). Quinones and quinone imines are considered chemically reactive species because they are electrophilic compounds, but they can also undergo redox cycling and cause oxidoreductive stress in cells. There are many other factors that impact on the overall toxicity of the discussed chemicals and drugs. First, the dose level and pharmacokinetics of the drug or chemical can influence its toxicity. For example lower daily dose levels of the drug may reduce the total body burden to reactive metabolite exposure upon drug administration. This is important in the case of aripiprazole which daily dose is 10− 30-fold lower than the daily dose of nefazodone. Second, the compounds generally have several metabolic pathways and, depending on what prevails, produce more or less highly reactive metabolites including quinones and quinone imines. The major pathway of detoxication of the reactive metabolites in humans is glucuronidation or reaction with glutathione, which usually leads in a less toxic metabolites. This explains why raloxifene is a safe drug despite the fact that it also undergoes P450 3A4mediated oxidation forming stable alkylating reactive species (raloxifene 6,7-o-quinone). Third, the overall toxicity of the compound on the specific cell targets is influenced by the reactivity of all its metabolites. Some of the reactive metabolites, such as benzene, gefitinib, dasatinib, lapatinib, nefazodone, paroxetine, and raloxifene metabolites, react with enzyme active site causing immediate enzyme inactivation. The other reactive metabolites migrate from the site of formation and bind to proteins, DNA or produce oxidative DNA, lipid, and protein damage. To understand these processes, the theory of “hard” and “soft“electrophiles should be taken into account. GSH also plays an important role in modulating the toxicity of quinones and quinone imines as noted previously. Reactive intermediates react with GSH in the presence of glutathione-Stransferases to form GSH conjugates, which are then excreted by kidneys. These reactions protect cells against the harmful effects of reactive intermediates. GSH depletion consistently enhanced the toxicity of these compounds. The precise mechanism of enhancement has not been investigated. Whether GSH conjugates plays a role in the toxicity of chemicals and drugs, form quinone and quinone imine species, is a question that needs further investigation. It has been shown that quinones and quinone imines play roles in mediating the toxic effects of amino or hydroxylated aromatic compounds. These electrophilic and redox active species can cause damage within cells by various pathways (Figure 32). It is well-known that the molecular structure influences the location and type of cellular nucleophiles targeted. Oxidative enzymes, metal ions, and in some cases molecular oxygen can catalyze the formation of quinoids that interact with cell nucleophiles (GSH, proteins and DNA) to promote inflammatory, anti-inflammatory, and anticancer actions and so induce toxicity. In addition, the formation of ROS contributes to the cytotoxic properties of the parent compounds. Redox cycling generates reactive oxygen species that cause lipid peroxidation, depletion of reducing equivalents, oxidation of DNA, and DNA strand breaks. Quinones and quinone imines could affect various cell signaling pathways that protect against inflammatory responses and cell damage. Further, ROS can

6. CONCLUSION AND FUTURE DIRECTIONS All the presented chemicals and drugs exhibit their toxicity as a result of bio-oxidation. Most of them produce liver toxicity in humans; some were carcinogens, while some presented drugs 24



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worked in the field of toxicology; in particular, she is engaged in the research of formation and toxicity of reactive metabolites, while the second research area is evaluation of potential endocrine disrupting chemicals and their mixtures.

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ACKNOWLEDGMENTS The authors thank Dr. Roger Pain and Dr. Janez Mavri for their critical reading of the manuscript and linguistic corrections.

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(1) Attia, S. M. (2010) Deleterious Effects of Reactive Metabolites. Oxid. Med. Cell. Longevity 3, 238−253. (2) Park, B. K., Kitteringham, N. R., Maggs, J. L., Pirmohamed, M., and Williams, D. P. (2005) The role of metabolic activation in drug-induced hepatotoxicity. Annu. Rev. Pharmacol. Toxicol. 45, 177−202. (3) Park, B. K., Laverty, H., Srivastava, A., Antoine, D. J., Naisbitt, D., and Williams, D. P. (2011) Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity. Chem.-Biol. Interact. 192, 30−36. (4) Uetrecht, J. (2007) Idiosyncratic drug reactions: current understanding. Annu. Rev. Pharmacol. Toxicol. 47, 513−539. (5) Vanhoutte, P. M. (2009) How we learned to say no. Arterioscler., Thromb., Vasc. Biol. 29, 1156−1160. (6) Bedard, K., and Krause, K.-H. (2007) The NOX family of ROSgenerating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245−313. (7) Chen, Q., Ngui, J. S., Doss, G. A., Wang, R. W., Cai, X., DiNinno, F. P., Blizzard, T. A., Hammond, M. L., Stearns, R. A., Evans, D. C., Baillie, T. A., and Tang, W. (2002) Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation. Chem. Res. Toxicol. 15, 907−914. (8) Kalgutkar, A. S., Dalvie, D. K., Aubrecht, J., Smith, E. B., Coffing, S. L., Cheung, J. R., Vage, C., Lame, M. E., Chiang, P., McClure, K. F., Maurer, T. S., Coelho, R. V., Soliman, V. F., and Schildknegt, K. (2007) Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl)pyrazine, a novel 5-hydroxytryptamine2c receptor agonist for the treatment of obesity: role of metabolic activation. Drug Metab. Dispos. 35, 848−858. (9) Ikehata, K., Duzhak, T. G., Galeva, N. A., Ji, T., Koen, Y. M., and Hanzlik, R. P. (2008) Protein targets of reactive metabolites of thiobenzamide in rat liver in vivo. Chem. Res. Toxicol. 21, 1432−1442. (10) Amacher, D. E. (2006) Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective. Curr. Drug Metab. 7, 219−229. (11) Wells, P. G., McCallum, G. P., Chen, C. S., Henderson, J. T., Lee, C. J. J., Perstin, J., Preston, T. J., Wiley, M. J., and Wong, A. W. (2009) Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer. Toxicol. Sci. 108, 4−18. (12) Wells, P. G., Lee, C. J. J., McCallum, G. P., Perstin, J., and Harper, P. A. (2010) Receptor and reactive intermediate-mediated mechanisms of teratogenesis. Handb. Exp. Pharmacol. 196, 131−162. (13) Skipper, P. L., Kim, M. Y., Sun, H.-L. P., Wogan, G. N., and Tannenbaum, S. R. (2010) Monocyclic aromatic amines as potential human carcinogens: old is new again. Carcinogenesis 31, 50−58. (14) Monks, T. J., and Jones, D. C. (2002) The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinonethioethers. Curr. Drug Metab. 3, 425−438. (15) McNaught, A. D., and Wilkinson, A. (1997) in Compendium of Chemical Terminology, Wiley-Blackwell. (16) Bolton, J. L., Trush, M. A., Penning, T. M., Dryhurst, G., and Monks, T. J. (2000) Role of quinones in toxicology†. Chem. Res. Toxicol. 13, 135−160. (17) Kumagai, Y., Shinkai, Y., Miura, T., and Cho, A. K. (2012) The chemical biology of naphthoquinones and its environmental implications. Annu. Rev. Pharmacol. Toxicol. 52, 221−247. (18) Monks, T. J., Hanzlik, R. P., Cohen, G. M., Ross, D., and Graham, D. G. (1992) Quinone chemistry and toxicity. Toxicol. Appl. Pharmacol. 112, 2−16.

Figure 32. Mechanism of action for quinones and quinone imines.

activate signaling pathways, which include protein kinase C and RAS. DNA binding occurs, such as formation of 8-oxodeoxyguanosine, which has been associated with aging and carcinogenesis. For example: OTA acts as a classical genotoxic carcinogen by bioactivation and covalent DNA adduction. In addition, alkylation and relationships to cytotoxicity are dependent on the chemical structure and the cellular environment in which they are formed. Future work should investigate carcinogenic and cytotoxic metabolites such as quinones and quinone imines of aromatic amines and hydroxylated aromatics to show their molecular targets as well as mechanism(s) of action, but in the meantime in vitro safety prediction will remain a critical topic for further investigation and debate.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: marija.sollner@ffa.uni-lj.si. Phone: +386-1-476-9572. Fax: +386-1-425-8031. ORCID

Marija Sollner Dolenc: 0000-0002-0560-3762 Funding

I.K. would like to acknowledge AdFutura foundation for awarded scholarship. This work was financed by program group “Medicinal Chemistry: Drug Design, Synthesis and Evaluation of the Drugs” (program code P1−0208). Notes

The authors declare no competing financial interest. Biographies Ivana Klopčič is a researcher scientist in Department of Dissolution Studies, Slovenian Development Center, Lek Pharmaceuticals, d.d. a Sandoz Company, where she focuses on validation of analytical procedures for dissolution test of new pharmaceutical drugs. She obtained M.Sc. degree in the study program Pharmacy at the Faculty of Pharmacy, University of Novi Sad, Serbia and Ph.D. degree in the study program Toxicology at the Faculty of Pharmacy, University of Ljubljana, Slovenia. She has supervised one B.Sc. student and is author of seven publications in peer-reviewed journals. Her Ph.D. thesis focused on in silico and in vitro evaluation of potential endocrine disrupting chemicals and their mixtures. Marija Sollner Dolenc is Full Professor at the Faculty of Pharmacy, University of Ljubljana. She obtained her Ph.D. in the field of Medicinal Chemistry at the same faculty. Her work was first focused on design and synthesis of biologically active compounds (immunomodulators, antibacterial, and anticancer agents). In the past few years, she has 25



