Effects of Food Phytochemicals on Xenobiotic Metabolism and

Chapter 2

Effects of Food Phytochemicals on Xenobiotic Metabolism and Tumorigenesis

Downloaded by STANFORD UNIV GREEN LIBR on June 8, 2012 | http://pubs.acs.org Publication Date: December 20, 1993 | doi: 10.1021/bk-1994-0546.ch002

Theresa J . Smith and Chung S. Yang Laboratory for Cancer Research, Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855-0789

Many food phytochemicals are known to affect the biotrans formation of xenobiotics, and may influence the toxicity and carcino genicity of environmental chemicals. In this article, some of the basic mechanisms of these actions are reviewed. Special attention is placed on studies with indoles, isothiocyanates, allium organosulfur compounds, flavonoids, phenolic acids, terpenoids, and psoralens. These compounds may alter the levels of phase I and phase II drugmetabolizing enzymes by affecting the transcriptional rates of their genes, the turnover rates of specific mRNAs or enzymes, or the enzyme activity by inhibitory or stimulatory actions. In many cases, the actions can be rather selective via their actions on specific enzymes, especially on the different forms of cytochrome P450 enzymes. The inhibitory actions of these phytochemicals against tumorigenesis have been studied extensively in animal models. The results help us to understand the possible beneficial or harmful effects of these compounds. Caution has to be applied when extrapolating the results to humans, however, because of species differences and the large doses used in animal studies.

The close relationship between food phytochemicals and xenobiotic metabolizing enzymes may be traced back to prehistoric days in "animal-plant warfare" during evolution (1). Plants synthesized chemicals for self-protection and animals had to develop xenobiotic-metabolizing enzymes such as cytochrome P450 (P450 ) for 1

1

Abbreviations used are: cytochrome P450, P450; indole-3-carbinol, I3C; aryl hydrocarbon hydroxylase, A H H ; ethoxyresorufin 0-deethylase, EROD; aromatic hydrocarbon receptor, Ah receptor; Λ^-nitrosodimethylamine, N D M A ; pentoxyresorufin 0-dealkylase, PROD; 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone, N N K ; benzo[a]pyrene, B[a]P; phenethyl isothiocyanate, PEITC; diallyl sulfide, D A S ; 7,12-dimethylbenz[a]anthracene, D M B A ; (-)-epigallocatechin-3-gallate, EGCG. 50097-6156/94/0546-0017$09.00/0 © 1994 American Chemical Society In Food Phytochemicals for Cancer Prevention I; Huang, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.

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FOOD PHYTOCHEMICALS I: FRUITS AND VEGETABLES

the detoxification of these chemicals. The evolution of the large number of P450 genes 400 million years ago may correspond to the advance of animals on to land where they encountered new terrestrial plants and phytochemicals. The work of many investigators in the past 30 years has clearly established that various dietary chemicals have marked effects on the metabolism of drugs, environmental chemicals, and certain endogenous substrates. In this review, the effects of food phytochemicals on phase I and phase II metabolism of xenobiotics and tumori genesis will be discussed.


