Chemicals and Drugs Forming Reactive Quinone and Quinone Imine

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Chemicals and Drugs Forming Reactive Quinone and Quinone Imine Metabolites Ivana Klop#i#, and Marija Sollner Dolenc Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00213 • Publication Date (Web): 30 Nov 2018 Downloaded from http://pubs.acs.org on December 1, 2018

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Chemical Research in Toxicology

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Chemicals and Drugs Forming Reactive Quinone and Quinone Imine Metabolites

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University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia

Ivana Klopčič and Marija Sollner Dolenc*

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ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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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: e.g. 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 and/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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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, i.e. 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 has to 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.10-13

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Figure 1. Metabolic fate of xenobiotics in mammals.1 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

Figure 2. 1: p-Benzoquinone. 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, inducing toxicity. They can be responsible for effects in vivo, including immunotoxicity, 5



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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. Being Michael acceptors they can alkylate proteins and/or DNA, thereby being responsible for damaging cells. Thus, they can react with sulphur 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 ageing 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

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

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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, that 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 peroxide-derived malondialdehyde DNA adducts.24 DNA is highly susceptible to damage by free radicals such as HO• since HO• very effectively attacks susceptible purines, generating 8-hydroxydeoxyguanosine (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 represent the involvement of these metabolites in the toxicity of a variety of selected chemicals and drugs.

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 toxicity (Table 1). In addition, not all RM-free compounds have guaranteed safety. Further, it is also well known that rare life-threatening 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. Table 1. Chemicals and drugs, their source, toxicity and the nature of the reactive intermediates. Chemical Source Toxicity Reactive Intermediate Solvent. Human Catechol, epoxide, Present in cigarette environmental hydroquinone, o smoke and car carcinogen. and pBenzene 19,25 30,32,33 exhaust. Produces bone benzoquinone. marrow damage in humans.26-28 Binds to proteins, 7



Solvent.

Naphthalene

α-tocopherol analogue.

3,4‐dihydro‐6‐hydroxy‐2,2‐ dimethyl‐7‐methoxy‐1‐(2H)‐ benzopyran (CR‐6)

Ochratoxin A

Pentachlorophenol

DNA.29,30 Mechanism based inactivation of P450.31 GSH depletion and covalent binding to macromolecule s.34,35 Mechanism based inactivator of P450.36

Mycotoxin. Present Kidney toxicant in moldy cereals, in rodents.40 38,39 oats and beans. Possible carcinogen in humans (group B).41 Oxidative DNA, lipid and protein damage. Biocide. Liver toxicant Present in indoor in rodents.49,50 and outdoor air Endocrine pollution, food discruption and 47,48 chain. probable carcinogen in humans.51-57 Form macromolecule adducts, produce lipid peroxidation and DNA damage.42,58-62

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Quinone.35

Benzoquinone, hydroquinone, catechol, o-quinone and protein-thiol reactive metabolites.37 Tetrachlorobenzoquiquinone none.42-44,

OTQ, hydroquinone (OTHQ).45,46

Tetrachlorohydroqui none (Cl4HQ), tetrachlorocatechol (Cl4CAT)63, tetrachloro-1,4benzosemiquinone (Cl4-1,4-SQ) tetrachloro-1,2benzosemiquinone (Cl4-1,2-SQ), tetrachloro-1,4benzoquinone (Cl41,4-BQ) and tetrachloro-1,2benzoquinone (Cl41,2-BQ).42,58

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Pharmaceutical.

Liver toxicant Quinone imine.65 in humans.64 Binds to proteins and produces GSHdepletion.

Pharmaceutical.

Liver toxicant Benzoquinone in humans.66 imine.67,68

Pharmaceutical.

Liver toxicant O-quinone in humans.69 quinone imine.

Pharmaceutical.

Hepatotoxic, potentially genotoxic (group 3). Binds to proteins, GSH and DNA.70 Immunemediated toxicant in 71 humans. Binds to proteins and produces GSH depletion.72,73 Immunemediated toxicant, produces liver and kidney toxicity and hemolytic anemia.74

Lumiracoxib

Diclofenac

Tolcapone

Paracetamol

Pharmaceutical.

Amodiaquine

Pharmaceutical.

Nomifensine

or

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Quinone imine.70

Quinone imine.72,73

N-hydroxylamine intermediate, quinone imine.75


Pharmaceutical.

Lapatinib

Pharmaceutical.

Desatinib

Pharmaceutical.