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(19) Boelsterli, U. A. (2003) in Mechanic Toxicology. The molecular basis of how chemicals disrupt biological target, CRC Press. (20) O’Brien, P. J. (1991) Molecular mechanisms of quinone cytotoxicity. Chem.-Biol. Interact. 80, 1−41. (21) Devasagayam, T. P. A., Tilak, J. C., Boloor, K. K., Sane, K. S., Ghaskadbi, S. S., and Lele, R. D. (2004) Free radicals and antioxidants in human health: current status and future prospects. J. Assoc. Physicians. India 52, 794−804. (22) Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T. D., Mazur, M., and Telser, J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44−84. (23) Fang, Y.-Z., Yang, S., and Wu, G. (2002) Free radicals, antioxidants, and nutrition. Nutrition 18, 872−879. (24) Marnett, L. J. (1999) Lipid peroxidation-DNA damage by malondialdehyde. Mutat. Res., Fundam. Mol. Mech. Mutagen. 424, 83− 95. (25) Wallace, L. (1996) Environmental exposure to benzene: an update. Environ. Health Perspect. 104, 1129−1136. (26) Aksoy, M., Dinçol, K., Akgün, T., Erdem, S., and Dinçol, G. (1971) Haematological effects of chronic benzene poisoning in 217 workers. Occup. Environ. Med. 28, 296−302. (27) Snyder, R., Kocsis, J. J., et al. (1975) Current concepts of chronic benzene toxicity. CRC Crit. Rev. Toxicol. 3, 265−288. (28) Infante, P. F., Rinsky, R. A., Wagoner, J. K., and Young, R. J. (1977) Leukaemia in benzene workers. Lancet 2, 76−78. (29) Leanderson, P., and Tagesson, C. (1990) Cigarette smokeinduced DNA-damage: role of hydroquinone and catechol in the formation of the oxidative DNA-adduct, 8-hydroxydeoxyguanosine. Chem.-Biol. Interact. 75, 71−81. (30) Snyder, R., Witz, G., and Goldstein, B. D. (1993) The toxicology of benzene. Environ. Health Perspect. 100, 293−306. (31) Gut, I., Nedelcheva, V., Soucek, P., Stopka, P., and Tichavská, B. (1996) Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity. Environ. Health Perspect. 104, 1211−1218. (32) Soucek, P., Filipcova, B., and Gut, I. (1994) Cytochrome P450 destruction and radical scavenging by benzene and its metabolites Evidence for the key role of quinones. Biochem. Pharmacol. 47, 2233− 2242. (33) Irons, R. D. (1985) Quinones as toxic metabolites of benzene. J. Toxicol. Environ. Health 16, 673−678. (34) Warren, D. L., Brown, D. L., and Buckpitt, A. R. (1982) Evidence for cytochrome P-450 mediated metabolism in the bronchiolar damage by naphthalene. Chem.-Biol. Interact. 40, 287−303. (35) Zheng, J., Cho, M., Jones, A. D., and Hammock, B. D. (1997) Evidence of quinone metabolites of naphthalene covalently bound to sulfur nucleophiles of proteins of murine Clara cells after exposure to naphthalene. Chem. Res. Toxicol. 10, 1008−1014. (36) Onderwater, R. C., Commandeur, J. N., Menge, W. M., and Vermeulen, N. P. (1999) Activation of microsomal glutathione Stransferase and inhibition of cytochrome P450 1A1 activity as a model system for detecting protein alkylation by thiourea-containing compounds in rat liver microsomes. Chem. Res. Toxicol. 12, 396−402. (37) Yenes, S., Commandeur, J. N. M., Vermeulen, N. P. E., and Messeguer, A. (2004) In vitro biotransformation of 3,4-dihydro-6hydroxy-2,2-dimethyl-7-methoxy-1(2H)-benzopyran (CR-6), a potent lipid peroxidation inhibitor and nitric oxide scavenger, in rat liver microsomes. Chem. Res. Toxicol. 17, 904−913. (38) Pohland, A. E., Nesheim, S., and Friedman, L. (1992) Ochratoxin A: a review (technical report). Pure Appl. Chem. 64, 1029−1046. (39) Jørgensen, K. (2005) Occurrence of ochratoxin A in commodities and processed food-a review of EU occurrence data. Food Addit. Contam. 22, 26−30. (40) (1989) Toxicology and carcinogenesis studies of ochratoxin A (CAS No. 303−47−9) in F344/N rats (gavage studies). Natl. Toxicol. Program, Vol. 358, pp. 1−142. (41) International Agency for Research on Cancer. (1993) Some naturally occurring substances: food items and constituents, heterocyclic

aromatic amines and mycotoxins, International Agency for Research on Cancer, Lyon. (42) Waidyanatha, S., Lin, P. H., and Rappaport, S. M. (1996) Characterization of chlorinated adducts of hemoglobin and albumin following administration of pentachlorophenol to rats. Chem. Res. Toxicol. 9, 647−653. (43) Nguyen, T. N. T., Bertagnolli, A. D., Villalta, P. W., Bühlmann, P., and Sturla, S. J. (2005) Characterization of a deoxyguanosine adduct of tetrachlorobenzoquinone: dichlorobenzoquinone-1, N2-etheno-2‘-deoxyguanosine. Chem. Res. Toxicol. 18, 1770−1776. (44) Vaidyanathan, V. G., Villalta, P. W., and Sturla, S. J. (2007) Nucleobase-dependent reactivity of a quinone metabolite of pentachlorophenol. Chem. Res. Toxicol. 20, 913−919. (45) Dai, J., Park, G., Wright, M. W., Adams, M., Akman, S. A., and Manderville, R. A. (2002) Detection and characterization of a glutathione conjugate of ochratoxin A. Chem. Res. Toxicol. 15, 1581− 1588. (46) Gillman, I. G., Clark, T. N., and Manderville, R. A. (1999) Oxidation of ochratoxin A by an Fe-porphyrin system: model for enzymatic activation and DNA cleavage. Chem. Res. Toxicol. 12, 1066− 1076. (47) Hattemer-Frey, H. A., and Travis, C. C. (1989) Pentachlorophenol: environmental partitioning and human exposure. Arch. Environ. Contam. Toxicol. 18, 482−489. (48) Jorens, P. G., and Schepens, P. J. (1993) Human pentachlorophenol poisoning. Hum. Exp. Toxicol. 12, 479−495. (49) Mcconnell, E. (1991) Toxicology and carcinogenesis studies of two grades of pentachlorophenol in B6C3F1 mice. Fundam. Appl. Toxicol. 17, 519−532. (50) (1999) NTP toxicology and carcinogenesis studies of pentachlorophenol (CAS No. 87−86−5) in F344/n rats (feed studies). Natl. Toxicol. Program, Vol. 483, pp. 1−182. (51) Greene, M. H., Brinton, L. A., Fraumeni, J. F., and D’Amico, R. (1978) Familial and sporadic Hodgkin’s disease associated with occupational wood exposure. Lancet 2, 626−627. (52) Hardell, L., and Sandström, A. (1979) Case-control study: softtissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br. J. Cancer 39, 711−717. (53) Pearce, N. E., Smith, A. H., Howard, J. K., Sheppard, R. A., Giles, H. J., and Teague, C. A. (1986) Non-Hodgkin’s lymphoma and exposure to phenoxyherbicides, chlorophenols, fencing work, and meat works employment: a case-control study. Occup. Environ. Med. 43, 75− 83. (54) Roberts, H. J. (1990) Pentachlorophenol-associated aplastic anemia, red cell aplasia, leukemia, and other blood disorders. J. Fla. Med. Assoc. 77, 86−90. (55) US Department of Health and Human Services. (2001) Toxicological profile for pentachlorophenol, Agency for Toxic Substance and Disease Registry. (56) Renner, G., and Hopfer, C. (1990) Metabolic studies on pentachlorophenol (PCP) in rats. Xenobiotica 20, 573−582. (57) Proudfoot, A. T. (2003) Pentachlorophenol poisoning. Toxicol. Rev. 22, 3−11. (58) van Ommen, B., Voncken, J. W., Müller, F., and van Bladeren, P. J. (1988) The oxidation of tetrachloro-1,4-hydroquinone by microsomes and purified cytochrome P-450b. Implications for covalent binding to protein and involvement of reactive oxygen species. Chem.Biol. Interact. 65, 247−259. (59) Lin, P. H., Waidyanatha, S., Pollack, G. M., Swenberg, J. A., and Rappaport, S. M. (1999) Dose-specific production of chlorinated quinone and semiquinone adducts in rodent livers following administration of pentachlorophenol. Toxicol. Sci. 47, 126−133. (60) Ehrlich, W. (1990) The effect of pentachlorophenol and its metabolite tetrachlorohydroquinone on cell growth and the induction of DNA damage in Chinese hamster ovary cells. Mutat. Res. Lett. 244, 299−302. (61) Witte, I., Juhl, U., and Butte, W. (1985) DNA-damaging properties and cytotoxicity in human fibroblasts of tetrachlorohy26



