Drug-Metabolizing Enzymes: Mechanisms and Functions - Toxicology

Current Drug Metabolism, 2000, 1, 107-132

107

Drug-Metabolizing Enzymes: Mechanisms and Functions Salah A. Sheweita* Department of Bioscience and Technology, Institute of Graduate Studies and Research, 163 Horreya Ave., PO Box 832, Alexandria University, Egypt Abstract: Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text.

1.

DRUG-METABOLIZING ENZYMES

Monooxygenase is involved in the oxidation of a wide range of substrates at the expense of molecular oxygen since one atom of the molecular oxygen enters the substrate and the other forms water, such a reaction being known as a monooxygenase or mixed-function oxidase reaction [1]. The main components of the mixed function oxidases (MFO) enzymes system are the cytochrome P-450 isoenzymes [2]. The name was given because the reduced form binds with carbon monoxide to give a complex with maximum absorption at 450 nm (3,4). Costas and Dennis in 1987, indicated that the cytochrome P-450 acts as the terminal oxygenases of the mixed-function oxidase systems of bacteria, yeast, plants, insects, fishes and other vertebrates. MFO catalyzes the *Address correspondence to this author at the Department of Bioscience and Technology, Institute of Graduate Studies and Research, 163 Horreya Ave., PO Box 832, Alexandria University, Egypt; Tel: No. 203-422-5007; Fax: 203-421-5792; E-mail: [email protected]

1389-2000/00 $25.00+.00

oxidation, and reduction of numerous endogenous and exogenous substances of widely diverse chemical structure [5]. In addition, they are also involved in the biosynthesis of cholesterol, steroid hormones, bile acids and the oxidative metabolism of fatty acids, lipophilic drugs and other chemical (6-8). Many forms of cytochrome P-450 have been isolated from both rodents and human tissues, and they have been classified into 17 families according to homologies of their amino acids sequences [9,10]. Another member of the hepatic monooxygenase system is NADPH-cytochrome P-450 reductase, which was firstly observed in whole liver by Horecker (1950) [11] and also in microsomes by Strittmater and Velic in 1956 [12]. The prosthetic group was identified as FAD (13-15). In addition to cytochrome P-450 and NADPH-cytochrome P450 reductase, the mixed-function oxidase contains also cytochrome b5 and NADHcytochrome b 5 reductase. The possible role of both

© 2000 Bentham Science Publishers Ltd.

108

Current Drug Metabolism, 2000, Vol. 1, No. 2

in the cytochrome P-450-dependent reactions is well known now than before (16-19]. 1.1 FACTORS ACTIVITY OF ENZYMES 1.1.1

AFFECTING THE DRUG-METABOLIZING

Organs

Lung Extrahepatic tissues have received relatively less attention than liver because of their low levels of mixed function oxidase activity [20]. The ethoxyresourfin O-deethylase (EROD) activity was lower in the lung than in the liver of rats [21]. Low levels of EROD activity were also detected in rabbit lung [22]. The lower EROD activity in lung compared to liver was confirmed using monoclonal antibodies against cytochrome P4501A1 [23]. Pulmonary levels of cytochrome P450 1A1 were found to be < 3% of the total microsomal cytochromes P-450 using the more sensitive Western blotting technique. EROD activity was induced after pretreatment of rats with 3-methylcholanthrene (MC) and 7,12-dimethylbenz(a)anthracene, and to a lesser extent by βnaphtoflavone (β-NF) [24-26]. A major form of pulmonary cytochrome P-450, different from the hepatic proteins, has been purified from rats after MC treatment, which catalyzed the oxidation of benzo (a) pyrene to various phenols, diols, and quinines [27,28]. Similarly, the pulmonary levels of total hemoprotein and aryl hydrocarbon hydroxylase activity were increased after pretreatment of rabbits with MC [29]. The extent of induction in the lung of rabbit was low compared with that seen in the liver [29]. Moreover, tetrachlorodibenzo-pdioxin (TCDD) and polychlorinated biphenyl (PCB) increased the pulmonary EROD activity and cytochrome P450 1A1 isozymes [30-35.]. Similarly, the inducibility of cytochrome P-450 1A2 in mouse lung by MC was studied using a monoclonal antibody raised against the rat hepatic cytochrome, which cross-reacted with the maurine pulmonary cytochrome P450 1A1. In MC-induced mice, cytochrome P450 1A was present in lung and hepatic parenchyma cells, but this isoenzyme was not detected in untreated or PB-induced lungs. Treatment of hamster with MC, β-NF, or PCB stimulated the activity of aryl hydrocarbon hydroxylase [AHH] in lung, whereas hepatic levels were not changed [36-39]. Induction of AHH activity by these agents may partly explain

Salah A. Sheweita

why the hamster is more susceptible to tumors of the respiratory tract than other animals [40]. Kidney The cytochrome P-4501A isozymes were detected in kidney but at levels markedly lower than those seen in liver of rats using monoclonal antibodies recognizing MC-induced cytochromes [41,42]. The lower activity of cytochrome P450 1A in kidney was induced after treatments of rats with either PAH, β-NF, or 2-AAF [43,44]. With TCDD as inducing agent, immuno quantification showed a marked increase in cytochrome P4501A1, which accounted for 30% of total rat kidney cytochrome P-450. Similarly, agents such as alcohol induced cytochrome P450 2E1 in the kidney [45]. 1.1.2

Immunological Aspects

Monoclonal antibodies allowed rapid identification and quantification of cytochromes belonging to the same gene family [46]. Nine monoclonal antibodies have been raised against cytochrome P4501A1 and reacting with six distinct epitopes, one of them was shared with cytochrome P4501A2 [46,47]. Cytochrome P4501A1 was detected at low levels in the liver of rats and at relatively higher levels in rabbit and guinea pig livers, whereas a protein that relate to cytochrome P4501A was present in all animals [47]. Using the monoclonal antibodies, cytochrome P450 1A isozymes were detected in rat, hamster, guinea pig, rabbit, and “responsive” mice, but not in “non-responsive” mice after induction with MC. Similarly, isosafrole induced cytochrome P4501A2 in all animals, but only cytochrome P4501A1 in the rabbit and hamster only [47]. 1.1.3

Age

It has been established that the activities of MFO are very low at birth but increase rapidly in adult and then subsequently decline in adult in all animal species including man [48-52]. For example, the cytochrome P450 1A mediated 2hydroxylation of biphenyl was present in neonatal rat and rabbit livers but this isozyme was not detected during adulthood [53,54]. Also, cytochrome P-450 1A1 mediated O-deethylation of EROD was relatively higher in the neonatal rat reaching a maximum 2 weeks after birth and then declined with age [55]. These observations were further confirmed since 3-week-old animals

Drug-Metabolizing Enzymes: Mechanisms and Functions

Current Drug Metabolism, 2000, Vol. 1, No. 2 109

exhibited higher EROD activity than 8-week-old animals [56].

of a new hemoprotein, which shows maximum absorption in its reduced carbon monoxidedifference spectrum at 448 nm (77).

1.1.4

The hepatic microsomal and nuclear cytochromes P-450 are antigenically similar [78], and also 3-methylcholanthrene (MC)-induces both of them [79]. Nuclear cytochromes P-450 are induced by many known compounds of the microsomal cytochromes, such as pregnenalone 16α-carbonitrile (PCN), phenobarbitone (PB), βnaphthoflavone (β-NF), and the chlorinated biphenyl mixture, Aroclor 1254 [80]. However, the mitochondrial mixed-function oxidases differ from the microsomal and nuclear enzymes in the electron donor system, the mitochondrial forms being able to operate with adrenodoxin, ferredoxin, or the microsomal cytochrome P-450 reductase, while the microsomal and nuclear forms function only in the presence of the reductase [81]. Despite intensive research, the induction process itself is poorly understood and the precise mechanisms of induction of mixed function oxidase by xenobiotics still complex and not yet fully elucidated.

Nutrition

Nutrition and diet may modulate the levels of cytochrome P-450 isoenzymes, resulting in changes in the metabolic fate of xenobiotics [5763]. The diet-mediated effects may be due to chemicals inherent in the diet, to contaminants or food additives, or to compounds generated during the process of cooking [64]. Some types of food have high contents of natural xenobiotics, which are potent inducers of the mixed-function oxidase system, such as saffron. Rats maintained on a diet containing cruciferous vegetables, such as sprouts and cabbage, probably because of their high content of indoles, exhibited both high levels of intestinal mixed-function oxidase activity [64]. Similar effects were observed in humans maintained on such diet [65,66]. Indeed, indole-3acetonitrile, indole-3-carbinol, and 3,3’-diindoylmethanes present in cruciferous vegetables have been identified as naturally occurring inducers of hepatical and intestinal aryl hydrocarbon hyrdoxylase [AHH], and of other enzyme activities [67]. Liver and intestinal EROD activities have been induced in rats by feeding cabbage-containing diet [68]. 1.1.5 Inducing Agents and Mechanism of Induction The administration of drugs or other xenobiotics may lead to an increase in the activities of various liver isozymes, which are responsible for the metabolism of foreign compounds [69-75]. If the increase in the activity of a drug-metabolizing enzyme is due to an increased level of the enzyme, then the process is known as induction and the agent is called an inducer (76). Inducers have been traditionally classified either as phenobarbital (PB) or 3-methylcholanthrene (3-MC), based on the cytochrome P450 isozymes that are increased (76). Inducers of both the PB and 3-MC type increase the total amount of cytochromes. Although PB-treated rats showed elevated microsomal cytochrome P-450 levels, while their synthesized hemoprotein had the same absorption maximum in its reduced carbon monoxide-difference spectrum at 450 nm as microsomal cytochrome P-450 from untreated animals (25,77). However, the biochemical and physical changes observed after 3-MC treatment were postulated to be due to the induced synthesis

Inducers of the cytochromes P-450 stimulate the synthesis of new isozymes by enhancing their rates of transcription. This mechanism appears to be common to all cytochrome P-450 proteins but does not extrude the presence of additional alternative mechanism. Nebert and his colleagues have contributed enormously to the elucidation of the complex process involved in the induction of the cytochromes P-450 [82]. The aromatic hydrocarbon (Ah) receptor has been demonstrated in the hepatic cytosol of mice, which binds avidly but noncovalently with the inducing agent which is associated with the induction of cytochromes P450 [83,84]. This hydrophobic receptor appears to be composed of two subunits but contains only one binding site [85,86] and the binding appears to involve one or more sulfhydryl groups whose integrity is essential [87]. It appears that the parent chemical rather than an intermediate or metabolite that interacts with the receptor [88]. In addition to the legend binding, a DNA-binding domain exists on the receptor [89,90]. The inducer-receptor complex translocated into the nucleus were associated with structural genes leading to increased transcription and synthesis of the Ah receptor protein and the cytochrome P-450 apoproteins, which in the cytosol interact with heme to form the P-450 holoenzymes [91]. A good correlation exists between the amount of complex