Gefitinib

Pharmaceutical.

Erlotinib

Pharmaceutical.

Nefazodone

Pharmaceutical.

Liver toxicant in humans.76 Mechanism based on inactivation of P450.76 Induces inhibition of the bile salt export pump (BSEP).77 Liver toxicant in humans.78-80 Mechanism based inactivator of P450.78-80 Liver toxicant in humans.78-80 Mechanism based inactivator of P450.78-80 Exhibits BSEP inhibition.77 Liver toxicant in humans.78-80 Mechanism based inactivator of P450.78-80 Liver toxicant in humans.81,82 Mechanism based inactivator of P450.83 Mitochondrial toxicant and inhibitor of bile transport.84,85

Quinone imine.76

Produces hypersensitivity in humans.86

Epoxides,87,88 a quinone imine,89 and an ortho-quinone.90

Carbamazepine

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Quinone imine,78-80 imine-methide.78

Quinone imine.78-80

Quinone imine.78-80

Quinone imine and benzoquinone.81,82

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Pharmaceutical.

Responsible for Quinone imine.92 idiosyncratic drug toxicity 91 (IDT).

Pharmaceutical.

Not toxic to Quinone imine.82 humans at therapeutic dose.

Pharmaceutical.

Liver toxicity in Quinone imine94 and humans.93,94 epoxide.95

Pharmaceutical.

Not toxic humans therapeutic dose. Mechanism based inactivator P450.96 Not toxic humans therapeutic dose.98

in Catechol96 and at quinone.97

Not toxic humans therapeutic dose.

in Catechol and orthoat quinone.99

Atorvastatin

Aripiprazole

Trazodone

Paroxetine

Pharmaceutical.

Tadalafil

of in Catechol and orthoat quinone.98

Pharmaceutical.

Carvedilol

o-

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Pharmaceutical.

Mechanism based inactivator P450.100

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Raloxifene-6,7-oquinone.7,100,101 of

Raloxifene

Endogenous estrogen.

Estradiol

Forms DNA Quinone.102,103 adducts, produces carcinogenicity, cell transformation and mutagenicity.10 2,103

Quinone.105,106,108,109 Covalent a binding to DNA, in proteins.105,106. Oxidative stress in liver and tissues.104,107 or Neurotransmitter. Neurotoxicity.1 Quinone 10 110 semiquinone.

Bisphenol A

Dopamine

Environmental contaminant, monomer polycarbonate plastics.104

Pharmaceutical.

Doxorubicin

242 243 244 245 246 247 248 249 250 251 252

Cardiotoxocty Semiquinone or 111 and pulmonary hydroquinone. toxicity.111,112 Cytotoxicity, mutagenicity and DNA damage.

1. Chemicals and toxins that form quinone reactive metabolites 1.1. 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 12


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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 1.1.1. Benzene-reactive metabolites Exposure to benzene occurs primarily via inhalation. After absorption, it is 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 1,2,4trihydroxybenzene.19 This process requires the participation of the specific isoform of P450P450 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

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 The hematotoxicity of benzene is mediated by its metabolites, such as phenol, catechol and hydroquinone. These are produced in liver121,127 and transported to the bone marrow128,129 where they are converted to biologically reactive intermediates such as p-benzoquinone by peroxidase-

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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 pbenzoquinone back to the p-hydroquinone, and to a large number of rapidly dividing cells, in which cell damage is readily manifested. Further, bone marrow exhibits much lower levels of glutathione that is involved in xenobiotic protection.19,133 Reactive species are catechol, hydroquinone (HQ), and benzoquinone (BQ). Their toxicity is a result of either direct interaction with proteins (e.g. P450) and DNA, 30,32,33 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 reacts 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 iron-catalyzed 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 in order 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.138140 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 sulphated for cell excretion. The alternative way to remove BQ 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 hydroquinone-induced 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 demonstrate 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

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its toxicity, since it was ineffective in preliminary studies. 1,2,4-benzenetriol 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. 1.2. 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 non-redox xenobiotic it can damage marine organisms and freshwater fish by producing ROS.151-153 NAP is genotoxic, and is an endocrine disruptor for fish154-156, 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, aluminium 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 1.2.1. 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,2R-epoxide (13, Figure 5).161,162 Epoxides can either be conjugated and excreted by kidneys or form 1-naphthol and 2naphthol (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-keto-reductase (AKR)). Further, 1,2-naphthalenediol (21, Figure 5) can be metabolized to form 1,2-naphthoquinone (22, Figure 5) or the glucuronide/sulphate conjugate (23, Figure 5). The third metabolic pathway for the dihydrodiol (20, Figure 5) is glucuronic acid/sulphate 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).