Review

droquinone, a pentachlorophenol metabolite. Mutat. Res., DNA Repair Rep. 145, 71−75. (62) Zhu, B. Z., Kitrossky, N., and Chevion, M. (2000) Evidence for production of hydroxyl radicals by pentachlorophenol metabolites and hydrogen peroxide: a metal-independent organic Fenton reaction. Biochem. Biophys. Res. Commun. 270, 942−946. (63) Ahlborg, U. G., Larsson, K., and Thunberg, T. (1978) Metabolism of pentachlorophenol in vivo and in vitro. Arch. Toxicol. 40, 45−53. (64) Kang, P., Dalvie, D., Smith, E., and Renner, M. (2009) Bioactivation of lumiracoxib by peroxidases and human liver microsomes: identification of multiple quinone imine intermediates and GSH adducts. Chem. Res. Toxicol. 22, 106−117. (65) Li, Y., Slatter, J. G., Zhang, Z., Li, Y., Doss, G. A., Braun, M. P., Stearns, R. A., Dean, D. C., Baillie, T. A., and Tang, W. (2008) In vitro metabolic activation of lumiracoxib in rat and human liver preparations. Drug Metab. Dispos. 36, 469−473. (66) Poon, G. K., Chen, Q., Teffera, Y., Ngui, J. S., Griffin, P. R., Braun, M. P., Doss, G. A., Freeden, C., Stearns, R. A., Evans, D. C., Baillie, T. A., and Tang, W. (2001) Bioactivation of diclofenac via benzoquinone imine intermediates-identification of urinary mercapturic acid derivatives in rats and humans. Drug Metab. Dispos. 29, 1608−1613. (67) Shen, S., Marchick, M. R., Davis, M. R., Doss, G. A., and Pohl, L. R. (1999) Metabolic activation of diclofenac by human cytochrome P450 3A4: role of 5-hydroxydiclofenac. Chem. Res. Toxicol. 12, 214− 222. (68) Tang, W., Stearns, R. A., Bandiera, S. M., Zhang, Y., Raab, C., Braun, M. P., Dean, D. C., Pang, J., Leung, K. H., Doss, G. A., Strauss, J. R., Kwei, G. Y., Rushmore, T. H., Chiu, S. H., and Baillie, T. A. (1999) Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites. Drug Metab. Dispos. 27, 365−372. (69) Smith, K. S., Smith, P. L., Heady, T. N., Trugman, J. M., Harman, W. D., and Macdonald, T. L. (2003) In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity. Chem. Res. Toxicol. 16, 123−128. (70) Klopčič, I., Poberžnik, M., Mavri, J., and Dolenc, M. S. (2015) A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione. Chem.-Biol. Interact. 242, 407−414. (71) Neftel, K. A., Woodtly, W., Schmid, M., Frick, P. G., and Fehr, J. (1986) Amodiaquine induced agranulocytosis and liver damage. Br. Med. J. (Clin. Res. Ed.) 292, 721−723. (72) Maggs, J. L., Tingle, M. D., Kitteringham, N. R., and Park, B. K. (1988) Drug-protein conjugates-XIV. Mechanisms of formation of protein-arylating intermediates from amodiaquine, a myelotoxin and hepatotoxin in man. Biochem. Pharmacol. 37, 303−311. (73) Christie, G., Breckenridge, A. M., and Park, B. K. (1989) Drugprotein conjugates-XVIII. Detection of antibodies towards the antimalarial amodiaquine and its quinone imine metabolite in man and the rat. Biochem. Pharmacol. 38, 1451−1458. (74) Salama, A., and Mueller-Eckhardt, C. (1985) The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia. N. Engl. J. Med. 313, 469−474. (75) Yu, J., Mathisen, D. E., Burdette, D., Brown, D. G., Becker, C., and Aharony, D. (2010) Identification of multiple glutathione conjugates of 8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (nomifensine) in liver microsomes and hepatocyte preparations: evidence of the bioactivation of nomifensine. Drug Metab. Dispos. 38, 46−60. (76) Teng, W. C., Oh, J. W., New, L. S., Wahlin, M. D., Nelson, S. D., Ho, H. K., and Chan, E. C. Y. (2010) Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol. Pharmacol. 78, 693−703. (77) Morgan, R. E., Trauner, M., van Staden, C. J., Lee, P. H., Ramachandran, B., Eschenberg, M., Afshari, C. A., Qualls, C. W., Lightfoot-Dunn, R., and Hamadeh, H. K. (2010) Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol. Sci. 118, 485−500.

(78) Li, X., He, Y., Ruiz, C. H., Koenig, M., Cameron, M. D., and Vojkovsky, T. (2009) Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways. Drug Metab. Dispos. 37, 1242−1250. (79) Li, X., Kamenecka, T. M., and Cameron, M. D. (2009) Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. Chem. Res. Toxicol. 22, 1736−1742. (80) Li, X., Kamenecka, T. M., and Cameron, M. D. (2010) Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile. Drug Metab. Dispos. 38, 1238−1245. (81) Kalgutkar, A. S., Vaz, A. D. N., Lame, M. E., Henne, K. R., Soglia, J., Zhao, S. X., Abramov, Y. A., Lombardo, F., Collin, C., Hendsch, Z. S., and Hop, C. E. C. A. (2005) Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab. Dispos. 33, 243−253. (82) Bauman, J. N., Frederick, K. S., Sawant, A., Walsky, R. L., Cox, L. M., Obach, R. S., and Kalgutkar, A. S. (2008) Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug. Drug Metab. Dispos. 36, 1016−1029. (83) Greene, D. S., and Barbhaiya, R. H. (1997) Clinical Pharmacokinetics of Nefazodone. Clin. Pharmacokinet. 33, 260−275. (84) Kostrubsky, S. E., Strom, S. C., Kalgutkar, A. S., Kulkarni, S., Atherton, J., Mireles, R., Feng, B., Kubik, R., Hanson, J., Urda, E., and Mutlib, A. E. (2006) Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. 90, 451− 459. (85) Dykens, J. A., Jamieson, J. D., Marroquin, L. D., Nadanaciva, S., Xu, J. J., Dunn, M. C., Smith, A. R., and Will, Y. (2008) In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol. Sci. 103, 335−345. (86) Shear, N. H., and Spielberg, S. P. (1988) Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J. Clin. Invest. 82, 1826−1832. (87) Bu, H.-Z., Zhao, P., Dalvie, D. K., and Pool, W. F. (2007) Identification of primary and sequential bioactivation pathways of carbamazepine in human liver microsomes using liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom. 21, 3317−3322. (88) Bu, H.-Z., Kang, P., Deese, A. J., Zhao, P., and Pool, W. F. (2005) Human in vitro glutathionyl and protein adducts of carbamazepine10,11-epoxide, a stable and pharmacologically active metabolite of carbamazepine. Drug Metab. Dispos. 33, 1920−1924. (89) Ju, C., and Uetrecht, J. P. (1999) Detection of 2hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate. J. Pharmacol. Exp. Ther. 288, 51−56. (90) Lillibridge, J. H., Amore, B. M., Slattery, J. T., Kalhorn, T. F., Nelson, S. D., Finnell, R. H., and Bennett, G. D. (1996) Protein-reactive metabolites of carbamazepine in mouse liver microsomes. Drug Metab. Dispos. 24, 509−514. (91) Nakayama, S., Atsumi, R., Takakusa, H., Kobayashi, Y., Kurihara, A., Nagai, Y., Nakai, D., and Okazaki, O. (2009) A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding. Drug Metab. Dispos. 37, 1970−1977. (92) Lennernäs, H. (2003) Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet. 42, 1141−1160. (93) Kalgutkar, A. S., Henne, K. R., Lame, M. E., Vaz, A. D. N., Collin, C., Soglia, J. R., Zhao, S. X., and Hop, C. E. C. A. (2005) Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4. Chem.-Biol. Interact. 155, 10−20. (94) Wen, B., Ma, L., Rodrigues, A. D., and Zhu, M. (2008) Detection of novel reactive metabolites of trazodone: evidence for CYP2D6mediated bioactivation of m-chlorophenylpiperazine. Drug Metab. Dispos. 36, 841−850. 27



Review

(95) Jauch, R., Kopitar, Z., Prox, A., and Zimmer, A. (1976) Pharmacokinetics and metabolism of trazodone in man (author’s transl). Arzneimittelforschung 26, 2084−2089. (96) Venkatakrishnan, K., and Obach, R. S. (2005) In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab. Dispos. 33, 845−852. (97) Zhao, S. X., Dalvie, D. K., Kelly, J. M., Soglia, J. R., Frederick, K. S., Smith, E. B., Obach, R. S., and Kalgutkar, A. S. (2007) NADPHdependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 20, 1649−1657. (98) Ring, B. J., Patterson, B. E., Mitchell, M. I., Vandenbranden, M., Gillespie, J., Bedding, A. W., Jewell, H., Payne, C. D., Forgue, S. T., Eckstein, J., Wrighton, S. A., and Phillips, D. L. (2005) Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo. Clin. Pharmacol. Ther. 77, 63−75. (99) Lim, H.-K., Chen, J., Sensenhauser, C., Cook, K., and Subrahmanyam, V. (2007) Metabolite identification by data-dependent accurate mass spectrometric analysis at resolving power of 60,000 in external calibration mode using an LTQ/Orbitrap. Rapid Commun. Mass Spectrom. 21, 1821−1832. (100) Dalvie, D., Kang, P., Zientek, M., Xiang, C., Zhou, S., and Obach, R. S. (2008) Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. Chem. Res. Toxicol. 21, 2260−2271. (101) Yu, L., Liu, H., Li, W., Zhang, F., Luckie, C., van Breemen, R. B., Thatcher, G. R. J., and Bolton, J. L. (2004) Oxidation of raloxifene to quinoids: potential toxic pathways via a diquinone methide and oquinones. Chem. Res. Toxicol. 17, 879−888. (102) Li, K.-M., Todorovic, R., Devanesan, P., Higginbotham, S., Köfeler, H., Ramanathan, R., Gross, M. L., Rogan, E. G., and Cavalieri, E. L. (2004) Metabolism and DNA binding studies of 4hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis 25, 289−297. (103) Stack, D. E., Byun, J., Gross, M. L., Rogan, E. G., and Cavalieri, E. L. (1996) Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides. Chem. Res. Toxicol. 9, 851−859. (104) Bindhumol, V., Chitra, K. C., and Mathur, P. P. (2003) Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology 188, 117−124. (105) Ben-Jonathan, N., and Steinmetz, R. (1998) Xenoestrogens: the emerging story of bisphenol A. Trends Endocrinol. Metab. 9, 124−128. (106) Atkinson, A., and Roy, D. (1995) In vitro conversion of environmental estrogenic chemical bisphenol A to DNA binding metabolite(s). Biochem. Biophys. Res. Commun. 210, 424−433. (107) Kabuto, H., Hasuike, S., Minagawa, N., and Shishibori, T. (2003) Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ. Res. 93, 31−35. (108) Atkinson, A., and Roy, D. (1995) In vivo DNA adduct formation by bisphenol A. Environ. Mol. Mutagen. 26, 60−66. (109) Sajiki, J. (2001) Decomposition of bisphenol A (BPA) by radical oxygen. Environ. Int. 27, 315−320. (110) Nicolis, S., Zucchelli, M., Monzani, E., and Casella, L. (2008) Myoglobin modification by enzyme-generated dopamine reactive species. Chem. - Eur. J. 14, 8661−8673. (111) Butler, J., and Hoey, B. M. (1987) Are reduced quinones necessarily involved in the antitumour activity of quinone drugs? Br. J. Cancer Suppl. 8, 53−59. (112) Minotti, G., Licata, S., Saponiero, A., Menna, P., Calafiore, A. M., Di Giammarco, G., Liberi, G., Animati, F., Cipollone, A., Manzini, S., and Maggi, C. A. (2000) Anthracycline metabolism and toxicity in human myocardium: comparisons between doxorubicin, epirubicin, and a novel disaccharide analogue with a reduced level of formation and [4Fe-4S] reactivity of its secondary alcohol metabolite. Chem. Res. Toxicol. 13, 1336−1341. (113) Maltoni, C., Ciliberti, A., Cotti, G., Conti, B., and Belpoggi, F. (1989) Benzene, an experimental multipotential carcinogen: results of