110


translocated into the nucleus and the amount of P450 mRNA induced [91]. Interaction of the inducing agent with the receptor increases the affinity of the receptor for DNA [89]. Many endogenous compounds, including steroid hormones, failed to interact with the receptor, and there is considerable evidence indicating that none of the characterized steroid receptors is similar to the Ah receptor [92,93]. It has been suggested that inducers may affect the initiation of protein synthesis and even translation central factors [94]. Phenobarbitone has been reported to increase C 14-leucine incorporation into proteins by rat liver polyribosomes [95]. The increased RNA and protein synthesis as well as the stabilization and decreased degradation of these components has been implicated in the induction of drug metabolizing activity [96]. Induction of cytochrome P-450 is a very complex process and may be mediated by several processes. Manen and his coworkers (1978) have suggested that the cyclic AMP is the intracellular mediator of monooxygenase induction [97]. The increased synthesis of cytochrome P-450 apoprotein produces an increased demand for heme [98]. The mechanism of monooxygenase induction might be also due to enhancing of deltaaminolevulinic acid (δALA) synthetase, the initial and rate-limiting step in the biosynthesis of the heme moiety of cytochrome P450s. It has been reported earlier that the activity of δALA synthetase was increased after a relatively short period of rat treatments with some heavy metals [99]; or may be due to inhibition of heme oxygenase, the first and rate-limiting enzyme in heme degradation [100], since P450s are hemoproteins. 1.1.6

Inhibitors

It has been recognized for many years that various chemical structures could inhibit drug metabolism by competing for binding sites on the mixed-function oxidase system (60, 101-103). It has been reported that agents (e.g., lipases or detergents) was found to alter either lipids environment of MFO or its protein structure [4]. These agents convert the metabolically active form of cytochrome P-450 into inactive form, cytochrome P420. [4]. In addition, inactivation may occur with many compounds such as carbon disulphide [104], 2-allyl-2-isopropyl acetamide [105] and allyl containing barbiturates [106], heavy metals [73], which destroy cytochrome P-

Salah A. Sheweita

450 both in vivo and in vitro. Mercurials such as mersalyl [107]; p-chloromercuribenzoate [108]; alkylating agents such as N-ethylinaleimide and N-nitrosamines have been used as inhibitors of many different metabolic transformations mediated by the mixed-function oxidase system [109,110]. Bioactivation of xenobiotics by MFO is a complex series of reactions and interference of inhibitors with any of them may represent a possible mechanism of inhibition [111]. Inhibitors of cytochrome P-450 isozymes have been used as a tool in studying the multiple forms of these isozymes, and provide a valuable technique for characterizing the nature of cytochrome P450. Various disease conditions such as malignancy, diabetes mellitus, malnutrition, schistosomal infection, malarial infection and other infections, can produce structural and biochemical changes in the liver capable of decreasing the levels of hepatic cytochrome P-450 and microsomal protein [112-116]. Flavonoids are a class of dietary phytochemicals that modulate various biological activities. Four hydroxylated flavone derivatives (3-hydroxy-, 5-hydroxy-, 7-hydroxy-, and 3,7dihydroxy flavone) were potent inhibitors of Cyp 1A1, and 1A2 [117]. Treatment of mice with oleanolic acid resulted in a significant decrease of P4502E1-dependent p-nitrophenol and aniline hydroxylase [118]. The protective effects of oleanolic acid against the carbon tetrachlorideinduced hepatotoxicity may be due to blocking of carbon tetrachloride bioactivation, which is mediated by P4502E1 [118]. Trans-1, 2dichloroethylene was a more potent inhibitor of Cyp2E1 than cis-1,2-dichloroethylene based on both in vivo and in vitro studies [119]. In another study, trans 1, 2-dichloroethylene yielded maximal inactivation of P450 2E1 than other P450 isozymes including 1A2, 2A1, 2B1, 2C6, 2C11, 2D1 and 3A after 24h of treatment [120]. The levels of hepatic P450 2B1/2, 2C11, and 3A1/2 were decreased, whereas P450 2E1 expression was not affected after treatment of rat with acriflavine, a protein kinase c inhibitor [121]. Moreover, organophosphates are still widely used worldwide and cause thousands of intoxication every year. Repetitive exposure to subclinical doses of parathion to rabbits for one week caused marked inhibition of cytochrome P450 [122]. The inhibitory effects of neurotransmitters, precursors, and metabolites on Cyp 1A2 enzyme activity were studied in human liver microsome [123]. Two indoleamines, serotonin and tryptamine showed an inhibitory effect on the


activity of phenacetin O-deethylase [123]. Other substances, which were either poor or partial inhibitors of Cyp1A2 were dopamine, L-tyrosine, adrenaline, indole-3-acetic acid, L-tryptophan, and 5-hydroxyindole acetic acid [123]. 1.2 MECHANISMS OF DRUG OXIDATION BY MIXED-FUNCTION OXIDASE SYSTEM The wide substrate specificity of the microsomal mixed-function oxidases is due largely to the multiplicity of the constitutive and inducible cytochromes P-450, which display different, but often overlapping substrate specificity. The mixedfunction-oxidase is primarily concerned with detoxication involving the formation of more polar, readily excretable metabolites [124]. Paradoxically, however, the same microsomal mixed-function oxidase system can affect the formation of more toxic and reactive intermediates, a process known as "metabolic activation or bioactivation" [125,126]. A likely explanation of this paradox is that the activation process may be attributed entirely to one or more specific gene families of the cytochrome P-450 proteins, while other gene families catalyze oxygenation which lead to detoxification. Thus the amount of a reactive intermediate formed is the result of these two competing processes, that is activation and detoxication catalyzed by different gene families of the hemoprotein [127]. As such not only the cellular levels but also the cytochrome P-450 isoenzyme population, will determine whether a chemical will be activated or deactivated and subsequently eliminated [125,126, 128,129]. It is well known that cytochrome P-450 acts as a terminal oxidase for the electron transport system of mixed-function oxidase, which is implicated in the biotransformation of many xenobiotics [130]. The two important cofactors have been realized to be the absolute requirement for such microsomal mediated reactions: namely, molecular oxygen and NADPH. Absolute demand for 0 2 was demonstrated through the incorporation of heavy oxygen (1802) into 3,4-dimethyl phenol [131]. Requirement of NADPH in microsomal drug oxidation has also been demonstrated by immunological studies with antibodies against NADPH-cytochrome P-450 reductase [132] as well as with purified components of the cytochrome P-450. Initially, a substrate binds to the apoprotein moiety of the ferric (Fe3+) hemoprotein to form


ferric substrate complex. This complex then undergoes a one-electron reduction by accepting this electron from NADPH via the flavoprotein enzyme, NADPH cytochrome P-450 reductase, which converts heme iron to the ferrous (Fe2+) state. This Fe2+complex reacts with molecular oxygen to produce an oxygenated hemoproteinsubstrate complex (02-Fe2+-substrate). The oxycytochrome P-450 complex undergoes a further one electron reduction. Although the origin of the second electron is not well established, several studies have suggested that this reduction may be mediated via NADH-cytochrome b5 reductase and cytochrome b5 [17-19]. This complex is then subjected to intra-molecular rearrangement and one atom of oxygen is inserted into substrate producing oxidized metabolites and the other atom for water formation. Finally, the hemoprotein product complex dissociated to give product and free enzyme, allowing the cycle to be repeated. 1.3 FUNCTIONS OF MIXED-FUNCTION OXIDASE SYSTEM There are many different forms of cytochrome P-450 such as P-448 and 446 are present in mammalian cells [33,46]. One of the most important differences between the cytochromes P448 and other families of the hemoproteins, from the point of view of chemical toxicity and disease etiology, their is contrasting role in the metabolic activation and detoxication of toxic chemicals and carcinogens [79,133-135]. Cytochrome P450 1A family almost always metabolically activates chemicals to reactive intermediates, that is electrophiles, which are resistant to subsequent conjugation and interact with intracellular macromolecules and nucleophiles, giving rise to toxicity and carcinogenicity [126]. In contrast, the phenobarbital-cytochromes P-450 (Cyp P-450 2B1/2) direct the overall oxidative metabolism of chemicals toward subsequent conjugation and detoxication. The reason for this marked difference is that the cytochrome P-450 1A family accepts large planar molecules, which they are able to oxygenate in conformationally hindered positions giving rise to epoxides and other oxygenated metabolites that are poorly acceptable substrates for epoxide hydrolase and other conjugating enzymes [126]. However, the PBcytochromes P-450 generally oxygenate globular molecules in unhindered positions to from epoxides and other oxygenated products which are readily acceptable substrates for epoxide hydrolase and other conjugates, thereby resulting in detoxication.

112


Salah A. Sheweita

Among the various classes of xenobiotics known to be selectively activated by the cytochromes P-450 1A, with the formation of reactive intermediates, are the polycyclic aromatic hydrocarbons (PAH), the aromatic amines and amides, the planar polyhalogenated biphenyls and other halogenated polycyclics, azo compounds, mycotoxins, and paracetamol [128,129,136]. However, there are a few known instances where PB-induction increases chemical toxicity, or the PB-cytochromes P-450 specifically metabolize chemicals via toxic pathways, and these include the activation of cyclophosphamide, and the toxicity of bromobenzene and carbon tetrachloride.

Britain was associated with the occupation of patients as chimney sweeps [143]. Since that time, people in other occupations have been demonstrated to have certain risk of developing cancer at some sites. Overall, however, occupational cancers are relatively rare events that affect only limited numbers of individuals. The bulk of human cancers were until recently considered to stem from unknown elements. It was primarily the examination of international incidence rates of various types of cancer, and the fact that the incidence depends in part on the site of residence, that led to the concept that many types of human cancer are caused, mediated, or modified by environmental factors [144-147].

1.3.1

Chemical carcinogens are defined operationally by their ability to induce tumors. Four types of response have generally been accepted as evidence of tumorigenicity: (1) an increased incidence of the tumor types occurring in controls; (2) the occurrence of tumors earlier than in controls; (3) the development of types of tumors not seen in controls; (4) an increased multiplicity of tumors in individual animals. Chemicals capable of eliciting one of these tumorigenic responses are thereby classified as carcinogens. They comprise a highly diverse collection, including organic and inorganic chemicals, solid-state materials, hormones, and immunosuppressants. In order to draw attention to the differences in properties of the diverse agents that can be considered as carcinogenic, Weisburger and Williams have developed a classification based on the mechanistic mode of action of carcinogen [146], which separate them into eight classes. These in turn can be divided into two general categories based on their ability to damage DNA [146]. Carcinogens that undergo covalent reactions with DNA are categorized as genotoxic, and those lacking this property are designated as epigenetic, the eight classes have been divided between these two categories [147]. The genotoxic category contains those agents that function as electrophilic reactants, a property of carcinogens originally postulated by Miller and Miller in 1976 [148]. In addition, carcinogenic chemicals that give rise to DNA damage through formation of free radicals derived from their own molecular structure or from altered cellular macromolecules, would be considered genotoxic. The second broad category, designated as epigenetic carcinogens, comprises those carcinogens for which no evidence of direct interaction with material exists or DNA [148]. Within this broad definition of carcinogens, many structural types of chemicals are included such as those in the class of the direct acting carcinogens

Metabolism of Endogenous Substrates

The cytochromes P-450 2C11 catalyze specific steroid hydroxylation from livers of both rats and rabbits [17,49,137-139]. The PB-cytochromes P450 and cytochromes P-450 1A can hydroxylate steroids, but generally do so at rates well below those occurring in crude microsomes, indicating that steroids are unlikely to be the primary endogenous substrates of these cytochromes. However, even in the hydroxylation of steroids, PB-cytochromes P-450 and MC-cytochromes P448 again show distinct differences in region selectivity with virtually no overlap [139]. In the 2-hydroxylation of 17β-estradiol, cytochrome P4501A2 is markedly more active than any other cytochrome P-450 protein [140]. Differences in the sites of oxygenations by the MC-cytochromes P-448 and PB-cytochromes P-450 are also seen with the endogenous substrate arachidonic acid [30]. Cytochrome P-448 proteins from livers of rats and rabbits pretreated with β-naphtoflavone (β-NF) formed primarily ω- and (ω-1)hydroxylated products, while, in contrast, preparations from animals pretreated with PB gave primarily four epoxides [141,142]. A cytochrome P-450 protein catalyzing the epoxidation of arachidonic acid has been isolated from human liver [142]. Interestingly, this protein had high catalytic activity toward 7-ethoxyresorufin and it might be related to cytochromes P-450 1A family [142]. 1.3.2 Metabolic Carcinogens