Xenobiotic-metabolizing Enzymes The metabolism of xenobiotics are catalyzed by a number of enzymes. These xenobiotic-metabolizing enzymes are involved in phase I and phase II reactions (Figure 1). Phase I reactions include oxidation, hydroxylation, reduction, and hydrolysis, resulting in more water soluble metabolites to facilitate subsequent conjugation reactions and their excretion. The cytochrome P450-dependent monooxygenase, also known as mixed-function oxidase, is the most extensively studied phase I enzyme system responsible for the oxidative metabolism of a large number of xenobiotics. P450s are a large group of enzymes encoded by the superfamily of C Y P genes (2). In the monooxygenase system NADPH:P450 oxidoreductase transfers electrons from N A D P H to P450 forming ferro-cytochrome P450 which catalyzes the activation of molecular oxygen, and one of the oxygen atoms is added to the substrate (3) (Figure 1). Other phase I enzymes include: microsomal flavincontaining monooxygenase, cyclooxygenase, lipoxygenase, hydrolases, mono amine oxidases, dehydrogenases, aromatases, and reductases (3,4). The products of the phase I reactions are usually substrates for phase II enzymes (Figure 1), but some xenobiotics can be directly conjugated, bypassing phase I metabolism. Phase II enzymes are involved primarily in conjugating reactions such as glucuronidation, sulfation and glutathione conjugation (Figure 1). The conjugated drug can then be excreted. UDP-glucuronosyltransferase (glucuronyl transferase) catalyzes the transfer of glucuronic acid from UDP-glucuronic acid to the com pound, forming a glucuronide conjugate. Sulfotransferase catalyzes the sulfation of xenobiotics containing a hydroxyl or amino group using 3'-pnosphoadenosine-5'phosphosulfate (PAPS) as the sulfate donor (3,4). Glutathione 5-transferase catalyzes the conjugation of epoxides, alkyl and aryl halides, sulfates, and 1,4unsaturated carbonyl compounds with glutathione (3). Glutathione S-transferases have been isolated from many sources and exists in multiple forms (isoenzymes). Mammalian glutathione ^-transferase isoenzymes are grouped into three classes (a, μ, and π) based upon their substrate specificities, structural homologies and immunological cross-reactivities (5) and there are at least 7 subunits (6). Transmethylases catalyzes the methylation of compounds containing Ο-, and Ngroups using S-adenosyl-L-methionine as the methyl donor (3,4). NAD(P)H: quinone oxidoreductase, also known as DT-diaphorase, is a phase I enzyme by definition, but is considered a phase II enzyme by some authors (7,8). NAD(P)H: quinone oxidoreductase is involved in the detoxification of quinones through a twoelectron reduction. Although the phase I and phase II enzymes are believed to be evolved for the detoxification of xenobiotics, they are also known to be involved in the generation of reactive intermediates, which attack cellular macromolecules, leading to toxicity and carcinogenesis. The roles of P450 enzymes in the activation of a

In Food Phytochemicals for Cancer Prevention I; Huang, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.


2. SMITH AND YANG

Phase I

Xenobiotic Metabolism and Tumorigenesis

Phase II

Figure 1. Phase I and phase II reactions involved in xenobiotic metabolism.


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FOOD PHYTOCHEMICALS I: FRUITS AND VEGETABLES

variety of toxicants and carcinogens are well recognized (9,10). The roles for phase II enzymes in the detoxification of many xenobiotics have been illustrated. In certain cases, however, they may be involved in the activation of carcinogens or toxicants; for example, the activation of certain arylamines by sulfotransferase (77). In addition, conjugation may also be a means of transporting activated metabolites to different tissues where it could be reactivated into reactive metabolites (12). Glutathione, a cofactor required for the glutathione ^-transferase reaction is known to be involved in the activation of certain halogenated compounds (6,13-15).


Mechanisms by Which Food Phytochemicals Affect Xenobiotic Metabolism Many food phytochemicals can alter the levels of enzymes involved in the phase I and phase II reactions. These naturally occurring constituents or their metabolites can regulate certain specific P450s but not affect others. Dietary compounds may affect rates of P450 gene transcription and translation, as well as the degradation of P450 mRNA and protein (16). These compounds can also inactivate P450s by covalently binding to the P450 apoprotein or heme moiety leading to the inactivation of these enzymes. Some dietary constituents can bind directly to the P450, whereas others require metabolic activation by specific P450s to form reactive intermediates which can then attack the P450 molecules. Food phytochemicals can also bind reversibly to the active sites of P450s, serving as competitive inhibitors. Food phytochemicals can interact with NADPH:P450 oxidoreductase and alter the levels of the reductase. Since NADPH:P450 oxidoreductase is required to transfer electrons from N A D P H to P450, a decrease or increase in the reductase level can either impair or stimulate the flow of electrons to P450, thus leading to an alteration in monooxygenase activities. With xenobiotics that are metabolized by different competing pathways, food phytochemicals may selectively affect certain pathways and alter the physiological effects, such as the toxicity or carcinogenicity of these compounds. The phase II enzymes can also be induced by various food phytochemicals. In many cases, the dietary inducers contain electrophilic centers (or acquire them by cellular metabolism) which elicit an electrophilic chemical signal that activates the transcription of genes coding for phase II enzymes (17,18). A n induction in phase II enzymes can lead to increased conjugation reaction and faster excretion of the drugs or environmental chemicals. The rates of the phase II reactions are also affected by the availability of cellular glutathione, UDP-glucuronic acid and PAPS. A large number of food phytochemicals are known to affect xenobiotic metabolism. The effects of some of the most extensively studied chemicals, most of them dietary constituents, are summarized in Table I. The specific effects of these chemicals on xenobiotic metabolism and carcinogenesis are discussed in subsequent sections. Indoles Cruciferous vegetables, such as cabbage, broccoli, cauliflower and Brussels sprouts contain glucosinolates. It has been estimated that approximately 30 mg of glucosinolates are consumed daily per person from cruciferous vegetables in the United Kingdom (19). Indole-3-carbinol (I3C) is present in cruciferous vegetables in the form of 3-indolylmethyl glucosinolate (glucobrassicin) (20). The glucobrassicin intake is estimated to be 12.5 mg/person from fresh sources and 7