the long-term bioassays performed at the Bologna Institute of Oncology. Environ. Health Perspect. 82, 109−124. (114) Maltoni, C., Conti, B., Cotti, G., and Belpoggi, F. (1985) Experimental studies on benzene carcinogenicity at the Bologna Institute of Oncology: current results and ongoing research. Am. J. Ind. Med. 7, 415−446. (115) Huff, J. E., Haseman, J. K., DeMarini, D. M., Eustis, S., Maronpot, R. R., Peters, A. C., Persing, R. L., Chrisp, C. E., and Jacobs, A. C. (1989) Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice. Environ. Health Perspect. 82, 125−163. (116) Cronkite, E. P., Drew, R. T., Inoue, T., Hirabayashi, Y., and Bullis, J. E. (1989) Hematotoxicity and carcinogenicity of inhaled benzene. Environ. Health Perspect. 82, 97−108. (117) Merletti, F., Heseltine, E., Saracci, R., Simonato, L., Vainio, H., and Wilbourn, J. (1984) Target organs for carcinogenicity of chemicals and industrial exposures in humans: a review of results in the IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Cancer Res. 44, 2244−2250. (118) Rinsky, R. A., Young, R. J., and Smith, A. B. (1981) Leukemia in benzene workers. Am. J. Ind. Med. 2, 217−245. (119) Ott, W. R., and Roberts, J. W. (1998) Everyday exposure to toxic pollutants. Sci. Am. 278, 86−91. (120) Snyder, R., and Hedli, C. C. (1996) An overview of benzene metabolism. Environ. Health Perspect. 104, 1165−1171. (121) Sammett, D., Lee, E. W., Kocsis, J. J., and Snyder, R. (1979) Partial hepatectomy reduces both metabolism and toxicity of benzene. J. Toxicol. Environ. Health 5, 785−792. (122) Andrews, L. S., Lee, E. W., Witmer, C. M., Kocsis, J. J., and Snyder, R. (1977) Effects of toluene on the metabolism, disposition and hemopoietic toxicity of [3H]benzene. Biochem. Pharmacol. 26, 293− 300. (123) Seaton, M. J., Schlosser, P. M., Bond, J. A., and Medinsky, M. A. (1994) Benzene metabolism by human liver microsomes in relation to cytochrome P450 2E1 activity. Carcinogenesis 15, 1799−1806. (124) Valentine, J. L., Lee, S. S., Seaton, M. J., Asgharian, B., Farris, G., Corton, J. C., Gonzalez, F. J., and Medinsky, M. A. (1996) Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression. Toxicol. Appl. Pharmacol. 141, 205−213. (125) Witz, G., Zhang, Z., and Goldstein, B. D. (1996) Reactive ringopened aldehyde metabolites in benzene hematotoxicity. Environ. Health Perspect. 104, 1195−1199. (126) Uzma, N., Kumar, B., Salar, K., Madhuri, A., and Reddy, A. (2008) In vitro and in vivo evaluation of toxic effect of benzene on lymphocytes and hepatocytes. Internet J. Toxicol. 6, 7846. (127) Tunek, A., Platt, K. L., Przybylski, M., and Oesch, F. (1980) Multi-step metabolic activation of benzene. Effect of superoxide dismutase on covalent binding to microsomal macromolecules, and identification of glutathione conjugates using high pressure liquid chromatography and field desorption mass spectrometry. Chem.-Biol. Interact. 33, 1−17. (128) Rickert, D. E., Baker, T. S., Bus, J. S., Barrow, C. S., and Irons, R. D. (1979) Benzene disposition in the rat after exposure by inhalation. Toxicol. Appl. Pharmacol. 49, 417−423. (129) Greenlee, W. F., Gross, E. A., and Irons, R. D. (1981) Relationship between benzene toxicity and the disposition of 14Clabelled benzene metabolites in the rat. Chem.-Biol. Interact. 33, 285− 299. (130) Smart, R. C., and Zannoni, V. G. (1984) DT-diaphorase and peroxidase influence the covalent binding of the metabolites of phenol the major metabolite of benzene. Mol. Pharmacol. 26, 105−111. (131) Schlosser, M. J., and Kalf, G. F. (1989) Metabolic activation of hydroquinone by macrophage peroxidase. Chem.-Biol. Interact. 72, 191−207. (132) Smith, M. T., Yager, J. W., Steinmetz, K. L., and Eastmond, D. A. (1989) Peroxidase-dependent metabolism of benzene’s phenolic metabolites and its potential role in benzene toxicity and carcinogenicity. Environ. Health Perspect. 82, 23−29. (133) Twerdok, L. E., Rembish, S. J., and Trush, M. A. (1992) Induction of quinone reductase and glutathione in bone marrow cells 28



Review

by 1,2-dithiole-3-thione: effect on hydroquinone-induced cytotoxicity. Toxicol. Appl. Pharmacol. 112, 273−281. (134) Apel, K., and Hirt, H. (2004) Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu. Rev. Plant Biol. 55, 373−399. (135) Guengerich, F. P., and Strickland, T. W. (1977) Metabolism of vinyl chloride: destruction of the heme of highly purified liver microsomal cytochrome P-450 by a metabolite. Mol. Pharmacol. 13, 993−1004. (136) Levin, W., Lu, A. Y. H., Jacobson, M., Kuntzman, R., Lee Poyer, J., and McCay, P. B. (1973) Lipid peroxidation and the degradation of cytochrome P-450 heme. Arch. Biochem. Biophys. 158, 842−852. (137) Schaefer, W. H., Harris, T. M., and Guengerich, F. P. (1985) Characterization of the enzymic and nonenzymic peroxidative degradation of iron porphyrins and cytochrome P-450 heme. Biochemistry 24, 3254−3263. (138) Smith, M. T. (1996) The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ. Health Perspect. 104, 1219−1225. (139) Li, Y., Lafuente, A., and Trush, M. A. (1994) Characterization of quinone reductase, glutathione and glutathione S-transferase in human myeloid cell lines: induction by 1,2-dithiole-3-thione and effects on hydroquinone-induced cytotoxicity. Life Sci. 54, 901−916. (140) Ross, D., Siegel, D., Schattenberg, D. G., Sun, X. M., and Moran, J. L. (1996) Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: identification of target cells and a potential role for modulation of apoptosis in benzene toxicity. Environ. Health Perspect. 104, 1177−1182. (141) Li, Y., and Trush, M. A. (1993) DNA damage resulting from the oxidation of hydroquinone by copper: role for a Cu(II)/Cu(I) redox cycle and reactive oxygen generation. Carcinogenesis 14, 1303−1311. (142) Li, Y., Kuppusamy, P., Zweier, J. L., and Trush, M. A. (1995) ESR evidence for the generation of reactive oxygen species from the copper-mediated oxidation of the benzene metabolite, hydroquinone: role in DNA damage. Chem.-Biol. Interact. 94, 101−120. (143) Li, Y., Kuppusamy, P., Zweier, J. L., and Trush, M. A. (1996) Role of Cu/Zn-superoxide dismutase in xenobiotic activation. I. Chemical reactions involved in the Cu/Zn-superoxide dismutaseaccelerated oxidation of the benzene metabolite 1,4-hydroquinone. Mol. Pharmacol. 49, 404−411. (144) Li, Y., Kuppusamy, P., Zweir, J. L., and Trush, M. A. (1996) Role of Cu/Zn-superoxide dismutase in xenobiotic activation. II. Biological effects resulting from the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone. Mol. Pharmacol. 49, 412−421. (145) Rothman, N., Smith, M. T., Hayes, R. B., Traver, R. D., Hoener, B., Campleman, S., Li, G. L., Dosemeci, M., Linet, M., Zhang, L., Xi, L., Wacholder, S., Lu, W., Meyer, K. B., Titenko-Holland, N., Stewart, J. T., Yin, S., and Ross, D. (1997) Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C–>T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res. 57, 2839−2842. (146) Moran, J. L., Siegel, D., and Ross, D. (1999) A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity. Proc. Natl. Acad. Sci. U. S. A. 96, 8150−8155. (147) Trush, M. A., Twerdok, L. E., Rembish, S. J., Zhu, H., and Li, Y. (1996) Analysis of target cell susceptibility as a basis for the development of a chemoprotective strategy against benzene-induced hematotoxicities. Environ. Health Perspect. 104, 1227−1234. (148) Lee, E. W., Kocsis, J. J., and Snyder, R. (1981) The use of ferrokinetics in the study of experimental anemia. Environ. Health Perspect. 39, 29−37. (149) Orzechowski, A., Schwarz, L. R., Schwegler, U., Bock, K. W., Snyder, R., and Schrenk, D. (1995) Benzene metabolism in rodent hepatocytes: role of sulphate conjugation. Xenobiotica 25, 1093−1102. (150) Sanctucci, K., and Shah, B. (2000) Association of naphthalene with acute hemolytic anemia. Acad. Emergency Med. 7, 42−47.