Activation

of

Chemical

The concept that some types of cancer might be caused by environmental factors traces back to the observation of the English physician Pott in the late 18th century that human scrotal cancer in Great


[146-148]. They do not require the participation of enzymes from the host organism to generate the key reactive intermediate of the ultimate carcinogens. However, they do not generally persist in the environment because of their high reactivity. The second class of genotoxic carcinogens, termed procarcinogens, is comprised of organic chemicals that are active only after metabolic conversion by the host. This class include most of the known chemical carcinogens, and in contrast to direct-acting carcinogens can exist in the environment in a relatively stable condition until taken in by an exposed individual and activated through biotransformation [147,148]. 1.3.2.1 Polycyclic Aromatic Hydrocarbons Polycyclic aromatic hydrocarbons are ubiquitous in the environment and some of them are believed to cause cancer in man [149-151]. Benzo[a]pyrene is present as a component of the total content of polynuclear aromatic compounds in the environment. Human exposure to benzo[a]pyrene occurs primarily through the smoking of tobacco, inhalation of polluted air and by ingestion of food and water contaminated by combustion effluents [145]. Benzo [a] pyrene has been shown to be carcinogenic to experimental animals [153-158]. It has produced tumors in all of animal species following different administrations including oral, skin and intratracheal routes. It has both a local and a systemic carcinogenic effect. In sub-human primates, there is convincing evidence of the ability of benzo(a)pyrene to produce local sarcomas following repeated subcutaneous injections and lung carcinomas following intratracheal instillation. It is also an initiator of skin carcinogenesis in mice, and it is carcinogenic in single-dose experiments and following prenatal exposure [159]. Polycyclic aromatic hydrocarbons (PAH) not only induce the cytochromes P-448 but also are preferentially metabolized by these enzymes. The cytochrome P450 system participates in the bioactivation of polycyclic aromatic hydrocarbons (PAHs) and other carcinogens to their reactive intermediates [160-163]. An important and very extensively studied member of the polycyclic aromatic hydrocarbons is benzo(a)pyrene which is mainly metabolized by cytochrome P450dependent aryl hydrocarbon hydroxylase into various derivatives, among which are electrophilic epoxides [147,157]. Solublized, purified Cytochrome P450 2A1 preparations were more efficient than the PB-cytochromes P-450 in


converting benzo(a)pyrene and (±)-transbenzo(a)pyrene -7,8-dihydrodiol, the precursor of the ultimate carcinogen, into mutagens [29,68]. Similarly hepatic microsomal preparations form MC-treated animals are markedly more efficient than similar preparations from PB-induced animals in activating benzo(a)pyrene to mutagens and in converting it to the 7,8-diol-9,10-epoxide [38]. Pretreatment of rats with PB increased the formation of the 4,5-diol of benzo(a)pyrene but had little or no effect on the 7,8-and 9,10-diol formation; the formation of all three diols was, however, induced by pretreatment with β-NF and MC, the least effect being seen with the 4,5 diol [161]. The MC-induced type increased in benzo (a) pyrene mutagenesis [160,164]. Intraperitoneal pretreatment of mice with MC increased the formation of benzo(a)pyrene 7,8-diol in both lung and liver, while no such effect was seen following treatment with phenobarbital [159]. Furthermore, pretreatment of mice by intratracheal instillation of benzo(a)pyrene increased markedly the covalent binding of the carcinogen to lung DNA [165]. Supporting these findings are immunological studies which showed that the metabolic activation of benzo(a)pyrene to mutagens was markedly inhibited by antibodies to cytochrome P4501A1 but was unaffected by antibodies against cytochrome P-450 2E1 [166]. Similarly, a monoclonal antibody against MC induced cytochromes P-448 inhibited the conversion of benzo(a) pyrene 7,8 diol to mutagens by liver microsomes from MC-induced responsive mice while no effect was seen with an antibody to PBinduced microsomes [167]. Finally, good correlation has been obtained between rat liver cytochrome P450 1A content determined by the ethoxyresourfin O-deethylase (EROD) assay and the activation of benzo(a)pyrene to mutagens in the Ames test by rat liver microsomes [167]. The alcohol-inducible cytochrome P-450 isoenzymes (P450 2 E1) appear not to catalyze the activation of PAH [168]. The carcinogenic potency and the extent of binding of these metabolites, epoxides, with DNA and proteins are correlated with the induction of cytochrome P-450-dependent aryl hydrocarbon hydroxylase activity [169,170]. The preferential activation of PAH by cytochromes P448 is not confined to benzo(a)pyrene. Cytochromes P-448 also convert MC, 6aminochrysene, benzo(a)anthracene, dibenzo(a,h) anthracene, dibenze(a,c) anthracene, and many other bay-region-containing PAH to highly mutagenic species [166,171,172].

114


1.3.2.2 Naturally Occurring Carcinogen (Aflatoxin B1) Until the early 1950s it was thought that virtually all-organic chemicals were man-made. However, in the beginning of 1955 it was increasingly realized that some chemical compounds elaborated by certain plants are carcinogenic. The demonstration in the early 1960s of the potent carcinogenicity of aflatoxins revealed that carcinogens are also found among metabolites of certain molds and microorganisms [173]. Thus, nature itself contributes a fair share to the cancer causing substances in the environment, the naturally occurring carcinogen [173]. Aflatoxins were discovered in England in 1960 when a Brazilian peanut meal was used as a protein supplement to poultry diets caused the acute deaths of more than 100,000 young turkeys from liver damage or turkey X disease [174]. At the same time, an outbreak of turkey X like disease in ducklings occurred in Kenya following the ingestion of African peanut meal [175]. Symptoms similar to turkey X disease were also reported in outbreaks in other form or domestic animals fed peanut meals. Coincidentally, an epizootic of liver cancer in hatchery-reared rainbow trout occurred in the United States and Europe in 1960 [176-178]. A commercial trout feed contaminated cottonseed meal was eventually found to be associated with the trout hepatoma problem. The magnitude of the problem inspired intensive research efforts by investigators throughout the world [179]. The toxic agent in peanut meal was narrowed down to a mixture of aflatoxins produced by a common mold, Aspergillus flavus, as secondary metabolites [175]. The mixture could be separated into four components by thin layer chromatography; these were designated BI, B2, G1, and G2 according to their fluorescent colors (B1 for blue, G1 for green) and relative mobility in the chromatogram [180,181]. 1.3.2.2.1 Metabolism and Mechanism of Action of Aflatoxin B1 Aflatoxin B1 is actively metabolized in a variety of animal species. Epoxidation of the 2,3 double bond of AFB1 is now generally accepted to be the key metabolic reaction eliciting the carcinogenic and mutagenic effects of the mycotoxin [182]. That the 2,3-double bond is a critical structural requirement for carcinogenicity and mutagenicity has been pinpointed by structure-activity relationship studies on a variety of structural analogs of AFB1 [183,184]. Moreover, quantum mechanical calculations have shown that the 2,3-

Salah A. Sheweita

double bond is the most reactive site in the molecule [185,186]. Although attempts to isolate the putative reactive intermediate, AFB1-2, 3oxide, have been unsuccessful because of instability, its formation can be deduced from its reaction products with cellular constituents and its hydrolysis products. Aflatoxin B1 binds covalently to nucleic acids after in vitro metabolic activation by liver microsomes [182,187-189] as well as in vivo studies [183,190]. The major acid hydrolysis products of AFB1-DNA adducts were identified as 2,3-dihydro-2- (N7-guanyl)-3-hydroxyaflatoxin B1 and 2,3-dihydro-2- (2,6-diamino-4-oxo-3, 4dihydro-pyrimid -5-ylformamido)-3-hydroxy aflatoxin B1 indicating the involvement of AFB1-2, 3oxide [189]. In the absence of exogenous nucleophiles, 2,3-dihydro-2,3-dihydroxy-aflatoxin B1, an expected hydrolysis product of AFB1-2,3oxide, is a major metabolite in the incubation of AFB1 with rat, hamster, and trout liver microsomes [184,191,192]. The relative importance of each individual pathway varies substantially, depending on the animal species and the experimental conditions. Essentially, the initial metabolism of AFB1 involves three principal types of reactions: (a) hydroxylation, (b) epoxidation, and (c) keto reduction. The former two reactions believed to be carried out principally by a microsomal mixedfunction oxidase system, the latter by a cytosolic NADPH-dependent reductase. In most animal species, the hydroxylated AFB1 metabolites may undergo phase II metabolism by conjugating with gulcuronic acid or sulfate [193]. The activation of this mycotoxin to mutagenic and carcinogenic products, involving epoxidation of the 2,3-double bond and possibly other oxygenation, appears to be catalyzed by the cytochromes P-448 and possibly other forms of the cytochromes [184,194]. A comparison of 5 purified rat cytochrome P-450 proteins in the activation of aflatoxin B1 into mutagens showed that cytochrome P4501A2 and a sex-related male form were the best efficient. Although a significant activity was also seen with cytochromes P-450 1A1 and P-4501A2 [195], other workers who further showed that although PB-uninducable forms have activated this mycotoxin, have documented the high efficiency of cytochrome P450 3A4 [196]. The hepatic microsomal enzyme system that catalyzes the 2,3-epoxidation of AFB1 exhibits the typical characteristics of a mixedfunction oxidase. Pretreatment of animals with Phenobarbital (but not with 3-methylcholanthrene) greatly enhances the in vitro formation of adducts of AFB1 with nucleic acids, suggesting the involvement of a cytochrome P-450-dependent system. However, somewhat inconsistent results


have been obtained from reconstitution experiments using purified cytochromes. In two of these studies purified hepatic cytochrome P450 1A species obtained from polychlorinated biphenyl- or 3-methylcholanthrene-treated rats were more effective than purified Phenobarbital-induced cytochrome P-450 2B1/2 in catalyzing the formation of a reactive intermediate that binds to DNA or exerts a mutagenic effect [195,196]. In a third study, purified Phenobarbital-induced rat liver cytochrome P-450 was more active than βnaphthoflavone-induced cytochrome P450 3A4 in catalyzing the formation of AFB1-DNA adduct [197-199]. 1.3.2.3