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Figure 5. The main pathways and metabolites of naphthalene in mammals. 13: Naphthalene-1,2epoxide; 14: 1-naphthol; 15: 2-naphthol; 16: 1-naphthylglucuronide/sulphate; 17: 2naphthylglucuronide/sulphate; 18: 1,4-dihydroxynaphthalene; 19: 1,4-naphthoquinone; 20: trans1,2-dihydro-1,2-dihydroxynaphthalene; 21: 1,2-dihydroxynaphthalene; 22: 1,2-naphthoquinone; 23: 2-hydroxynaphthyl-1-glucuronide/sulphate; 24: trans-1,2-dihydro-2-hydroxynaphthyl-1glucuronide/sulphate; 25: naphthylmercapuric acids. UGT/ST: UDPglucuronyltransferase/sulphotransferase; GSH: glutathione-SH; R1: glucuronic acid/sulphate residue; R2: N-acetyl-L-cysteine residue, EH: epoxide hydrolase, AKR: aldo-keto-reductase.157 Reactive species (naphthoquinones) that are involved in naphthalene toxicity, could lead to increased production of ROS, such as superoxide anion and hydroxyl radical16,160,169-171, depleting glutathione and resulting in the formation of oxidative stress or in increased covalent adduct formation with proteins and DNA bases.172-176 1.3. CR-6 The 3,4-dihydro-6-hydroxy-2,2-dimethyl-7-methoxy-1-(2H)-benzopyran is a free radical scavenger and α-tocopherol 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 5nitroderivative and 1,4-benzoquinone.178 On oral administration, antioxidant CR-6 reaches the rat brain tissue and, after transient ischemia, protects the brain from re-perfusion 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 16


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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 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 1.3.1. 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 non-enzymatically promoted cyclization to give the spiro compound (27b, Fgure 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, 27abenzoquinone, 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 de-alkylation. The formation of the corresponding o-quinone derivative has also been identified, by HPLC (31, Figure 6).37

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Figure 6. P 450 mediated metabolic activation of CR-6. 26: CR-6 (3,4-dihydro-6-hydroxy-2,2dimethyl-7-methoxy-1-(2H)-benzopyran), 27a: 2-(3’-hydroxy-3’-methylbutyl-5-methoxy-1,4benzoquinone, 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-dimethyl1(2H)-benzopyran-6,7-dione.37 CR-6 antioxidant is an inhibitor of P450 isoenzyme activity. It showed inhibition of the 7ethoxyresorufin 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. 1.4. Ochratoxin A Ochratoxin A (OTA) - (N-{[(3R)-5-chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl] carbonyl}-3-phenyl-L-alanine) is a mycotoxine produced by some 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

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There is evidence that in rodents it causes kidney tumor.40 For human 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 1.4.1. Chemical structure of ochratoxins The chemical structures of ochratoxin A, B and C are shown below (32, Figure 7). Ochratoxin B is less toxic than ochratoxin A and does not inhibit protein biosynthesis in hepatoma cells.194 O

C

OR O

OH O O

N H

CH3 32

467 Ochratoxin A Ochratoxin B Ochratoxin C

468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490

X

X -Cl -H -Cl

R -H -H -CH2-CH3

Figure 7. 32: Ochratoxins. Ochratoxin A possesses a chlorine atom on C5 of the dihydro-methyl-isocoumarin ring system, 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 is consists ofphenylalanine 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 1.4.2. 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 formamidopyrimidine-DNA-glycosylase (Fpg).200-206 Furthermore, OTA exposure is a source of both ROS and RNS,199 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

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cell lines.204 The second mechanism of indirect genotoxicity is disruption of mitosis for OTAmediated 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 1.4.3. 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 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

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 20


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Furthermore, OTA, in the presence of P450, generates the electrophilic quinone OTQ that reacts covalently with GSH to form the GSH conjugate (oxidative de-chlorination). The formed metabolite (OTQ) reacts with reducing agent (e.g. ascorbate) and it is reduced to hydroquinone N-{[(3R, S)-5,8-dihydroxy-3-methyl-1-oxo-3,4 dihydro-1H-isochromen-7-yl] carbonyl}-Lphenylalanine (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 Based on 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. 1.4.4. 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 know that photolysis of OTA generates the phenolic radical225 that reacts at the C8 site of dG (Figure 9).226, 227

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 confirmed that OTA acts as a classical genotoxic carcinogen by bioactivation and covalent DNA addition.