(151) Shi, H., Sui, Y., Wang, X., Luo, Y., and Ji, L. (2005) Hydroxyl radical production and oxidative damage induced by cadmium and naphthalene in liver of Carassius auratus. Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol. 140, 115−121. (152) Collén, J., Pinto, E., Pedersén, M., and Colepicolo, P. (2003) Induction of oxidative stress in the red macroalga Gracilaria tenuistipitata by pollutant metals. Arch. Environ. Contam. Toxicol. 45, 337−342. (153) Vijayavel, K., Gomathi, R. D., Durgabhavani, K., and Balasubramanian, M. P. (2004) Sublethal effect of naphthalene on lipid peroxidation and antioxidant status in the edible marine crab Scylla serrata. Mar. Pollut. Bull. 48, 429−433. (154) Pacheco, M., and Santos, M. A. (2002) Naphthalene and βnaphthoflavone effects on Anguilla anguilla L. hepatic metabolism and erythrocytic nuclear abnormalities. Environ. Int. 28, 285−293. (155) Levitan, W. M., and Taylor, M. H. (1979) Physiology of salinitydependent naphthalene toxicity in Fundulus heteroclitus. J. Fish. Res. Board Can. 36, 615−620. (156) Teles, M., Pacheco, M., and Santos, M. A. (2003) Anguilla anguilla L. liver ethoxyresorufin O-deethylation, glutathione Stranferase, erythrocytic nuclear abnormalities, and endocrine responses to naphthalene and β-naphthoflavone. Ecotoxicol. Environ. Saf. 55, 98− 107. (157) Preuss, R., Angerer, J. R., and Drexler, H. (2003) Naphthalenean environmental and occupational toxicant. Int. Arch. Occup. Environ. Health 76, 556−576. (158) Simmonds, M. S. J. (2004) IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 82, some traditional herbal medicines, some mycotoxins, naphthalene and styrene. Phytochemistry 65, 139. (159) Cho, T. M., Rose, R. L., and Hodgson, E. (2006) In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes. Drug Metab. Dispos. 34, 176−183. (160) Stohs, S. (2002) Naphthalene toxicity and antioxidant nutrients. Toxicology 180, 97−105. (161) Jerina, D. M., Daly, J. W., Witkop, B., Zaltzman-Nirenberg, P., and Udenfriend, S. (1970) 1,2-Naphthalene oxide as an intermediate in the microsomal hydroxylation of naphthalene. Biochemistry 9, 147− 156. (162) Tsuruda, L. S., Lamé, M. W., and Jones, A. D. (1995) Formation of epoxide and quinone protein adducts in B6C3F1 mice treated with naphthalene, sulfate conjugate of 1,4-dihydroxynaphthalene and 1,4naphthoquinone. Arch. Toxicol. 69, 362−367. (163) Bakke, J., Struble, C., Gustafsson, J. A., and Gustafsson, B. (1985) Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats. Proc. Natl. Acad. Sci. U. S. A. 82, 668−671. (164) Boyland, E., and Sims, P. (1958) Metabolism of polycyclic compounds. 12. An acid-labile precursor of 1-naphthylmercapturic acid and naphthol: an N-acetyl-S-(1:2-dihydrohydroxynaphthyl)-l-cysteine. Biochem. J. 68, 440−447. (165) Chen, K. C., and Dorough, H. W. (1979) Glutathione and mercapturic acid conjugations in the metabolism of naphthalene and 1naphthyl N-methylcarbamate (carbaryl). Drug Chem. Toxicol. 2, 331− 354. (166) Pakenham, G., Lango, J., Buonarati, M., Morin, D., and Buckpitt, A. (2002) Urinary naphthalene mercapturates as biomarkers of exposure and stereoselectivity of naphthalene epoxidation. Drug Metab. Dispos. 30, 247−253. (167) Rozman, K., Summer, K. H., Rozman, T., Greim, H., et al. (1982) Elimination of thioethers following administration of naphthalene and diethylmaleate to the rhesus monkey. Drug Chem. Toxicol. 5, 265−275. (168) Stillwell, W. G., Bouwsma, O. J., Thenot, J. P., Horning, M. G., Griffin, G. W., Ishikawa, K., and Takaku, M. (1978) Methylthio metabolites of naphthalen excreted by the rat. Res. Commun. Chem. Pathol. Pharmacol. 20, 509−530. 29



Review

(169) Yu, D., Berlin, J. A., Penning, T. M., and Field, J. (2002) Reactive oxygen species generated by PAH o-quinones cause changein-function mutations in p53. Chem. Res. Toxicol. 15, 832−842. (170) Wilson, A. S., Davis, C. D., Williams, D. P., Buckpitt, A. R., Pirmohamed, M., and Park, B. K. (1996) Characterisation of the toxic metabolite(s) of naphthalene. Toxicology 114, 233−242. (171) Bagchi, D., Balmoori, J., Bagchi, M., Ye, X., Williams, C. B., and Stohs, S. J. (2000) Role of p53 tumor suppressor gene in the toxicity of TCDD, endrin, naphthalene, and chromium (vi) in liver and brain tissues of mice. Free Radical Biol. Med. 28, 895−903. (172) Denissenko, M. F., Pao, A., Tang, M., and Pfeifer, G. P. (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274, 430−432. (173) Greene, J. F., Zheng, J., Grant, D. F., and Hammock, B. D. (2000) Cytotoxicity of 1,2-epoxynaphthalene is correlated with protein binding and in situ glutathione depletion in cytochrome P4501A1 expressing Sf-21 cells. Toxicol. Sci. 53, 352−360. (174) Hemminki, K. (1993) DNA adducts, mutations and cancer. Carcinogenesis 14, 2007−2012. (175) Troester, M. A., Lindstrom, A. B., Waidyanatha, S., Kupper, L. L., and Rappaport, S. M. (2002) Stability of hemoglobin and albumin adducts of naphthalene oxide, 1,2-naphthoquinone, and 1,4-naphthoquinone. Toxicol. Sci. 68, 314−321. (176) Waidyanatha, S., Troester, M. A., Lindstrom, A. B., and Rappaport, S. M. (2002) Measurement of hemoglobin and albumin adducts of naphthalene-1,2-oxide, 1,2-naphthoquinone and 1,4naphthoquinone after administration of naphthalene to F344 rats. Chem.-Biol. Interact. 141, 189−210. (177) O’Driscoll, C., Doonan, F., Sanvicens, N., Messeguer, A., and Cotter, T. G. (2011) A novel free radical scavenger rescues retinal cells in vivo. Exp. Eye Res. 93, 65−74. (178) Yenes, S., and Messeguer, A. (1999) A study of the reaction of different phenol substrates with nitric oxide and peroxynitrite. Tetrahedron 55, 14111−14122. (179) Pérez-Asensio, F. J., de la Rosa, X., Jiménez-Altayó, F., Gorina, R., Martínez, E., Messeguer, A., Vila, E., Chamorro, A., and Planas, A. M. (2010) Antioxidant CR-6 protects against reperfusion injury after a transient episode of focal brain ischemia in rats. J. Cereb. Blood Flow Metab. 30, 638−652. (180) Jiménez-Altayó, F., Caracuel, L., Pérez-Asensio, F. J., MartínezRevelles, S., Messeguer, A., Planas, A. M., and Vila, E. (2009) Participation of oxidative stress on rat middle cerebral artery changes induced by focal cerebral ischemia: beneficial effects of 3,4-dihydro-6hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6). J. Pharmacol. Exp. Ther. 331, 429−436. (181) Montoliu, C., Llansola, M., Sáez, R., Yenes, S., Messeguer, A., and Felipo, V. (1999) Prevention of glutamate neurotoxicity in cultured neurons by 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)benzopyran (CR-6), a scavenger of nitric oxide. Biochem. Pharmacol. 58, 255−261. (182) Miranda, M., Muriach, M., Almansa, I., Arnal, E., Messeguer, A., Díaz-Llopis, M., Romero, F. J., and Bosch-Morell, F. (2007) CR-6 protects glutathione peroxidase activity in experimental diabetes. Free Radical Biol. Med. 43, 1494−1498. (183) Sanvicens, N., Gómez-Vicente, V., Masip, I., Messeguer, A., and Cotter, T. G. (2004) Oxidative stress-induced apoptosis in retinal photoreceptor cells is mediated by calpains and caspases and blocked by the oxygen radical scavenger CR-6. J. Biol. Chem. 279, 39268−39278. (184) Sanvicens, N., Gómez-Vicente, V., Messeguer, A., and Cotter, T. G. (2006) The radical scavenger CR-6 protects SH-SY5Y neuroblastoma cells from oxidative stress-induced apoptosis: effect on survival pathways. J. Neurochem. 98, 735−747. (185) Morgenstern, R., DePierre, J. W., and Jörnvall, H. (1985) Microsomal glutathione transferase. Primary structure. J. Biol. Chem. 260, 13976−13983. (186) Commandeur, J. N., Stijntjes, G. J., and Vermeulen, N. P. (1995) Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics. Pharmacol. Rev. 47, 271−330.

(187) Morgenstern, R., and DePierre, J. W. (1983) Microsomal glutathione transferase. Purification in unactivated form and further characterization of the activation process, substrate specificity and amino acid composition. Eur. J. Biochem. 134, 591−597. (188) Andersson, C., Weinander, R., Lundqvist, G., DePierre, J. W., and Morgenstern, R. (1994) Functional and structural membrane topology of rat liver microsomal glutathione transferase. Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 1204, 298−304. (189) van der Merwe, K. J., Steyn, P. S., Fourie, L., et al. (1965) Ochratoxin A, a toxic metabolite produced by Aspergillus ochraceus Wilh. Nature 205, 1112−1113. (190) Pfohl-Leszkowicz, A., and Manderville, R. A. (2007) Ochratoxin A: an overview on toxicity and carcinogenicity in animals and humans. Mol. Nutr. Food Res. 51, 61−99. (191) WHO (2001) Evaluation of certain mycotoxins in food. Fiftysixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep. Ser. 906, 1−62. (192) Manderville, R. A. (2005) A case for the genotoxicity of ochratoxin A by bioactivation and covalent DNA adduction. Chem. Res. Toxicol. 18, 1091−1097. (193) Turesky, R. J. (2005) Perspective: ochratoxin A is not a genotoxic carcinogen. Chem. Res. Toxicol. 18, 1082−1090. (194) Castegnaro, M. (1991) Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours, Vol. 115, WHO. (195) Petzinger, E., and Ziegler, K. (2000) Ochratoxin A from a toxicological perspective. J. Vet. Pharmacol. Ther. 23, 91−98. (196) Chu, F. S., Noh, I., and Chang, C. C. (1972) Structural requirements for ochratoxin intoxication. Life Sci. 11, 503−508. (197) Bredenkamp, M. W., Dillen, J. L. M., van Rooyen, P. H., and Steyn, P. S. (1989) Crystal structures and conformational analysis of ochratoxin A and B: probing the chemical structure causing toxicity. J. Chem. Soc., Perkin Trans. 2 2, 1835−1839. (198) Föllmann, W., Hillebrand, I. E., Creppy, E. E., and Bolt, H. M. (1995) Sister chromatid exchange frequency in cultured isolated porcine urinary bladder epithelial cells (PUBEC) treated with ochratoxin A and alpha. Arch. Toxicol. 69, 280−286. (199) Marin-Kuan, M., Ehrlich, V., Delatour, T., Cavin, C., and Schilter, B. (2011) Evidence for a role of oxidative stress in the carcinogenicity of ochratoxin A. J. Toxicol. 2011, 645361−15. (200) Gautier, J. C., Holzhaeuser, D., Markovic, J., Gremaud, E., Schilter, B., and Turesky, R. J. (2001) Oxidative damage and stress response from ochratoxin A exposure in rats. Free Radical Biol. Med. 30, 1089−1098. (201) Schaaf, G. J., Nijmeijer, S. M., Maas, R. F. M., Roestenberg, P., de Groene, E. M., and Fink-Gremmels, J. (2002) The role of oxidative stress in the ochratoxin A-mediated toxicity in proximal tubular cells. Biochim. Biophys. Acta, Mol. Basis Dis. 1588, 149−158. (202) Kamp, H. G., Eisenbrand, G., Janzowski, C., Kiossev, J., Latendresse, J. R., Schlatter, J., and Turesky, R. J. (2005) Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats. Mol. Nutr. Food Res. 49, 1160−1167. (203) Mally, A., Pepe, G., Ravoori, S., Fiore, M., Gupta, R. C., Dekant, W., and Mosesso, P. (2005) Ochratoxin A causes DNA damage and cytogenetic effects but no DNA adducts in rats. Chem. Res. Toxicol. 18, 1253−1261. (204) Kamp, H. G., Eisenbrand, G., Schlatter, J., Würth, K., and Janzowski, C. (2005) Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity and apoptosis in mammalian cell lines and primary cells. Toxicology 206, 413−425. (205) Arbillaga, L., Azqueta, A., Ezpeleta, O., and López de Cerain, A. (2006) Oxidative DNA damage induced by ochratoxin A in the HK-2 human kidney cell line: evidence of the relationship with cytotoxicity. Mutagenesis 22, 35−42. (206) Ali, R., Mittelstaedt, R. A., Shaddock, J. G., Ding, W., Bhalli, J. A., Khan, Q. M., and Heflich, R. H. (2011) Comparative analysis of micronuclei and DNA damage induced by ochratoxin A in two mammalian cell lines. Mutat. Res., Genet. Toxicol. Environ. Mutagen. 723, 58−64. 30