N-Nitrosamines

N-nitrosoamines are an important class of environmental carcinogens, and their potential role as causative agents in the carcinogenesis of some human neoplastic diseases has been extensively reviewed [200-206]. There are two potential sources of human exposure to nitrosamines. Firstly, certain dietary items are known to contain nitrosoamines [207]. Secondly, A more important source of nitrosamines is almost certainly from ingested amines and nitrite. The nitrite can come from foods containing nitrite, such as cured meat and fish, or be present in saliva and enter the stomach in that way. Nitrosotable amines can be of enormous variety. A majority of drugs and medicines are nitrosotable amines; many agricultural chemicals are nitrosotable amino compounds, and many constituents of food themselves, as well as food additives, are amines of this type [208-212]. The amino acid proline is one example of naturally occurring nitrosotable amines, although it gives rise to a noncarcinogenic nitroso derivative. More recent studies have shown that the urinary levels of nitrosamines are higher in Egyptian schistosomal patients than those of the controls [213,214]. 1.3.2.3.1 Bioactivatlon of N-nitroso Compounds N-nitrosourea and related compounds (nitrosoamides, nitrosoguanidine, nitrosourethans, nitrosocyanamides ) are chemically reactive, and decompose at physiological pH to form electrophilic alkylating agents. N-nitrosamines, on the other hand, are stable at neutral pH, and require metabolic transformation in vivo in order to exert their carcinogenic effects [215-220]. This difference explains why nitrosourea tend to produce tumors at or near the site of application,


whereas nitrosamines produce tumors in tissues remote from the site of administration. Nitrosamines are potent carcinogens for a variety of animal species and metabolic activation is known to be required for their carcinogenecity. Dimethylnitrosamine (DMN) has been used frequently as a prototype compound in studying the metabolism of nitrosamines [217]. It is known that the metabolism of DMN can be mediated by a liver microsomal fraction which requires NADPH and molecular oxygen. There are two enzyme species responsible for the N-demethylation of dimethylnitrosamine (DMN) through an oxidative N-demethylation reaction, namely DMN-Ndemethylases I and II (which can operate at ~ 4 mM and ~200 mM of DMN respectively) [69,221]. It was found that following the Ndemethylation of dimethylnitrosamine (DMN), a diazonium ion is produced leading ultimately to the formation of carbonium ion that methylates DNA [222-224]. It was suggested that the carcinogenic effects of alkylating agents are proportional to the activities of their activating enzymes in the liver [225,226] since more of the active metabolites might be produced [226], when the demethylases are activated. Therefore, the carcinogenic effects of carbonium ion resulting from activation of N-nitrosodimethylamine might be increased toward the liver and probably other organs. It has, therefore been postulated that the reaction involves oxidative demethylation to eliminate formaldehyde, which has been identified as a product, and carbonium ion, which alkylates accessible nucleophiles, including nucleic acids, proteins and water. 1.3.2.3.2 Role of Cytochrome P450 2E1 in the Activation of N-Nitrosamines Among six purified human cytochrome P450 forms, the alcohol-induced P450 2E1 was the most efficient in catalyzing the demethylation and denitrosation of dimethylntrosamine (DMN) [227231]. Moreover studies with purified rat liver P450 isozymes demonstrated that Cyp2E1 is more active than other forms in catalyzing the metabolism of dimethylnitrosamine [231,232]. Other P450 forms such as phenobarbital-inducible P450b showed substantial activities only at high substrate concentrations of dimethylnitrosamine, suggesting high Km values [69,231,233]. These observations are consistent with the concept that the multiple Km values for dimethylnitrosamine N-demethylase found in microsomes are due to the catalytic activity of multiple forms of P450 [229].

116


The key role of dimethylnitrosamine Ndemethylase in the activation of dimethylnitrosamine has been demonstrated in several different system: [1] cytochrome P450 2E1 was more efficient than other forms in the activation of dimethylnitrosamine to a mutagen in Chinese hamster [233]; [2] some of the previously reported species and age difference in DMN have been interpreted on the basis of the quantity of P450 2E1 present in the hepatic microsomes of rats and hamasters of different age [234]; and [3] pretreatment of rats with ethanol or acetone increased DMN-induced methylation of DNA in vivo and in vitro and potentiated hepatotoxicity [235,236]. The ultimate effect of N-nitrosamines will depend upon the rate of activation and the rate of detoxification. As the activated carcinogen reacts with various nucleophilic sites in addition to nucleic acids) and as water is the most plentiful cellular component, reaction with water could be regarded as detoxifying process [237]. Similarly, the trapping of reactive intermediates by protein and other cellular components also provides protection against the mutagenic and carcinogenic effects of N-nitrosamines although not against some of the cytotoxic effects of these agents [237]. In addition, there are other mechanisms of metabolic detoxification of N-nitrosamines by glutathione S-transferases [238], all of which limit the formation of the highly reactive electrophilic intermediates. Although trapping of reactive metabolites by glutathione conjugation appears to be the primary defense mechanism against the harmful effects of reactive intermediates, in some cases the conjugation of an ultimate carcinogen with glutathione can form genotoxic species [239]. The electrophilic intermediates produced by chemical decomposition of nitrosourea and related compounds, or by metabolic activation of nitrosamines, react rapidly with cellular nucleophiles. Attention has been focused on reactions with DNA because this is generally considered to be the critical cellular target for carcinogens during tumor initiation [223,240]. Although 7-methylguanine (66.8 %) is the most abundant modified base in DNA produced by dimethy-lnitrosamine, a variety of other products have been identified [216,217,240]. These include alkylphosphate triesters (12 %), 1-,3- and 7methyladenine ( 0.9 %, 2.3%, 0.7%); and 06methylguanine (6.1%) and unidentified products. Not all DNA lesions have the same biological importance [223,240]. Methylation of the 7position of guanine shows no correlation with

Salah A. Sheweita

carcinogenic activity, but several striking correlation have been obtained between tissue susceptibility to tumor induction and the initial extent of formation and subsequent persistence of 06-methyl guanine residue [223,240]. 1.3.2.4

Aromatic Amines and Amides

The aromatic amines include some very important industrial chemicals used as intermediates in the manufacture of dyes and pigments for textile, paints, plastics, paper and hair dyes; they also include drugs, pesticides and antioxidants used in the preparation of rubber for the manufacture of tires and cables [241,242]. Studies of bladder cancer among workers in the dyestuff industry and later among rubber workers hold an important place in the history of occupational bladder cancer. Epidemiological studies of the hazards to workers in the chemical industry established that benzidine and 2naphthylamine are carcinogenic to humans [241,242]. It was shown that rubber workers also had increased risk for bladder cancer, attributed largely to exposure to aromatic amines [241,242]. Most aromatic amines are initially activated by Nhydroxylation, mainly in the liver via a cytochrome P-450 catalyzed reaction [243,244]. Studies of bladder cancer among workers in the dyestuffs industry, and later among rubber workers, hold an important place in the history of "occupational" bladder cancer. This evidence led to the International Labor Organization to declare certain aromatic amines as human carcinogen [245]. The epidemiological study for the hazards on workers in the chemical industry, established that benzidine and 2-naphthylamine were carcinogenic to human [245,246]. In another study carried out at about the same time, it was shown that rubber workers had also an increased risk for bladder cancer, attributed largely to exposure to aromatic amines. 4-aminobiphenyl was widely used in the industry at that time, and it was shown shortly afterwards that it caused bladder cancer in humans [246,247]. The epidemiological finding subsequently prompted discontinuation of production and prevented widespread use of 4aminobiphenyl in other countries. Recent epidemiological studies have demonstrated an elevated occurrence of bladder cancer among workers exposed to para-chloro-ortho-toluidine. Since it also induced malignant tumors in experimental animals, this compound and its strong acid salts are probably carcinogenic to human [248].


1.3.2.4.1 Metabolic Activation of 2Acetylaminofluorene Activation of 2-acetylaminofluorene (2-AAF) proceeds through N-hydroxylation which is catalyzed exclusively by cytochromes P-448 [249251], confirming previous observations where antibodies to cytochromes P-448, but not PBcytochromes P-450, decreased the Nhydroxylation and covalent binding of the carcinogen [252-254]. Pretreatment of animals with 2-AAF or MC increases the N-hydroxylation of the amide, and increases the cytochromes P-448 content as determined by EROD activity [255,256]. Similarly, rabbit liver microsomes catalyze the N-hydroxylation of 2-AAF. Furthermore, monoclonal antibodies to MCinduced cytochromes P-448 inhibited the Nhydroxylation of 2-AAF [257], and the mutagenicity of 2-AAF was inhibited 60% by antibodies to cytochrome P450 3A4 but only 35% by antibodies to cytochrome P-450. Nhydroxylation of acetylaminofluorene occurs to the greatest extent in the liver and is catalyzed by a cytochrome P-450 and NADPH-generating system in the endoplasmic reticulum [251,258]. A major fraction of N-hydroxy-AFF is converted to its 0glucuronide, which is excreted in the bile and urine [259,260,261]. This glucuronide has weak electrophilic reactivity, but its N-deacetylated derivative is a potent electrophile, although the latter compound is not a known metabolite [262]. Male Sprague-Dawley rats and male and female rats of the Fisher strain, all of which are highly susceptible to hepatic tumor induction, have a high level of cytosolic 3'-phosphoadenosine-5'phosphosulfate (PAPS)-mediated sulfotransferase activity for N-hydroxy-AAF in their livers [263266]. The activity of sulfotransferases in liver cytosol under various experimental conditions correlates with the extent of covalent binding of several of amines and amides to macromolecules and with susceptibility of animals to the hepatocarcinogenicity of N-hydroxy-AAF. Thus, the sulfuric acid ester appears to be the major ultimate carcinogenic metabolite of N-hydroxyAFF in the liver [267,268]. N, 0-acyltransferase, which catalyses the transfer of the N-acetyl group of N-hydroxy-AAF to the oxygen atom of the corresponding hydroxyamine (formed by N-deacetylation), occurs in a wide variety of tissues in rat and other species [269,270]. The 0-acetyl derivative of Nhydroxy-2-aminofluorene is a very strong electrophile. Because of the wide tissue distribution of N, 0-acyltransferase, this metabolic pathway is an alternative mechanism for the


metabolic activation of N-hydroxy-AAF or other hydroxamic acids in tissues. Since arylaminated residues are major products found in rat liver DNA following administration of N-hydroxy-AAF this acyltransferase may also play a role in the formation of 2-aminofluorene moieties which become attached to DNA [271,272] The major hepatic nucleic acid adducts in rat liver from N-hydroxy-AFF-treated animals are N2-(guan-8-yl)-AAF or aminofluorene derivatives. In addition, 3-(guan-N2-yl)-AFF has been identified in hepatic DNA. The latter modified base persists much longer in DNA than the first adduct [253,273]. 1.3.2.4.2 Metabolic Activation of N,NDimethylaminoazobenzene The N-hydroxylation of N-methylaminoazobenzene and the metabolic activation of N, Ndimethylaminoazobezene are catalyzed by cytochromes P-448 [274,275]; cytochrome P4501A2 catalyzes the N-hydroxylation of Nmethylaminoazobenzene at twice the rate of cytochrome P4501A1 although the latter is more active in ring hydroxylation [26,27,68]. N-methyl4-aminoazobenzene (MAB) is a proximate carcinogenic metabolite formed from N, Ndimethylaminoazobenzene through oxidative Ndemethylation. This hepatocarcinogen is then Nhydroxylated by a flavoprotein that requires NADPH, but not cytochrome P-450 [277]. Carcinogenicity studies in rats and mice led to the conclusion that N-hydroxy metabolites of MAB and other amino azo dyes are proximate carcinogens [278]. N-hydroxy-MAB is esterified by a PAPS-dependent cytosolic system in rat liver [279]; this ester is presumed to be the ultimate carcinogenic metabolite. Livers of rats administered MAB in vivo contained the same nucleic acid and protein-bound adducts that are formed on incubation of the synthetic benzoic acid ester of N-hydroxy-MAB with nucleophiles in vitro [280]; the nucleic acid adducts are N-(guan8-yl)-MAB derivatives [280]. Protein-bound cysteine derivatives are formed in vivo and these amino acid adducts have been characterized. The susceptibilities of the livers of the rat and several rodent species correlate with the capacities of these tissues to form N-hydroxy-MAB and the sulfate ester of this product [277,279]. Thus the addition of sulfate ester to the diet of rats enhances the induction of liver tumors by the related amino azo dye, 3'-methyl-N,N-dimethyl-4-aminoazobenzene [281].