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1.5. 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 1.5.1. 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-1,4benzosemiquinone (Cl4-1,4-SQ) and tetrachloro-1,2-benzosemiquinone (Cl4-1,2-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 pathway 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

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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: Cl4-1,2BQ.242 As 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 metalindependent 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.

2. Drugs that form quinone imine reactive metabolites 2.1. 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

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Figure 11. Structure of 49: 2-[(2-fluoro-6-chlorophenyl) amino]-5-methyl-benzene acetic acid. In humans, it is metabolized primarly via P450 enzymes.246 The major circulating metabolite of lumiracoxib in human is 4-hydroxylumiracoxib.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.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

Figure 12. Bioactivation of lumiracoxib in humans. Hydroxylumiracoxib; 52: Quinone imine; 53: GSH.64

50:

Lumiracoxib;

51:

4-

Structurally, lumiracoxib is related to diclofenac (54, Figure 13), the only differences being a methyl substituent on the 5-position and replacement of the dichloroaniline moiety of diclofenac by a fluorochloroaniline ring system (49, Figure 11).65

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Figure 13. Structure of 54: Diclofenac. 2.2. 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 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 informationthat oxidative bioactivation of diclofenac in humans proceeds via bezoquinone imine intermediates (55, Figure 14).

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Figure 14. Sheme for the P450-mediated bioactivation of diclofenac to quinone imines. 55: Diclofenac; 56: 4-Hydroxydiclofenac; 57: 5-Hydroxydiclofenac; 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 2.3. 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 26


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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

Figure 15. Metabolism of tolcapone in humans. 64: Tolcapone; 65: 3-O-β, D-glucuronide; 66: Amine derivative; 67: Quinone-imine; 68: Amine glucuronide; 69: Amine sulphate; 70: Quinone-imine; 71: Primary alcohol metabolite; 72: Carboxylic acid; 73: 3-Omethyltolcapone.247 2.4. Paracetamol

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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 N-acetyl-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 electrophilic intermediate (NAPQI).261 QIs react, by a 1,4-Michael addition, with nucleophiles such as reduced GSH, protein thiols and nucleic bases.70

Figure 16. Paracetamol bioactivation to reactive species (quinone imine). 74: Paracetamol, 75: Paracetamol-o-glucironide, 76: Paracetamol sulphate, 77: N-acetyl-p-quinone imine (NAPQI), 78: Paracetamol 3-glutathione.262 2.5. 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 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

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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 Furthermore, interchanging the 3- and 4-substituents in amodiaquine would lead to analogues 81, 82 and 83, (Figure 17) that 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 2.6. 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 and/or autoantibodies directed against the drug and/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 N-hydroxylamines 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 this 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

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Figure 18. Bioactivation of the nomifensine; 84: Nomifensine; 85: Nomifensine nitrosoamine; 86: Quinone imine. 2.7. Tyrosine kinase inhibitors 2.7.1. 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 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 Odealkylated 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

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Figure 19. The formation of reactive metabolites by P450 3A4. 87: Lapatinib; 88: O-dealkylated lapatinib; 89: Quinone imine; 90: LAPA-G1; 91: LAPA-G2.76 2.7.2. 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.7880 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 quinine-imine intermediate (96 and 98, Figure 20).79,80 Dasatinib inactivation proceeds through hydroxylation at the para-position of the 2chloro-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

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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. 2.8. 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 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 phydroxynefazodone, a major circulating metabolite, para-hydroxyaniline analog and wellestablished 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

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P450 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

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

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2.9. 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 Thirtytwo 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 N-glucuronidation with formation of the active carbamazepine-10,11-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 2,3arene oxidation, including epoxides (carbamazepine-2,3-epoxide and carbamazepine-10,11epoxide),87,88 a quinone imine metabolite derived from metabolism of major metabolite 2hydroxycarbamazepine,89 and an ortho-quinone metabolite that is formed from catechol 2,3dihydroxy 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

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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: oQuinone.90 2.10. Atorvastatin Atorvastatin is the 3-hydroxy-3-methylglutaryl 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 bio-activation pathway is P450 3A4-mediated monohydroxylation on the acetanilide structural alert with formation of the ortho- and para-hydroxyacetanilide 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. 2.11. Aripiprazole 35



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Since its introduction in 2003, aripiprazole has been used as an atypical antipsychotic. As with nefazodone, P450-mediated metabolism on the 2,3-dichlorophenyl 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 10 to 30-fold lower (520 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).