Review

(207) Shigenaga, M. K., Gimeno, C. J., and Ames, B. N. (1989) Urinary 8-hydroxy-2’-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc. Natl. Acad. Sci. U. S. A. 86, 9697−9701. (208) Cavin, C., Delatour, T., Marin-Kuan, M., Fenaille, F., Holzhäuser, D., Guignard, G., Bezençon, C., Piguet, D., Parisod, V., Richoz-Payot, J., and Schilter, B. (2009) Ochratoxin A-mediated DNA and protein damage: roles of nitrosative and oxidative stresses. Toxicol. Sci. 110, 84−94. (209) Murray, A. R., Kisin, E., Castranova, V., Kommineni, C., Gunther, M. R., and Shvedova, A. A. (2007) Phenol-induced in vivo oxidative stress in skin: evidence for enhanced free radical generation, thiol oxidation, and antioxidant depletion. Chem. Res. Toxicol. 20, 1769−1777. (210) Stoyanovsky, D. A., Goldman, R., Jonnalagadda, S. S., Day, B. W., Claycamp, H. G., and Kagan, V. E. (1996) Detection and characterization of the electron paramagnetic resonance-silent glutathionyl-5,5-dimethyl-1-pyrroline N-oxide adduct derived from redox cycling of phenoxyl radicals in model systems and HL-60 cells. Arch. Biochem. Biophys. 330, 3−11. (211) Mally, A., and Dekant, W. (2009) Mycotoxins and the kidney: modes of action for renal tumor formation by ochratoxin A in rodents. Mol. Nutr. Food Res. 53, 467−478. (212) Rached, E., Pfeiffer, E., Dekant, W., and Mally, A. (2006) Ochratoxin A: apoptosis and aberrant exit from mitosis due to perturbation of microtubule dynamics? Toxicol. Sci. 92, 78−86. (213) Adler, M., Müller, K., Rached, E., Dekant, W., and Mally, A. (2009) Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. Carcinogenesis 30, 711−719. (214) Czakai, K., Müller, K., Mosesso, P., Pepe, G., Schulze, M., Gohla, A., Patnaik, D., Dekant, W., Higgins, J. M. G., and Mally, A. (2011) Perturbation of mitosis through inhibition of histone acetyltransferases: the key to ochratoxin a toxicity and carcinogenicity? Toxicol. Sci. 122, 317−329. (215) Bhandari, S., Kalowski, S., Collett, P., Cooke, B. E., Kerr, P., Newland, R., Dowling, J., and Horvath, J. (2002) Karyomegalic nephropathy: an uncommon cause of progressive renal failure. Nephrol. Dial. Transplant. 17, 1914−1920. (216) Pfohl-Leszkowicz, A., Bartsch, H., Azémar, B., Mohr, U., Estève, J., and Castegnaro, M. (2002) MESNA protects rats against nephrotoxicity but not carcinogenicity induced by ochratoxin A, implicating two separate pathways. Facta Univ. Ser. Med. 9, 57−63. (217) Lin, P.-H., La, D. K., Upton, P. B., and Swenberg, J. A. (2002) Analysis of DNA adducts in rats exposed to pentachlorophenol. Carcinogenesis 23, 365−369. (218) Samokyszyn, V. M., Freeman, J. P., Maddipati, K. R., and Lloyd, R. V. (1995) Peroxidase-catalyzed oxidation of pentachlorophenol. Chem. Res. Toxicol. 8, 349−355. (219) Dai, J., Wright, M. W., and Manderville, R. A. (2003) An oxygen-bonded C8-deoxyguanosine nucleoside adduct of pentachlorophenol by peroxidase activation: evidence for ambident C8 reactivity by phenoxyl radicals. Chem. Res. Toxicol. 16, 817−821. (220) Dai, J., Sloat, A. L., Wright, M. W., and Manderville, R. A. (2005) Role of phenoxyl radicals in DNA adduction by chlorophenol xenobiotics following peroxidase activation. Chem. Res. Toxicol. 18, 771−779. (221) Lawson, T., Gannett, P. M., Yau, W.-M., Dalal, N. S., and Toth, B. (1995) Different patterns of mutagenicity of arenediazonium ions in V79 cells and Salmonella typhimurium TA102: evidence for different mechanisms of action. J. Agric. Food Chem. 43, 2627−2635. (222) Hiramoto, K., Kaku, M., Sueyoshi, A., Fujise, M., and Kikugawa, K. (1995) DNA base and deoxyribose modification by the carboncentered radical generated from 4-(hydroxymethyl)benzenediazonium salt, a carcinogen in mushroom. Chem. Res. Toxicol. 8, 356−362. (223) Gannett, P. M., Powell, J. H., Rao, R., Shi, X., Lawson, T., Kolar, C., and Toth, B. (1999) C8-Arylguanine and C8-aryladenine formation in calf thymus DNA from arenediazonium ions. Chem. Res. Toxicol. 12, 297−304.

(224) Dai, J., Wright, M. W., and Manderville, R. A. (2003) Ochratoxin A forms a carbon-bonded C8-deoxyguanosine nucleoside adduct: implications for C8 reactivity by a phenolic radical. J. Am. Chem. Soc. 125, 3716−3717. (225) Il’ichev, Y. V., Perry, J. L., Manderville, R. A., Chignell, C. F., and Simon, J. D. (2001) The pH-dependent primary photoreactions of ochratoxin A. J. Phys. Chem. B 105, 11369−11376. (226) Manderville, R. A. (2009) Structural and biological impact of radical addition reactions with DNA nucleobases. Adv. Phys. Org. Chem. 43, 177−218. (227) Faucet, V., Pfohl-Leszkowicz, A., Dai, J., Castegnaro, M., and Manderville, R. A. (2004) Evidence for covalent DNA adduction by ochratoxin A following chronic exposure to rat and subacute exposure to pig. Chem. Res. Toxicol. 17, 1289−1296. (228) Manderville, R., and Pfohl-Leszkowicz, A. (2008) Bioactivation and DNA adduction as a rationale for ochratoxin A carcinogenesis. World Mycotoxin J. 1, 357−367. (229) Umemura, T., Sai-Kato, K., Takagi, A., Hasegawa, R., and Kurokawa, Y. (1996) Oxidative DNA damage and cell proliferation in the livers of B6C3F1 mice exposed to pentachlorophenol in their diet. Toxicol. Sci. 30, 285−289. (230) Morgan, D. P. (1989) Recognition and management of pesticide poisonings, DIANE Publishing. (231) Colosio, C., Maroni, M., Barcellini, W., Meroni, P., Alcini, D., Colombi, A., Cavallo, D., and Foa, V. (1993) Toxicological and immune findings in workers exposed to pentachlorophenol (PCP). Arch. Environ. Health 48, 81−88. (232) Wilson, N. K., Chuang, J. C., Morgan, M. K., Lordo, R. A., and Sheldon, L. S. (2007) An observational study of the potential exposures of preschool children to pentachlorophenol, bisphenol A, and nonylphenol at home and daycare. Environ. Res. 103, 9−20. (233) Thompson, T. S., and Treble, R. G. (1994) Preliminary results of a survey of pentachlorophenol levels in human urine. Bull. Environ. Contam. Toxicol. 53, 274−279. (234) Carrizo, D., Grimalt, J. O., Ribas-Fito, N., Torrent, M., and Sunyer, J. (2008) Pentachlorobenzene, hexachlorobenzene, and pentachlorophenol in children’s serum from industrial and rural populations after restricted use. Ecotoxicol. Environ. Saf. 71, 260−266. (235) Daniel, V., Huber, W., Bauer, K., Suesal, C., Mytilineos, J., Melk, A., Conradt, C., and Opelz, G. (2001) Association of elevated blood levels of pentachlorophenol (PCP) with cellular and humoral immunodeficiencies. Arch. Environ. Health 56, 77−83. (236) Uhl, S., Schmid, P., and Schlatter, C. (1986) Pharmacokinetics of pentachlorophenol in man. Arch. Toxicol. 58, 182−186. (237) Triebig, G., Krekeler, H., Gossler, K., and Valentin, H. (1980) Investigations on neurotoxicity of chemical substances at the workplace. II. Determination of the motor and sensory nerve conduction velocity in persons occupationally exposed to pentachlorophenol (author’s transl). Int. Arch. Occup. Environ. Health 48, 357− 367. (238) Wang, Y. J., Ho, Y. S., Jeng, J. H., Su, H. J., and Lee, C. C. (2000) Different cell death mechanisms and gene expression in human cells induced by pentachlorophenol and its major metabolite, tetrachlorohydroquinone. Chem.-Biol. Interact. 128, 173−188. (239) O’Donoghue, J. L. (1985) Neurotoxicity of industrial and commercial chemicals, CRC Press, Boca Raton, FL. (240) Dorsey, W. C., Tchounwou, P. B., and Ford, B. D. (2006) Neuregulin 1-beta cytoprotective role in AML 12 mouse hepatocytes exposed to pentachlorophenol. Int. J. Environ. Res. Public Health 3, 11− 22. (241) Lin, P. H., Waidyanatha, S., Pollack, G. M., and Rappaport, S. M. (1997) Dosimetry of chlorinated quinone metabolites of pentachlorophenol in the livers of rats and mice based upon measurement of protein adducts. Toxicol. Appl. Pharmacol. 145, 399−408. (242) Tsai, C.-H., Lin, P.-H., Waidyanatha, S., and Rappaport, S. M. (2001) Characterization of metabolic activation of pentachlorophenol to quinones and semiquinones in rodent liver. Chem.-Biol. Interact. 134, 55−71. 31