118


The cleavage of azo bonds, catalyzed by the enzyme azo reductase, may lead to detoxification of certain carcinogenic and mutagenic azo dyes, such as N,N-dimethyaminoazobenzene. In other instances, such a reaction may activate azo compound [282]. 1.4 ENZYMES INACTIVATION

OF

CARCINOGEN

1.4.1 Glutathione and other Amino Acids Conjugation Glutathione (GSH) is present in most plant and animal tissues from which the human diet is derived. GSH can function as an antioxidant, maintain ascorbate in a reduced and functional form, directly react with and inactivate toxic electrophiles in the diet, and can be broken down to yield cysteine [283]. Studies have shown that dietary GSH enhances metabolic clearance of dietary peroxidized lipids and decreases their net absorption [284] and that consumption of food high in GSH content is associated with about a 50% reduction in risk of oral and pharyngeal cancer [285]. Therefore, an improved understanding of the distribution of GSH in foods and the factors affecting GSH absorption and distribution can be expected to provide the basis for improved food selection and preparation to reduce risk of chronic diseases. Glutathione (GSH) one of the most abundant intracellular thiols, aids in the protection of cells from the lethal effects of toxic and carcinogenic compounds [286,287]. It has shown to be an important determinant of cellular sensitivity to a wide variety of drugs and other cytotoxic compounds [288-290]. Both oxidation-reduction reactions may eventually result in GSH depletion even though the former type of reaction primarily leads to glutathione oxidation and should be effectively compensated by glutathione reductase activity [291]. GSH depletion is often associated with cytotoxicity, and there are some indications that conjugation reactions can be more detrimental to the cell than redox cycles [292, 293]. It thus seems possible that GSH depletion may promote tumor development through a mechanism that involves cytotoxicity and other different ways [294, 295]. The cytosolic glutathione-S-transferase and GSH play an important role in the detoxification of many environmental chemicals including mutagens and carcinogens [296-300]. Their main function is the conjugation of GSH to a variety of electrophilic compounds. Recent studies have demonstrated that GSH and GST reduced the

Salah A. Sheweita

covalent binding of epoxides of well known chemical carcinogens, e.g. aflatoxin B1 and benzo [a]pyrene, with DNA [301-305]. It has been reported that such DNA-binding was found to be effective in decreasing the hepatocarcinogenesis caused by these compounds [306,307]. Glutathione conjugates are not excreted per se but rather undergo further enzymatic modification of the peptide moiety resulting in the urinary or biliary excretion of cysteinyl-sulfur substituted, nacylcysteines, more commonly referred to mercapturic acids [295]. Mercapturic acid formation is initiated by glutathionase conjugation followed by removal of the glutamate moiety by glutathionase and subsequent removal of glycine by a peptidase enzyme, the latter two enzymes being present in both liver, gastrointestinal tract and kidney. In the final step, the amino group of cysteine is acetylated by a hepatic n-acetylase resulting in formation of the mercapturic acid derivative. This latter acetylation reaction is reversible and deacetylases can reform the amino metabolite [308]. It is clear that glutathione conjugation serves as a protective mechanism whereby potentially toxic, electrophilic metabolites, are detoxified either as glutathione conjugates or mercapturic acids [306308]. However, it is becoming increasingly recognized that glutathione conjugation is not exclusively a detoxification reaction and that certain xenobiotics are toxicologically activated by this conjugation route, either as such or as a result of further processing of the glutathione conjugate. Therefore, cellular levels of glutathione are an important determinant of xenobiotic toxicity [292,293,307]. The covalent binding of electrophilic metabolites to DNA has been extensively studied as primary mechanism of triggering mutagenic or carcinogenic events. Some studies have successfully identified the target amino acids to which drug metabolites bind during the covalent interactions with proteins. In general, the most reactive target sites in proteins include the nucleophilic centers of cysteine, methionine, histidine and tyrosine [309]. Thiol sulfur represents a particularly potent nucleophilic site in a protein. Ample evidence suggests that protein sulfhydryl groups may be important sites for attack by electrophilic drug metabolites resulting in covalent binding. Sulfhydryl blocking agents often decreases the covalent binding of drug to protein thiols [310,311]. Exposure of Chinese hamster to potassium chromate leads to the formation of


stable complexes between DNA and amino acids ([312]. Cysteine, glutamic acid, and histidine were the major amino acids crosslinked to DNA in chromate-treated hamster [312] 1.4.2

Glutathione-S-Transferase (GST)

The glutathione-S-transferase enzymes are soluble proteins predominantly found in the cytosol of hepatocytes and catalyze the conjugation of a variety of compounds with the endogenous tripeptide, glutathione. Cytosolic glutathione S-transferases can be divided into four families, termed alph (α), mu (µ), Pi(π), and theta (φ), having different but sometimes overlapping substrate specificities [298,302,313-315]. Glutathione S-transferases are subjected to activation by endogenous disulfides and by various intermediates that form during the metabolism of drugs and other foreign compounds [316]. Individual variation in the expression of GST isozymes is well documented [317]. For example, the levels of GSTα class isozymes can vary markedly between individuals [318], and in the case of GSTµ class, as a consequence of genetic polymorphism, about 45% of individuals do not express GSTµ subunits [319]. Such variation in expression of GST isozymes may predispose individuals to the toxic effects of environmental carcinogens. A number of studies demonstrating that high levels of GSTπ in neoplastic nodules in several rat models of hepatocarcinogenesis have prompted investigations of GSTπ levels in human tumors. The predominant form in most human tumors investigated was class GSTπ and comparison of matched pairs of normal and tumor tissues revealed high levels in stomach, colon, bladder, cervix and lung tumors [320-323]. GSTπ serves as a marker for hepatotoxicity in rodent system [324], and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity and depletion of GSH levels might potentiate the deleterious effects of many environmental toxicants and carcinogens. Glutathione-S-transferases (GSTs) have the capacity to detoxify electrophilic xenobiotics by catalyzing the formation of glutathione (GSH) conjugates. GSTs are also engaged in the intracellular transport of variety of hormones, endogenous metabolites, and drugs, by virtue of their capacity to bind these substances [325]. A series of carcinogens drugs, metabolites, and related compounds were analyzed for binding to GST [326]. Broad specificity of binding is evident, but relative affinities are not determined by


lipophilicity alone. This is exemplified by the striking differences between 2,3-benzo(a) anthracene, which was bound with high affinity, and 1,2-benzo(a)anthracene, which was classified as non-binding. Distinct structural requirements emerged from these results [326]. Steric factors appear to dictate binding; the polysubstituted anthracenes such as the dibenzanthracenes, pyrene, chrysene and other polycyclic aromatic compounds were bound. Similarly, dibenz(a,j) acridine was bound whereas acridine and acridine orange were not bound [306]. It is well known that parasites and heavy metals caused marked changes in GST activity, and GSH levels [327-329]. Inducers of GSTs are generally considered as protective compounds against cancer, acting as blocking agents. The human diet contains many compounds that inhibit various steps of the carcinogenic process [330]. The coffee specific diterpenses cafestol and kahweol have been reported to be anti-carcinogenic in several animal models. It has been postulated that this activity may be related to their ability to the induction of glutathione S-transferase π class [331]. GSTπ was induced in the stomach by coumarin and αangelicalactone and in the pancrease by flavone [332]. Several dietary compounds have been demonstrated to reduce gastrointestinal cancer rates in both human and animals. For example, sulforaphane, indole-3-carbinol, D-limonene and relafen induced GSTα levels in small intestine and livers, GSTµ levels in stomach and small intestine, GSTπ levels in stomach and small and large intestine [333]. Aqueous extracts of either green or black tea were administered to rats as the sole drinking fluid for 4 weeks. Hepatic GST activity and UDP-Glucuronyl transferase were induced [333]. On the other hand, many different chemical compounds and dietary items were found to inhibit the expression and the activity of GST isozymes. Trivalent antimony was a potent inhibitor of glutathione S-transferases from human erythrocytes [335]. Based on this inhibition characteristics and the preferential accumulation of trivalent antimony in mammalian erythrocytes, for example, during therapeutic treatment of Leishmaniasis, antimony levels in erythrocytes may be high enough to depress GST activity, which might compromise the ability of erythrocytes to detoxify electrophilic xenobiotics [335]. Animals treated with acriflavine, a protein kinase c inhibitor, and allyl disulfide showed complete blockage of GST gene expression as early as 12 h of treatment [299]. Analogues of

120


glutathione preferentially inhibit GSTα, have less effect on µ isozymes, and finally have little effect on rat φ and π isozymes [336-338]. 1.4.3

Glutathione Reductase

Glutathione reductase from several tissue sources has been extensively characterized. Its catalytic mechanism, amino acid sequence and its three dimensional crystal structure have been determined [339,340]. But little is known about the physiological regulation of its activity. The role of glutathione reductase is to maintain the cellular level of reduced glutathione. Its substrates and/or products in vivo do not regulate glutathione reductase activity. However, there have been several reports hinting at the in vivo inhibition of the enzyme by GSH. No details of the inhibition were provided in these early reports [341,342]. The first such detailed report on the inhibition of glutathione reductase by GSH appeared in the literature [343]. In that study, GSH was shown to be a non-linear, non-competitive inhibitor of glutathione reductase [343]. The inhibition of glutathione reductase by GSH appear to be a wide spread phenomenon that should hereafter be considered in any treatment of GSH metabolism or homeostasis on the enzymes from human platelets, bovine intestinal mucosa, yeast and E. coli were all inhibited by this peptide [341-343]. The extent and the type of inhibition, however, appears to be dependent on the enzyme source [341-343]. This species-dependent difference in inhibition patterns for glutathione reductase by GSH reported here is, to the best of knowledge, the first example of an observed functional difference in the generally highly conserved glutathione reductase enzyme. Physiologically, the consideration of this inhibition has important consequences because normal levels of GSH can regulate the enzyme [343]. Presumably, the enzyme will be inhibited by GSH under normal cellular conditions and will therefore be less able to convert oxidized form (GSSG) to reduced form (GSH), providing a concentration of GSSG to be maintained at higher than other wise expected concentration [342]. 1.4.4

UDP-Glucuronyl Transferase

Only a few years ago it was generally accepted, that phase II metabolites of drugs, such as O- or Nglucuronides, are rapidly excreted following their formation in the body and that these metabolites

Salah A. Sheweita

are not active or reactive [344,345]. The resulting acyl glucuronides were found to be electrophiles, reacting with sulfhydryl group. Conjugation with D-glucuronic acid represents the major route for elimination and detoxification of drugs and endogenous compounds possessing a carboxylic acid function [346,347]. Carcinogens and their reactive metabolites may also be metabolized by alternative routes (e.g., by conjugation or by hydroxylase activities) to relatively harmless intermediates that can be eliminated from the body, although in some cases these may be further transformed into highly reactive chemical species [348,349]. As with the enzymes of carcinogen activation those responsible for inactivation may play pivotal roles in the determination of the target tissue specificity of a particular carcinogen. It has also been suggested that the sulfation of certain chemical carcinogens could lead to more toxic conjugates, which can cause cell necrosis [350352]. A major fraction of the N-hydroxy derivatives of aromatic amines is converted to the glucuronide, which is then excreted in the bile and urine [350]. However, the glucuronide also may be hydrolyzed to release the free N-hydroxy arylamine, which is a potent electrophile [353]. 1.4.5

Sulfate Conjugation

Many drugs are oxidized to a variety of phenols, alcohols or hydroxylamines which can then serve as excellent substrates for subsequent to sulfates conjugation, forming the readily excretable sulfate esters. However, inorganic sulfate is relatively inert and must first be activated by ATP [263]. For phenolic metabolites, the key enzyme in this sequence is sulfotransferase. The sulfotransferase enzymes are soluble enzymes found in many tissues including liver, kidney, gut and platelets and catalyze the sulfation of drugs such as paracetamol, isoprenaline and salicylamide and many steroids. It appears that the sulphotransferase exist in multiple enzyme forms with the steroid sulfating enzymes being distinct from the sulfotransferases responsible for drug conjugation reaction [354356]. It should be emphasized that sulfate conjugation reactions are not as widespread or as of quantitative importance as glucuronide conjugation reactions, due in part to the limited bioavailability of inorganic sulfate and hence PAPS. This is particularly true when a drug is actively metabolized to phenolic products or when high body burdens of phenolic drugs are reached (for example, in overdose), resulting in effective saturation of this metabolic pathway [357].