Figure 24. Reactive metabolites of antipsychotic drug aripiprazole in HLM. 115: Aripiprazole; 116: Quinone imine; 117: Quinone imine. 2.12. Trazodone Trazodone has been in use as a second-generation non-tricyclic 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 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 para-hydroxy-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, 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 36


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dihydrodiol metabolite of trazodone in human urine.95 Trazodone can thus form stable dihydrodiol or/and 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 above-described reactive metabolites.85

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

3. Presence of methylene dioxyphenyl functional group in chemical: structural alert or not for forming quinones? 3.1. 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 37



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(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 oquinone 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

Figure 26. Bioactivation/Detoxication pathways of paroxetine in human hepatic tissue. 124: Paroxetine; 125: Paroxetine-catechol; 126: o-Quinone; 127: Human metabolites of paroxetine. 3.2. Tadalafil The next example of drug which forms the benzoquinone metabolites and has also the 1,3benzidioxole 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 and/or DDIs in erectile dysfunction treatment.98 3.3. 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 38


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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. 3.4. 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 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

Figure 27. Oxidation of raloxifene to reactive species in human hepatic tissue. 128: Raloxifene; 129: 7-Hydroxyraloxifene; 130: Raloxifene-6,7-o-quinone; 131: Raloxifene di-quinone methide. (modif.101) 3.5. 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, and/or via expression of

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specific genes that normally control cell growth and proliferation.277,278 The International Agency 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 2hydroxyestradiol (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

Figure 28. Major metabolic pathways of the estradiol. 132: Estradiol, 133: Estrone, 134: 2Hydroxyestradiol, 135: Estradiol-2,3-semiquinone, 136: Estradiol-2,3-quinone, 137: 4Hydroxyestradiol, 138: Estradiol-3,4-semiquinone, 139: Estradiol-3,4-quinone. 17αHydroxysteroid dehydrogenase, 17α-HSD.279 3.6. 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 and/or produce oxidative stress (140, Figure 29).106 Exposure is also associated 40


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with inflammation and/or oxidative damage in brain, testes, kidney and sperm, and peroxidation 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 sulphate.290-296 The oxidized product of BPA is catechol analogue, which may act via semiquinone and/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

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 3.7. 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.

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Figure 30. Metabolic pathways of dopamine. 148: Dopamine, 149: Dopamine o-semiquinone, 150: Dopamine quinone, 151: 3,4-dihydroxyphenylacetic acid (DOPAC) which also forms quinones upon oxidation, MAO: Monoamine oxidase, DBH: Dopamine beta-hydroxylase, NE: Norepinephrine, PNMT: Phenylethanolamine N-methyltransferase, EPI: Epinephrine.299 3.8. Doxorubicin Doxorubicin, a clinically active anticancer drug for treating solid and hematological malignancies, is used for inhibition and/or interference with topoisomerase II. However, the use of doxorubicin is limited by its accumulation in the heart, primarily in mitochondria, and dosedependent 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.

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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

Conclusion and future directions All the presented chemicals and drugs exhibit their toxicity as a result of biooxidation. Most of them produce liver toxicity in humans; some were carcinogens while some presented drugs 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 to 30-fold lower than the daily dose of nefazodone. Secondly, 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, that usually leads in a less toxic metabolites. This explains why raloxifene is a safe drug despite the fact that it also undergoes P450 3A4-mediated

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oxidation forming stable alkylating reactive species (raloxifene 6,7-o-quinone). Thirdly, 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. In order 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.

Figure 32. Mechanism of action for quinones and quinone imines. It has been shown that quinones and quinone imines play roles in mediating the toxic effects of amino and/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, antiinflammatory, 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 activate signaling pathways, which include protein kinase C and RAS. DNA binding occurs, such as 44


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formation of 8-oxodeoxyguanosine, which has been associated with ageing 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. AUTHOR INFORMATION Corresponding Author * Tel.: +386-1-476-9572. Fax: +386-1-425-8031. E-mail address: [email protected]. Funding One of us (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. 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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2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031

Biographies: 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 last few years, she works on 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. 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.

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Chemicals and Drugs Forming Reactive Quinone and Quinone Imine

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