Review

carcinogenic o-anisidine and its binding to DNA. Mutat. Res., Fundam. Mol. Mech. Mutagen. 500, 49−66. (261) Tan, S., Sagara, Y., Liu, Y., Maher, P., and Schubert, D. (1998) The regulation of reactive oxygen species production during programmed cell death. J. Cell Biol. 141, 1423−1432. (262) Jeff Slepin, M. (1984) Acetaminophen overdose in young children. J. Emerg. Med. 2, 148−149. (263) Churchill, F. C., Patchen, L. C., Campbell, C. C., Schwartz, I. K., Nguyen-Dinh, P., and Dickinson, C. M. (1985) Amodiaquine as a prodrug: importance of metabolite(s) in the antimalarial effect of amodiaquine in humans. Life Sci. 36, 53−62. (264) O’Neill, P. M., Harrison, A. C., Storr, R. C., Hawley, S. R., Ward, S. A., and Park, B. K. (1994) The effect of fluorine substitution on the metabolism and antimalarial activity of amodiaquine. J. Med. Chem. 37, 1362−1370. (265) O’Neill, P. M., Shone, A. E., Stanford, D., Nixon, G., Asadollahy, E., Park, B. K., Maggs, J. L., Roberts, P., Stocks, P. A., Biagini, G., Bray, P. G., Davies, J., Berry, N., Hall, C., Rimmer, K., Winstanley, P. A., Hindley, S., Bambal, R. B., Davis, C. B., Bates, M., Gresham, S. L., Brigandi, R. A., Gomez-de-Las-Heras, F. M., Gargallo, D. V., Parapini, S., Vivas, L., Lander, H., Taramelli, D., and Ward, S. A. (2009) Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4’-fluoro and 4’-chloro analogues of amodiaquine. Identification of a suitable “back-up” compound for N-tert-butyl isoquine. J. Med. Chem. 52, 1828−1844. (266) Spraggs, C. F., Budde, L. R., Briley, L. P., Bing, N., Cox, C. J., King, K. S., Whittaker, J. C., Mooser, V. E., Preston, A. J., Stein, S. H., and Cardon, L. R. (2011) HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J. Clin. Oncol. 29, 667−673. (267) Lertratanangkoon, K., and Horning, M. G. (1982) Metabolism of carbamazepine. Drug Metab. Dispos. 10, 1−10. (268) Maggs, J. L., Pirmohamed, M., Kitteringham, N. R., and Park, B. K. (1997) Characterization of the metabolites of carbamazepine in patient urine by liquid chromatography/mass spectrometry. Drug Metab. Dispos. 25, 275−280. (269) Pirmohamed, M., Kitteringham, N. R., Guenthner, T. M., Breckenridge, A. M., and Park, B. K. (1992) An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem. Pharmacol. 43, 1675−1682. (270) Spielberg, S. P., Gordon, G. B., Blake, D. A., Mellits, E. D., and Bross, D. S. (1981) Anticonvulsant toxicity in vitro: possible role of arene oxides. J. Pharmacol. Exp. Ther. 217, 386−389. (271) Pearce, R. E., Lu, W., Wang, Y., Uetrecht, J. P., Correia, M. A., and Leeder, J. S. (2008) Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine. Drug Metab. Dispos. 36, 1637−1649. (272) Leeder, J. S., Gaedigk, A., Lu, X., and Cook, V. A. (1996) Epitope mapping studies with human anti-cytochrome P450 3A antibodies. Mol. Pharmacol. 49, 234−243. (273) Paoletti, R., Corsini, A., and Bellosta, S. (2002) Pharmacological interactions of statins. Atheroscler. Suppl. 3, 35−40. (274) Fernandes, N. F., Martin, R. R., and Schenker, S. (2000) Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity. Am. J. Gastroenterol. 95, 532−535. (275) Zhou, H. H., and Wood, A. J. (1995) Stereoselective disposition of carvedilol is determined by CYP2D6. Clin. Pharmacol. Ther. 57, 518− 524. (276) Kemp, D. C., Fan, P. W., and Stevens, J. C. (2002) Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Drug Metab. Dispos. 30, 694−700. (277) Russo, J., and Russo, I. H. (2006) The role of estrogen in the initiation of breast cancer. J. Steroid Biochem. Mol. Biol. 102, 89−96. (278) Cavalieri, E. L., and Rogan, E. G. (2011) Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J. Steroid Biochem. Mol. Biol. 125, 169−180.

(243) den Besten, C., van Bladeren, P. J., Duizer, E., Vervoort, J., and Rietjens, I. M. (1993) Cytochrome P450-mediated oxidation of pentafluorophenol to tetrafluorobenzoquinone as the primary reaction product. Chem. Res. Toxicol. 6, 674−680. (244) Rietjens, I. M., den Besten, C., Hanzlik, R. P., and van Bladeren, P. J. (1997) Cytochrome P450-catalyzed oxidation of halobenzene derivatives. Chem. Res. Toxicol. 10, 629−635. (245) Lin, P. H., Waidyanatha, S., and Rappaport, S. M. (1996) Investigation of liver binding of pentachlorophenol based upon measurement of protein adducts. Biomarkers 1, 232−243. (246) Mangold, J. B., Gu, H., Rodriguez, L. C., Bonner, J., Dickson, J., and Rordorf, C. (2004) Pharmacokinetics and metabolism of lumiracoxib in healthy male subjects. Drug Metab. Dispos. 32, 566−571. (247) Jorga, K., Fotteler, B., Heizmann, P., and Gasser, R. (1999) Metabolism and excretion of tolcapone, a novel inhibitor of catechol-Omethyltransferase. Br. J. Clin. Pharmacol. 48, 513−520. (248) Martignoni, E., Cosentino, M., Ferrari, M., Porta, G., Mattarucchi, E., Marino, F., Lecchini, S., and Nappi, G. (2005) Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism. Neurology 65, 1820−1822. (249) Korlipara, L. V. P., Cooper, J. M., and Schapira, A. H. V. (2004) Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells. Neuropharmacology 46, 562−569. (250) Jensen, M. S., Rebordosa, C., Thulstrup, A. M., Toft, G., Sørensen, H. T., Bonde, J. P., Henriksen, T. B., and Olsen, J. (2010) Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology 21, 779− 785. (251) Kristensen, D. M., Hass, U., Lesné, L., Lottrup, G., Jacobsen, P. R., Desdoits-Lethimonier, C., Boberg, J., Petersen, J. H., Toppari, J., Jensen, T. K., Brunak, S., Skakkebaek, N. E., Nellemann, C., Main, K. M., Jégou, B., and Leffers, H. (2011) Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum. Reprod. 26, 235−244. (252) Isidori, M., Bellotta, M., Cangiano, M., and Parrella, A. (2009) Estrogenic activity of pharmaceuticals in the aquatic environment. Environ. Int. 35, 826−829. (253) Fent, K., Escher, C., and Caminada, D. (2006) Estrogenic activity of pharmaceuticals and pharmaceutical mixtures in a yeast reporter gene system. Reprod. Toxicol. 22, 175−185. (254) Kristensen, D. M., Lesné, L., Le Fol, V., Desdoits-Lethimonier, C., Dejucq-Rainsford, N., Leffers, H., and Jégou, B. (2012) Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis. Int. J. Androl. 35, 377−384. (255) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans and International Agency for Research on Cancer. (1999) Some chemicals that cause tumours of the kidney or urinary bladder in rodents and some other substances, International Agency for Research on Cancer. (256) Court, M. H., Duan, S. X., von Moltke, L. L., Greenblatt, D. J., Patten, C. J., Miners, J. O., and Mackenzie, P. I. (2001) Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J. Pharmacol. Exp. Ther. 299, 998−1006. (257) Mutlib, A. E., Goosen, T. C., Bauman, J. N., Williams, J. A., Kulkarni, S., and Kostrubsky, S. (2006) Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem. Res. Toxicol. 19, 701−709. (258) Patten, C. J., Thomas, P. E., Guy, R. L., Lee, M., Gonzalez, F. J., Guengerich, F. P., and Yang, C. S. (1993) Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem. Res. Toxicol. 6, 511−518. (259) Lee, S. S. T., Buters, J. T. M., Pineau, T., Fernandez-Salguero, P., and Gonzalez, F. J. (1996) Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem. 271, 12063−12067. (260) Stiborová, M., Mikšanová, M., Havlíček, V., Schmeiser, H. H., and Frei, E. (2002) Mechanism of peroxidase-mediated oxidation of 32