1.4.6

N-Acetyltransferase

Xenobiotic-metabolizing enzymes constitute an important line of defense against a variety of carcinogens. The wide variation in carcinogen metabolism in human has long been regarded as an important determinant of individual susceptibility to chemical carcinogenesis. The carcinogenicity of several arylamines and amides for the liver and the urinary bladder has prompted studies on the metabolism of these carcinogens and on their reactive metabolites, which are catalyzed by mixed-function oxidases in the hepatic endoplasmic reticulum [358]. Distinct genes, designated NAT1 and NAT2 code for N-acetyltransferase activities in human. NAT1 activity appears to be monomorphically distributed in human tissues, while the latter exhibits a polymorphism that allows the detection of phenotypically slow and rapid metabolizers [359]. The NAT2 polymorphism can have a significant effect on individual susceptibility to aromatic amine-induced cancers. N-Acetylation of arylamines represents a competing pathway for Noxidation, a necessary metabolic activation-step occurring in the liver. The unconjugated Nhydroxy metabolites can then enter the circulation, and be transported to the urinary bladder lumen, where reabsorption and covalent binding to urothelial DNA can occur [360]. Low activity of arylamine N-acetyltransferase 2 (slow NAT2 acetylator) was consistently associated with urinary bladder cancer risk [361]. Also, NAT2 plays a significant role in risk of lung cancer among non-smokers Chinese women [362]. Some studies have shown that meat consumption is associated with breast cancer risk. Several heterocyclic amines, formed in cooking of meats, are mammary carcinogens in laboratory models [363,364]. Heterocyclic amines are activated and rapid NAT2 activity may increase risk associated with these compounds [363,364], Since NAT2 increased the binding of quinoline, a heterocyclic amine derivative, with DNA by 12 fold, while NAT1 increased such binding by 4 fold [364]. 1.4.7

Epoxide Hydrolase

Epoxide hydrolase is widely distributed throughout the animal kingdom, including human. In the rat, it almost occurs with highest activity being found in the liver and smaller amount being found in kidney, lung, and adrenal gland. In liver, epoxide hydrolase occurs predominantly in the


endoplasmic reticulum fraction, membranes, and the cytosol [365].

nuclear

The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inflammatory mediators as well as xenobiotic transformations [366]. Epoxide hydrolase is induced by most of the xenobiotic inducers of the mixed-function oxidase system. Decamethylcyclopentasiloxane (D5) is a cyclic siloxane with a wide range of commercial applications. Liver microsomal epoxide hydrolase activity and immunoreactive protein increased 1.7- and 1.4fold, respectively, in the D5-exposed group [367]. The naturally occurring organosulfur compounds (OSCs) diallyl sulfide (DAS), diallyl disulfide (DADS) and dipropyl sulfide (DPS) were studied with respect to their effects on microsomal epoxide hydrolase (mEH). DADS increased the mEH levels in the liver, intestine, and kidney, while DAS and DPS moderately induced mEH level in the liver [368]. A series of organosulfur compounds were developed as chemopreventive active compounds against hepatotoxicity and carcinogenicity of aflatoxin B1 [369]. The mechanism of chemoprotection involved in the inhibition of the P450-mediated metabolic activation of chemical carcinogens and enhancement of electrophilic detoxification through induction of epoxide hydrolase, which would facilitate the clearance of activated metabolites through conjugation reaction [369]. . Although hydrolysis in most of the cases result in detoxication, in some cases hydrolysis may lead to activated molecules that may attack macromolecules (proteins, RNAs, DNAs), resulting in toxicity [370]. On the other hand, the discovery of substituted ureas and carbamates as potent inhibitors were found to enhance cytotoxicity of trans-stilbene oxide, which is active as the epoxide, but reduce cytotoxicity of leukotoxin, which is activated by epoxide hydrolase to its toxic diol [366]. They also reduce toxicity of leukotoxin in vivo in mice and prevent symptoms suggestive of acute respiratory distress syndrome [366]. Genetic polymorphisms of biotransformation enzymes are in a number of cases a major factor involved in the interindividual variability in xenobiotic metabolism and toxicity [371]. This may lead to interindividual variability in efficacy of drugs and disease susceptibility. Polymorphisms in exons 3 and 4 of microsomal epoxide hydrolase in 101 patients with colon cancer and compared the results with 203 control samples.

122


The frequency of the exon 3 T to C mutation was higher in cancer patients than in control [372]. This sequence alteration changes tyrosine residue 113 to histidine and is associated with lower enzyme activity when expressed in vitro. Therefore, slow epoxide hydrolase activity may be a risk factor for colon cancer [372].

Salah A. Sheweita

PAPS

=

3'-Phosphoadenosine-5'phosphosulfate

MAB

=

N-Methyl-4-aminoazobenzene

DAB

=

N, N-Dimethylaminoazobenzene

GSH

=

Glutathione (reduced form)

CONCLUSION

GSSG

=

Glutathione (oxidized form)

This review represents the importance of cytochrome P450 in the oxidation of xenobiotics and carcinogens. Cytochromes P450 are multigene families with broad substrate specificities. The expression of different P450 isozymes is dependent on many endogenous or exogenous factors. Each P450 isozyme is responsible for oxidation of certain drug into more or less active metabolites. The toxicity and carcinogenicity of chemical carcinogens are mainly dependent on the level of their activating enzymes and also on the balance with detoxifying enzymes such as glutathione S-transferase.

GST

=

Glutathione-S-transferase

GR

=

Glutathione reductase

NAT

=

N-Acetyltransferase

EH

=

Epoxide hydrolase

DAS

=

Diallyl sulfide

DADS

=

Diallyl disulfide

DPS

=

Dipropyl sulfide

ABBREVIATIONS

REFERENCES

Cyp

=

Cytochrome

[1]

Herman, A. (1990) Carcinogenesis, 11(5), 707-712..

MFO

=

Mixed-function oxidase

[2]

Oliw, E.H.; Guengerich, F.P.; and Oates, J.A. (1982) J. Biol. Chem., 257(7), 3771-3781.

MC

=

3-Methylcholanthrene

[3]

PB

=

Phenobarbitone

Omura, T. and Sato, R. (1962) J. Biol. Chem., 237, 1375-1376.

β-NF

β-Naphtoflavone

[4]

=

Omura, T. and Sato, R. (1964) J. Biol. Chem., 239, 2370-2378.

Ah

=

Aryl hydrocarbon

[5]

Costas, I. and Dennis, V.P. (1987) Biochem. Pharmacol., 24, 4197-4207.

PAHs

=

Polycyclic aromatic hydrocarbons

[6]

Chen G.F.; Ronis M.J.; Ingelman-Sundberg M.; Badger T.M. (1999) Xenobiotica, 29(5), 437-51.

TCDD

=

Tetrachlorodibenzo-p-dioxin [7]

PCB

=

Polychlorinated biphenyl

Shou, M; Korzekwa, K.R.; Brooks, E.N.; Krausz, K.W.; Gonzalez, F.J.; Gelboin, H.V. (1997) Carcinogenesis, 18(1), 207-14.

EROD

=

Ethoxyresourfin O-deethylase

[8]

B(a)P

=

Benzo (a) pyrene

Lee, R.F. (1998) Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol., 121(1-3), 173-9.

[9]

AHH

=

Aryl hydrocarbon hydroxylase

2-AAF

=

2-Acetylaminofluorene

Yu, J.; Chang, P.K.; Ehrlich, K.C.; Cary, J.W.; Montalbano, B.; Dyer, J.M.; Bhatnagar,. D.; Cleveland, T.E.; (1998) Appl. Environ. Microbiol., 64(12), 4834-41.

AFB1

=

Aflatoxin B1

[10]

DMN

=

Dimethylnitrosamine

Ma, J, Qu, W.; Scarborough, P.E.; Tomer, K.B.; Moomaw, C.R.; Maronpot, R.; Davis, L.S.; Breyer, M.D.; and Zeldin, D.C. (1999) J. Biol. Chem., 274(25), 17777-88.



[11]

Horecher, B. L. (1950) J Biol. Chem., 183, 593-605.

[30]

Gilday, D.; Bellward, G.D,, Sanderson, J.T.; Janz, D.M.; and Rifkind, A.B. (1998) Toxicol. Appl. Pharmacol., 150(1),106-16.

[12]

Strittmater, P. and Velick, S. F. (1956) J. Biol. Chem., 221, 277-286.

[13]

Wiiliams, C. H. and Kamin, H. (1962) J. Bio. Chem., 237, 587-595.

[31]

Lee, C.A.; Lawrence, B.P.; Kerkvliet, N.I.; and Rifkind, A.B. (1998 ) Toxicol. Appl. Pharmacol., 153(1) 1-11.

[14]

Wang, L.E.; Yang, M.; and Xie, G. (1997) Wei Sheng Yen Chiu, 26(4), 217-20.

[32]

Mahajan, S.S. and Rifkind, A.B. (1999) Toxicol. Appl. Pharmacol., 155(1 ), 96-106.

[15]

De Vetten, N.; Horst, J.; Van Schaik, H.P, de Boer, A.; Mol, J.; and Koes, R. (1999) Proc. Natl. Acad. Sci. USA, 19 96(2), 778-83.

[33]

Walker, N.J.; Portier, C.J.; Lax, S.F.; Crofts, F.G.; Li Y, Lucier G.W. and Sutter T.R. (1999) Toxicol. Appl. Pharmacol., 154(3) 279-86.

[16]

Hildebrandt, A. and Estabrook, R. W. (1971) Arch. Biochem. Biophys., 14, 66-79. .

[34]

Gilday, D.; Bellward, G.D, Sanderson, JT.; Janz, D.M.; and Rifkind, A.B (1998) Toxicol. Appl. Pharmacol., 150(1) 106-16.

[17]

Yamazaki, H.; Nakano, M.; Imai, Y.; Ueng, Y.F.; Guengerich, F.P, and Shimada, T. (1996) Arch. Biochem. Biophys., 325(2 ), 174-82.

[35]

Machala, M.; Drbek P, Nea J, Kol_ov_ J, Svobodov, Z (1998) Ecotoxicol. Environ. Saf., 41(1) 107-11.

[18]

Voice, M.W.; Zhang, Y.; Wolf, C.R.; Burchell, B.; Friedberg, T. (1999) Arch. Biochem. Biophys., 366(1), 116-24.