Ethoxyresorufin O-deethylase, aminopyrine N-demethylase and biphenyl 4-hydroxylase activities Metabolism of nifedipine, aflatoxin Βχ, and benzo[a]pyrene

A single arrow indicates a pretreatment effect; double arrows indicates an in vitro effect; triple arrows indicate both effects. Continued on next page

a

u

P450 2E1, 6-testosterone hydroxylase activity 74,78,80-82, I 84-89,91-92 4^4^ N D M A demethylase activity and metabolism of Af-nitrosobenzylmethylamine, Af-nitrosodiethylamine and N N K U p-nitrophenol hydroxylase activity and metabolism of aflatoxin B i P450 2B1, pentoxyresorufin O-dealkylase, ethoxyresorufin O-deethylase, 16a- and 16p-testosterone Î hydroxylase, glutathione S-transferase, glutathione peroxidase and glutathione reductase activities

Diallyl sulfide

Naringenin

P450 2E1, ethoxyresorufin O-deethylase, erythromycin A/-demethylase activities and metabolism of Af-nitrosonornicotine and iV-nitrosopyrrolidine N D M A demethylase, and metabolism of NNK, A^-nitrosobenzylmethylamine and N-nitrosomethylamylamine P450 2B1, pentoxyresorufin O-deethylase, glutathione 5-transferase, ΝAD(P)H:quinone oxidoreductase and UDP-glucuronyl transferase activities

I

Isothiocyanates

98,100-102

8,33,51,52, 56-64,68-71

P450s 1A1, 2B1, aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase, benzo[a]pyrene 24-34,37,39, oxidase, p-nitroanisole O-demethylase, aniline C-hydroxylase, pentoxyresorufin O-dealkylase, 40,46 testosterone 6α-, 16α- and Ιόβ-hydroxylase, estradiol 2-hydroxylase activities and demethylation of N N K and N D M A Ethoxyresorufin O-deethylase, NAD(P)H:quinone oxidoreductase and UDP-glucuronyl transferase activities

Indole-3-carbinol Τ

References

Xenobiotic Metabolism and Enzymes

Compound

3

Table I. Effects of Food Phytochemicals on Xenobiotic Metabolism



N A D P H cytochrome c reductase, ethoxyresorufin-O-deethylase, benzphetamine 7V-demethylase activities and N N K oc-hydroxylation 7V-hydroxylation and deacetylation of 2-acetylaminofluorene

N A D P H cytochrome c reductase, pentoxyresorufin O-dealkylase, ethoxyresorufin O-deethylase, p-nitrophenol hydroxylase, aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase activities and N N K metabolism

P450 and prostaglandin synthase Benzo[a]pyrene metabolism

Aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase activities Epoxide hydrolase activity and metabolism of benzo[a]pyrene Glutathione S-transferase and NAD(P)H:quinone oxidoreductase activities

ii

ii

ÎT ii

Hi

Catechin

Epicatechins

Isoflavone

Tannic acid

ii Î

tf

P450, pentoxyresorufin O-dealkylase, glutathione ^-transferase and UDP-glucuronyl transferase activities Î Î Î N A D P H cytochrome c reductase,ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase activities and zoxazolamine metabolism ÎÎ Metabolism of benzo[

Effects of Food Phytochemicals on Xenobiotic Metabolism and

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