Review

(279) Ptak, A., and Gregoraszczuk, E. L. (2013) Oestrogens, xenoestrogens and hormone-dependent cancers. In Carcinogenesis (Tonissen, K., Ed.) pp 63−86, InTech. (280) Kitamura, S., Suzuki, T., Sanoh, S., Kohta, R., Jinno, N., Sugihara, K., Yoshihara, S., Fujimoto, N., Watanabe, H., and Ohta, S. (2005) Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related compounds. Toxicol. Sci. 84, 249−259. (281) Xin, F., Jiang, L., Liu, X., Geng, C., Wang, W., Zhong, L., Yang, G., and Chen, M. (2014) Bisphenol A induces oxidative stressassociated DNA damage in INS-1 cells. Mutat. Res., Genet. Toxicol. Environ. Mutagen. 769, 29−33. (282) Brotons, J. A., Olea-Serrano, M. F., Villalobos, M., Pedraza, V., and Olea, N. (1995) Xenoestrogens released from lacquer coatings in food cans. Environ. Health Perspect. 103, 608−612. (283) Hashimoto, Y., Moriguchi, Y., Oshima, H., Kawaguchi, M., Miyazaki, K., and Nakamura, M. (2001) Measurement of estrogenic activity of chemicals for the development of new dental polymers. Toxicol. In Vitro 15, 421−425. (284) Olea, N., Pulgar, R., Pérez, P., Olea-Serrano, F., Rivas, A., Novillo-Fertrell, A., Pedraza, V., Soto, A. M., and Sonnenschein, C. (1996) Estrogenicity of resin-based composites and sealants used in dentistry. Environ. Health Perspect. 104, 298−305. (285) Kabuto, H., Amakawa, M., and Shishibori, T. (2004) Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci. 74, 2931−2940. (286) Yang, Y. J., Hong, Y.-C., Oh, S.-Y., Park, M.-S., Kim, H., Leem, J.-H., and Ha, E.-H. (2009) Bisphenol A exposure is associated with oxidative stress and inflammation in postmenopausal women. Environ. Res. 109, 797−801. (287) Chitra, K. (2003) Induction of oxidative stress by bisphenol A in the epididymal sperm of rats. Toxicology 185, 119−127. (288) Obata, T., Kinemuchi, H., and Aomine, M. (2002) Protective effect of diltiazem, a L-type calcium channel antagonist, on bisphenol Aenhanced hydroxyl radical generation by 1-methyl-4-phenylpyridinium ion in rat striatum. Neurosci. Lett. 334, 211−213. (289) Benachour, N., and Aris, A. (2009) Toxic effects of low doses of bisphenol A on human placental cells. Toxicol. Appl. Pharmacol. 241, 322−328. (290) Domoradzki, J. Y., Thornton, C. M., Pottenger, L. H., Hansen, S. C., Card, T. L., Markham, D. A., Dryzga, M. D., Shiotsuka, R. N., and Waechter, J. M. (2004) Age and dose dependency of the pharmacokinetics and metabolism of bisphenol A in neonatal sprague-dawley rats following oral administration. Toxicol. Sci. 77, 230−242. (291) Snyder, R. W., Maness, S. C., Gaido, K. W., Welsch, F., Sumner, S. C., and Fennell, T. R. (2000) Metabolism and disposition of bisphenol A in female rats. Toxicol. Appl. Pharmacol. 168, 225−234. (292) Völkel, W., Colnot, T., Csanády, G. A., Filser, J. G., and Dekant, W. (2002) Metabolism and kinetics of bisphenol A in humans at low doses following oral administration. Chem. Res. Toxicol. 15, 1281−1287. (293) Domoradzki, J. Y. (2003) Metabolism and pharmacokinetics of bisphenol A (BPA) and the embryo-fetal distribution of BPA and BPAmonoglucuronide in CD Sprague-Dawley rats at three gestational stages. Toxicol. Sci. 76, 21−34. (294) Pritchett, J. J., Kuester, R. K., and Sipes, I. G. (2002) Metabolism of bisphenol A in primary cultured hepatocytes from mice, rats, and humans. Drug Metab. Dispos. 30, 1180−1185. (295) Hayashi, O., Kameshiro, M., Masuda, M., and Satoh, K. (2008) Bioaccumulation and metabolism of [14C]bisphenol A in the brackish water bivalve Corbicula japonica. Biosci., Biotechnol., Biochem. 72, 3219−3224. (296) Fini, J.-B., Dolo, L., Cravedi, J.-P., Demeneix, B., and Zalko, D. (2009) Metabolism of the endocrine disruptor BPA by Xenopus laevis Tadpoles. Ann. N. Y. Acad. Sci. 1163, 394−397. (297) Yoshida, M., Ono, H., Mori, Y., Chuda, Y., and Mori, M. (2002) Oxygenation of bisphenol A to quinones by polyphenol oxidase in vegetables. J. Agric. Food Chem. 50, 4377−4381.

(298) Yoshida, M., Ono, H., Mori, Y., Chuda, Y., and Onishi, K. (2001) Oxidation of bisphenol A and related compounds. Biosci., Biotechnol., Biochem. 65, 1444−1446. (299) Stokes, A. H., Hastings, T. G., and Vrana, K. E. (1999) Cytotoxic and genotoxic potential of dopamine. J. Neurosci. Res. 55, 659−665. (300) Halliwell, B. (1992) Reactive oxygen species and the central nervous system. J. Neurochem. 59, 1609−1623. (301) Donaldson, J., McGregor, D., and LaBella, F. (1982) Manganese neurotoxicity: a model for free radical mediated neurodegeneration? Can. J. Physiol. Pharmacol. 60, 1398−1405. (302) Halliwell, B., and Gutteridge, J. M. (1984) Oxygen toxicity, oxygen radicals. Biochem. J. 219, 1−14. (303) Wick, M., Byers, L., and Frei, E. (1977) L-dopa: selective toxicity for melanoma cells in vitro. Science 197, 468−469. (304) Graham, D. G. (1978) Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol. Pharmacol. 14, 633−643. (305) Hastings, T. G. (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J. Neurochem. 64, 919−924. (306) Napolitano, A., Crescenzi, O., Pezzella, A., and Prota, G. (1995) Generation of the neurotoxin 6-hydroxydopamine by peroxidase/ H2O2 oxidation of dopamine. J. Med. Chem. 38, 917−922. (307) Stokes, A. H., Brown, B. G., Lee, C. K., Doolittle, D. J., and Vrana, K. E. (1996) Tyrosinase enhances the covalent modification of DNA by dopamine. Mol. Brain Res. 42, 167−170. (308) Weiss, R. B. (1992) The anthracyclines: will we ever find a better doxorubicin? Semin. Oncol. 19, 670−686. (309) Long, B. H., Musial, S. T., and Brattain, M. G. (1984) Comparison of cytotoxicity and DNA breakage activity of congeners of podophyllotoxin including VP16−213 and VM26: a quantitative structure-activity relationship. Biochemistry 23, 1183−1188. (310) Nitiss, J. L. (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer 9, 338−350. (311) Sinha, B. K., and Mason, R. P. (2015) Is metabolic activation of topoisomerase II poisons important in the mechanism of cytotoxicity? J. Drug Metab. Toxicol. 6, 186. (312) Bachur, N. R., Gordon, S. L., Gee, M. V., and Kon, H. (1979) NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc. Natl. Acad. Sci. U. S. A. 76, 954−957. (313) Sato, S., Iwaizumi, M., Handa, K., and Tamura, Y. (1977) Electron spin resonance study on the mode of generation of free radicals of daunomycin, adriamycin, and carboquone in NAD(P)Hmicrosome system. Gan 68, 603−608. (314) Kalyanaraman, B., Nemec, J., and Sinha, B. K. (1989) Characterization of free radicals produced during oxidation of etoposide (VP-16) and its catechol and quinone derivatives. An ESR study. Biochemistry 28, 4839−4846. (315) Sinha, B. K., Katki, A. G., Batist, G., Cowan, K. H., and Myers, C. E. (1987) Adriamycin-stimulated hydroxyl radical formation in human breast tumor cells. Biochem. Pharmacol. 36, 793−796. (316) Sinha, B. K., Katki, A. G., Batist, G., Cowan, K. H., and Myers, C. E. (1987) Differential formation of hydroxyl radicals by adriamycin in sensitive and resistant MCF-7 human breast tumor cells: implications for the mechanism of action. Biochemistry 26, 3776−3781. (317) Sinha, B. K., and Chignell, C. F. (1979) Binding mode of chemically activated semiquinone free radicals from quinone anticancer agents to DNA. Chem.-Biol. Interact. 28, 301−308. (318) Sinha, B. K. (1980) Binding specificity of chemically and enzymatically activated anthracycline anticancer agents to nucleic acids. Chem.-Biol. Interact. 30, 67−77. (319) Sinha, B. K., and Sik, R. H. (1980) Binding of [14C]-adriamycin to cellular macromolecules in vivo. Biochem. Pharmacol. 29, 1867− 1868. (320) Sinha, B. K., Trush, M. A., Kennedy, K. A., and Mimnaugh, E. G. (1984) Enzymatic activation and binding of adriamycin to nuclear DNA. Cancer Res. 44, 2892−2896. (321) Cullinane, C., and Phillips, D. R. (1990) Induction of stable transcriptional blockage sites by adriamycin: GpC specificity of 33



Review

apparent adriamycin-DNA adducts and dependence on iron(III) ions. Biochemistry 29, 5638−5646. (322) Cullinane, C., van Rosmalen, A., and Phillips, D. R. (1994) Does adriamycin induce interstrand cross-links in DNA? Biochemistry 33, 4632−4638. (323) Cullinane, C. (2000) Interstrand cross-linking by adriamycin in nuclear and mitochondrial DNA of MCF-7 cells. Nucleic Acids Res. 28, 1019−1025. (324) Cutts, S., Nudelman, A., Rephaeli, A., and Phillips, D. (2005) The power and potential of doxorubicin-DNA adducts. IUBMB Life 57, 73−81. (325) van Rosmalen, A., Cullinane, C., Cutts, S. M., and Phillips, D. R. (1995) Stability of adriamycin-induced DNA adducts and interstrand crosslinks. Nucleic Acids Res. 23, 42−50.

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Chemicals and Drugs Forming Reactive Quinone and Quinone Imine

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