[36]

Hietanen, E.; Malaveille, C.; Friedman, F.K.; Park, S.S.; Béréziat, J.C.; Brun, G.; Bartsch, H.; and Gelboin, H.V.(1986) Cancer Res., 46(2), 524-531.

[19]

Matsusue, K.; Ariyoshi, N.; Oguri, K.; Koga, N, and Yoshimura, H. (1996) Chemosphere, 32(3), 517-23 .

[37]

Pacheco, M.; and Santos, M.A. (1998) Ecotoxicol Environ Saf.; 40(1-2) 71-6.

[20]

Song, B.J.; Fujino, T.; Park, S.S.; Friedman, F.K.; and Gelboin, H.V.(1984): J Biol Chem., 259, 1394-1397 .

[38]

Mino, K.; Watanabe, J.; Kanamura, S.J. (1998) Histochem. Cytochem., 46(10), 1151-60.

[21]

Ioannides, C.; Lum, P.Y.; and Parke, D.V. (1984) Xenobiotica, 1, 119-137.

[39]

[22]

Bresnick, E.; Vaught, J.B.; Chuang, A.H.; Stoming, T.A.; Bockman, D.; and Mukhtar, H. (1977) Arch. Biochem. Biophys., 16,181-275.

Koga, N.; Kikuichi, N.; Kanamaru, T.; Kuroki, H.; Matsusue, K.; Ishida, C.; Ariyoshi N, Oguri K, and Yoshimura H (1998) Chemosphere, 37(9-12), 1895904.

[40]

Henry, M.C.; Port, C.D.; Bates, R.R.; and Kaufman DG(1973) Cancer Res., 33(7), 1585-92.

[23]

Song, B.J.; Fujino, T.; Park, S.S.; Friedman, F.K.; and Gelboin, H.V. (1984) J. Biol. Chem., 259, 1394-1397.

[41]

Song, B.J.; Fujino, T.; Park, S.S.; Friedman, F.K. and Gelboin, H.V. (1984) J. Biol. Chem., 259(3), 1394-7.

[24]

Santostefano, M.J.; Ross, D.G.; Savas, U.; Jefcoate, C.R.; Birnbaum, L.S. (1997) Biochem. Biophys. Res. Commun., 233, 20-4.

[42]

Cheng, K.C.; Gelbin, H. V.; Song, B.; Parl, S. S.; and Friedman (1984). J. Biol. Chem., 259, 12279-84.

[25]

Ertl, R.P.; Stegeman, J.J.; Winston, G.W. (1998) Biochem. Pharmacol., 55(9), 1513-21.

[43]

Ioannides, C.; Lum, Y. P. and Parke, D. V. (1984) Xenobiotica, 14, 119-124.

[26]

Ahmed, R.S.; and Pawar, S S.; (1997) Indian J. Exp. Biol., 35(1), 46-9.

[44]

Iwasaki, K.; Lum, Y. P.; Ioannides, C.; and Parke, D. V. (1986) Biochem. Pharmacol., 35, 3879-3884.

[27]

Sagami, I.; and Watanabe, M. (1983) J Biochem., (Tokyo), 93(6), 1499-508.

[45]

Ding, X.X.; Koop, D.R.; Crump, B.L.; and Coon, M.J. (1986) Mol. Pharmacol., 30,4 370-8.

[28]

Rojas, M.; Alexandrov K.; Cascorbi, I.; Brockmöller, J.; Likhachev, A.; Pozharisski, K.; Bouvier, G.; Auburtin, G.; Mayer, L.; Kopp-Schneider, A.; Roots, I.; and Bartsch, H. (1998) Pharmacogenetics, 8(2), 109-18.

[46]

Ioannides, C.; and Parke, D.V (1990) Drug Metab. Rev., 22(1) 1-85.

[47]

Thomas P.E.; Reik L.M.; Ryan D.E.; Levin W. (1998) J. Biol. Chem., 1984 259(6), 3890-9.

Ueng, T.H.; and Alvares, Pharmacol., 1, 221-8.

[48]

Lake B.G.; Charzat C. Tredger J.M.; Renwick A.B.; Beamand J.A.; Price R.J. (1996) Xenobiotica, 26(3) 297-306.

[29]

A.P.

(1982)

Mol

124


Salah A. Sheweita

[49]

Yamazaki H.; Shaw P.M.; Guengerich F.P.; Shimada T. (1998) Chem. Res. Toxicol., 11(6), 659-65 .

[69]

Mostafa, M.H. and Sheweita, S.A. (1992) Ramazzini Newsletter, 2, 15-22.

[50]

Hanioka N.; Jinno H.; Nishimura T.; Ando M. (1997) Arch. Toxicol., 72,1 9-16.

[70]

Sheweita, S. A. and Mostafa, M. H. (1996) Cancer Lett., 106, 243-249.

[51]

Lee C.A.; Manyike P.T.; Thummel K.E.; Nelson S.D.; Slattery J.T. (1997) Drug Metab. Dispos., 25(10), 1150-6.

[71]

Mostafa, M. H.; Sheweita, S. A. and Abdel- Moneam, N. M. (1990) Environ. Res., 52, 77-82.

[72] [52]

Marczylo T.; Ioannides C. (1990) Toxicol., 134(2-3), 127-41.

Mostafa, M.H.; Sheweita, S.A.; and O’Connor, P.J. (1999) Clin. Microbiol. Rev., 12(1), 97-111.

[73] [53]

Basu T.K.; Dickerson J.W.; Parke D.V. (1971) Biochem J., 124(1), 19-24.

Sheweita, S. A. (1999) Environ. Nutritional Interact., 2(3),1-9.

[74] [54]

Atlas S.A.; Boobis A.R.; Felton J.S.; Thorgeirsson S.S.; Nebert D.W. (1977) J. Biol. Chem., 252(13), 4712-21.

Chen R.M.; Chou M.W.; Ueng T.H. (1998) Arch Toxicol., 72(7) 395-401.

[75]

Pappas P.; Stephanou P.; Vasiliou V.; Marselos M. (1998) Eur. J. Drug Metab. Pharmacokinet., 23(4), 457-60.

[76]

Petra, R.; Michael, P. I.; Franz, O.; and Larry, W. (1987) Biochem. Pharmacol., 36, 4355-4359.

[77]

Alvares, A.P.; Schilling, G.; Levin, W.; and Kuntzman, R. (1967) Biochem. Bviophys. Res. Commun., 29, 521-526.

[78]

Nebert, D. W.; Nelson, D. R. and Feyereisen, R. (1989) Xenobiotica, 19(10) ,1149-60.

[79]

Bresnick, E.; Vaught, J.B.; Chuang, A.H.; Stoming, T.A.; Bockman, D.; and Mukhtar, H. (1977) Arch. Biochemistry Biophysic., 16,181-275.

[80]

Troisi G.M.; Mason C.F. (1997) Chemosphere, 35(9), 1933-46.

[81]

Josephy P.D.; Evans D.H.; Parikh A.; Guengerich F.P. (1998) Chem. Res. Toxicol., 11, 1 70-4.

[82]

Nebert, D.W.; and Jensen, N.M. (1979) CRC Crit. Rev. Biochem., 6, 401-437.

[83]

Poland, A.; Glover, E.; and Kende, A.S. (1976) J. Biol. Chem., 251, 4936-4946.

[84]

Pohjanvirta R.; Viluksela M.; Tuomisto J.T.; Unkila M.; Karasinska J.; Franc M.A.; Holowenko M.; Giannone J.V.; Harper P.A.; Tuomisto J.; Okey A.B. (1999) Toxicol. Appl. Pharmacol., 155(1), 82-95.

[55]

Lum P.Y.; Walker S.; Ioannides C. (1985) Toxicol., 35(4), 307-17.

[56]

Blanck A.; Aström A.; Hansson T.; De Pierre J.W. and Gustafsson J.A. (1986) Carcinogenesis, 7, 4 57582.

[57]

Jorquera F.; Culebras J.M.; González-Gallego J. (1996) J. Nutrition., 12(6), 442-7.

[58]

El-Bayoumy K.; Prokopczyk B.; Peterson L.A.; Desai D.; Amin S.; Reddy B.S.; Hoffmann D.; Wynder E. (1996) Nutr. Cancer, 26(1), 1-10.

[59]

Ahn D.; Putt D.; Kresty L.; Stoner G.D.; Fromm D.; Hollenberg P.F. (1996) Carcinogenesis, 17(4), 821-8.

[60]

Irizar A. and Ioannides C. (1998) Toxicol., 126(3), 179-93.

[61]

Atanasova-Goranova V.K.; Dimova P.I.; Pevicharova G.T. (1997) Br. J. Nutr., 78(2), 335-45.

[62]

Jewell C.; O'Brien N.M. (1999) Br J Nutr., 81(3), 235-42.

[63]

Leo M.A. and Lieber C.S. (1999) Am. J. Clin. Nutr., 69(6), 1071-85.

[64]

Pantuck E.J.; Hsiao K.C.; Loub W.D.; Wattenberg L.W.; Kuntzman R.; Conney A.H. (1976) J. Pharmacol. Exp. Ther., 198(2), 278-83.

[65]

Rikans L.E.; Notley B.A.; Pharmacol., 31(14), 2339-43.

Biochem.

[85]

Hamnah, R.R.; Lund, J,Pollinge, L.; Gillner, M.; and Gustaffson, J.A. (1986) Eur. J. Biochem., 156, 237243.

[66]

Kahl G.F.; Friederici D.E.; Bigelow S.W.; Okey A.B.; Nebert D.W.; (1980) Dev. Pharmacol. Ther., 1(2-3), 137-62.

[86]

Gonzalez F.J.; Fernandez-Salguero P. (1998) Drug Metab Dispos., 26(12), 1194-8.

[67]

Loub W.D.; Wattenberg L.W.; Davis D.W. (1975) J. Natl. Cancer Inst., 54(4), 985-8.

[87]

Denison, M.S.; Vella, L.M.; and Okey, A. B. (1987) Arch. Biochem. Biophys., 252, 388-395.

[68]

McDanell R.; McLean A.E.; Hanley A.B.; Heaney R.K.; Fenwick G.R. (1987) Food Chem. Toxicol., 25(5), 363-8.

[88]

Wroblewski, V.J.; and Olson, J. R.(1988) Drug Metab. Dispos., 16, 43-51 .

(1982)


[89]

Hannah, R.R.; Lund, J.; Poellinger, L.; Gillner, M.; and Gustafsson, J.A. (1986) Eur. J. Biochem., 156, 237-242.

[90]

Durrin, L.K.; Jones, P.B.; Fisher, J.M.; Galeazzi, D.R.; and Whitlock, J.P. Jr (1987) J. Cell. Biochem., 35(2), 153-156.

[91] [92]

Tukey, R.H.; Hannah, R.R.; Negishi, M.; Nebert, D.W.; and Eisen, H.J. (1982) Cell, 31, 275-284. Okey, A. B.; Bonny, G.P.; Mason, M.E.; Kahl, G.F.; Eisen, H.J.; Guenthner, T.M. and Nebert D.W. (1979) J. Biol. Chem., 254, 11636-11648.

[93]

Green, S.; and Chambon, P. (1986) Nature, 324, 615617.

[94]

Lancols, K. D. and Bresnick, E. (1973) Drug Metab. Dispos., 1, 239-247.

[95]

Ragnotti, G.; and Aletti, M. G. (1975) Biochem. J., 146, 1-12.

[96]

Shuster, L. and Jick, H. (1966) J. Biol. Chem., 241, 5361-5365.

[97]

Manen, C.A.; Costa, M.; Sipes, I.G. and Russell, D.H. (1978) Biochem. Pharmacol., 27(2), 219-24.

[98]

Giger, U.; and Meyer, U. A. (1981) Biochem. J., 198, 321-329.

[99]

Arizono, K.; Sakamoto, J.; Mikajiri, M.; Murashima, A.; and Ariyyoshi, T. (1993) Trace Elements in Med., 10: 80-84.


[109]

Yusuf A.; Rao P.M.; Rajalakshmi S.; Sarma D.S. (1999) Carcinogenesis, 20(8),1641-4.

[110] Sheweita, S. A. and Mostafa, M. H. (1996) Cancer lett., 106, 243-249. [111] Netter, K. J. (1973) Drug Metabol. Dispos., 1, 162163. [112] Mostafa, M. H.; Sheweita, S. A.; El-Kowedy, A. H. and Badawi, A. F. (1993) Int. J. Oncology, 2, 695699. [113] Sheweita, S.A.; Mostafa, M/H.; Doenhoff, M.; Margison, G.P.; O’Connor, P.J.; and Elder, R.H. (1998) Proceeding of fourth Symposium on Cytochrome P450 Biodiversity and Biotechnology”, Strasbourg, France. [114] Sheweita, S. A.; Safwat A. Mangoura and Adel G. ElShemi, (1998) J. Helminthology., 72, 72-77. [115] Samy L. H.; Sheweita, S. A.; Mostafa, M. H.; Awad , A. F.; Mashaal, N. M. and Soliman, A. A. (1996): Oncol. Report., 3(4), 769-773. [116] Sheweita, S. A. (1999) Environm. Nutrit. Interaction, 2(3):1-9. [117] Zhai, S.; Dai, R.; Friedman, F. K. and Vestal, R. E. (1998) Drug Metabo. Dispos., 26(10), 989-992. [118] Jeong, H. G. (1999) Toxicol. Lett., 105(3), 215-222.

[100] Eaton, D. L.; Stacey, N. H.; Wong, K.-L.; and Klaassen, C. D. (1980) Toxicol. Appl. Pharmacol., 55: 393-402. [101] Thurman, R. G. and Kuffman, F. C. (1980) Am. Soc. Pharmacol. Therap.; 31, 229-246. [102] Lee C.K.; Fulp C.; Bombick B.R.; Doolittle D.J. (1996) Mutat. Res., 367(2), 83-92. [103] Mathews J.M.; Etheridge A.S.; Raymer J.H.; Black S.R.; Pulliam D.W. Jr., Bucher J. (1998) Chem. Res. Toxicol., 11(7), 778-85. [104] Bond, E. J. and DeMatteis, F. (1969) Biochem. Pharmacol., 18, 2531-2549. [105] DeMatteis, F. (1973). Drug. Metab. Dispos., 1, 267274. [106] Levin, W.; Jacobson, M.; Sernatinger, E.; and Kuntzman, R. (1973) Drug. Metab. Dispos., 1, 265275. [107] Franklin, M. R.; and Estabrook, R. W. (1971) Arch. Biochem. Biophys., 143, 318-329. [108] Illing, H. P. and Netter, K. J. (1975) Xenobiotica, 5, 1-15.

[119] Lilly, P. D.; Thornton Manning, J. R.; Gargas, M. L.; Clewell, H. J.; and Anderson, M. E. (1998) Arch. Toxicol., 72(10), 609-622. [120] Mathews, J. M.; Etheridge, A. S.; Raymer, J. H.; Black, S. R.; Pulliam, D. W. and Bucher, J. R. (1998) Chem. Res. Toxicol., 11(7), 778-785. [121] Kim, S.G.; Cho, J. Y.; Chung, Y. S.; Ahn, E. T.; Lee, K. Y.; and Han, Y. B. (1998) Drug Metabol. Dispos., 26(1), 66-72. [122] Segura, P.; Chvez, J.; Monta, L. M.; Vargas, M. H.; Delaunois, A.; Carbajal, V.; and Gustin, P. (1999) Naunyn. Schmidebergs Arch. Pharmacol., 360(6), 649-710. [123] Agndez, J.A.; Gallardo, L.; Martnez, C.; Gervasini, G.; and Bentez, J. (1998) Pharmacogenetics, 8(3), 251-258. [124] King R.S.; Teitel C.H.; Shaddock J.G.; Casciano D.A.; Kadlubar F.F. (1999) Cancer Lett., 143(2), 16771. [125] Ioannides, C.; Lum, P.Y.; and Parke, D.V. (1984) Xenobiotica, 1, 119-137. [126] Ioannides, C. and Parke, D.V. (1987) Biochem Pharmacol., 36, 4192-4197 .

126


[127] Lu, A. Y. and West, S. B. (1979) Pharmacol. Rev., 31(4), 277-95. [128] Ryan, D.E.; Thomas, P.E.; and Levin, W. (1982) Arch. Biochem. Biophys., 216(1), 272-288. [129] Oliw, E.H.; Guengerich, F.P.; and Oates, J.A. (1982) J. Biol Chem., 257(7), 3771-3781. [130] Gillette, J. R.; Davis, D. C. and Sasame, H. A. (1972) Ann. Rev. Pharmacol. Toxicol., 12, 57-84. [131] Mason, H. S. (1957) Adv. Enzymol., 19, 79-233. [132] Mason, H. S.; North, J. C. and Vannester, M. (1965) Fed. Proc., 24, 1172-1180. [133] Poland, A.; Glover, E.; Ebetino, F.H.; and Kende (1986): J. Biol. Chem. 261: 6352-6365. [134] Thomas, P.E.; Korzeniowski, D.; Bresnick, E.; Bornstein, W.A.; Kasper, C.B.; Fahl, W.E.; Jefcoate, C.R. and Levin, W. (1979) Arch. Biochem. Biophys., 192, 22-26.

Salah A. Sheweita

[148] Miller, E. C. and Miller, J. A. (1976) In Chemical carcinogens, (Searle, C. E. Ed.) American Chemical Society, Washington, D. C. [149] Whyatt R.M.; Bell D.A.; Jedrychowski W.; Santella R.M.; Garte S.J.; Cosma G.; Manchester D.K.; Young T.L.; Cooper T.B.; Ottman R.; Perera F. (1998) Carcinogenesis, 19(8), 1389-92. [150] Kim J.H.; Stansbury K.H.; Walker N.J.; Trush M.A.; Strickland P.T.; Sutter T.R. (1998) Carcinogenesis, 19(10), 1847-53. [151] Parrish A.R.; Fisher R.; Bral C.M.; Burghardt R.C.; Gandolfi A.J.; Brendel K.; Ramos K.S. (1998) Toxicol. Appl. Pharmacol., 152(2), 302-8. [152] Whyatt R.M.; Santella R.M.; Jedrychowski W.; Garte S.J.; Bell D.A.; Ottman R.; Gladek-Yarborough A.; Cosma G.; Young T.L.; Cooper T.B.; Randall M.C.; Manchester D.K.; Perera F. (1998) Environ Health Perspect 106 Suppl 3, 821-6. [153] Sagami, I.; Ohmachi, T.; Fujii, H.; and Watanabe, M. (1987) Xenobiotica, 17, 189-198.

[135] Bresnick, E.; Stoming, T.A.; Vaught, J.B.; Thakker, D.R.; and Jerina, D.M. (1977) Arch. Biochem. Biophys., 183, 31-37.

[154] Burke, M. D. and Prough, R. A. (1976) Biochem Pharmacol., 25, 2187-2195.

[136] Gillette, J. R.; Davis, D.C. and Sesame, H. A. (1972) Ann. Rev. Pharmacol., 12:57-84.

[155] Henry, M.C.; Port, C.D.; Bates, R.R. and Kaufman, D.G. (1973) Cancer Res., 33,1585-1592.

[137] Wood, A.W.; Ryan, D.E.; Thomas, P.E.; and Levin, W. (1983) J. Biol Chem., 258, 8839-8847.

[156] Gelboin, H. V. (1980) Physiol. Rev., 6, 1107-1166.

[138] Waxman, D.J. (1984) J Biol Chem., 25, 15481-15489.

[157] Huberman, E.; Sachs, L.; Yang, S. K. and Gelboin, H. V. (1976) Proc. NatI. Acad. Sci. USA, 73, 607-701.

[139] Cheng, K.C. and Schenkman, J.B. (1984) Drug Metab. Dispos., 1, 222-234.

[158] Weibel, F. J. and Gelboin, H. V. (1975) Biochem. Pharmacol., 24, 1511-1515.

[140] Jansson, I.; Mole, J. and Schenkman, J.B. (1985) J. Biol. Chem., 26, 7084-7093.

[159] Hall, M.; and Grover, P.L. (1986) Chem Biol. Interact., 59(3): 265-8.

[141] Oliw, E.H.; Guengerich, F.P.; and Oates, J.A. (1982) J. Biol. Chem., 257(7), 3771-3781.

[160] Phillipson, C.E.; Ioannides, C.; Barrett, D.C.; Parke, D.V.(1985) Int. J. Biochem., 17(1), 37-42.

[142] Laniado-Schwartzman, M.; Davis, K.L.; McGiff, J.C.; Levere R.D. and Abraham, N.G. (1988) J. Biol. Chem., 263(5), 2536-2542.

[161] Oesch, F.; Bentley, P.; Golan, M.; and Stasiecki, P.(1985) Cancer Res., 45(1), 4838-4843.

[143] Pott, P. (1775) Chirugical observation relative to the cataract, the polypus of the nose, the cancer of the scrotum, the different kinds of ruptures, and the modification of the toes and feet. Hawakes, Clarke and Collins (eds), London. [144] Higginson, J. (1972) Roy. Soc. Health J., 92, 291-6. [145] Wynder, E. L. and Mabuchi, K. (1972) Preve. Medic., 1(3), 300-34. [146] Weisburger, J. H. and Williams, G.M. (1980) Cancer Prev., 34,180-190. [147] Tricker A.R. (1997) Eur. J. Cancer Prev., 6(3), 22668.

[162] Guengerich, F. P. (1991) J. Biol. Chem., 226,1001910022. [163] Ioannides, C.; Parkinson, C. and Parke, D.V. (1981) Xenobiotica, 17, 1-8. [164] Wood, A.W.; Chang, R.L.; Levin, W.; Thomas, P.E.; Ryan, D.; Stoming, T.A.; Thakker, D.R.; Jerina, D.M. and Conney, A.H. (1978) Cancer Res., 1, 3398-3404. [165] Mitchell, C.E. (1985) Biochem. Pharmacol., 34(4), 545-51. [166] Kawajiri, K.; Yonekawa, H.; Harada, N.; Noshiro, M.; Omura, T. and Tagashira, Y. (1980) Cancer Res., 4(5 ), 1652-1657.


[167] Hietanen, E.; Malaveille, C.; Friedman, F.K.; Park, S.S.; Béréziat, J.C.; Brun, G.; Bartsch, H.; and Gelboin, H.V.(1986) Cancer Res., 46(2), 524-531. [168] Kawano, S.; Kamataki, T.; Maeda, K.; Kato, R.; Nakao, T.; and Mizoguchi, I.(1985) Fundam. Appl. Toxicol., 3, 487-498.


[188] Garner, R.C.; Miller, E.C. and Miller, J.A. (1972) Cancer Res., 32,1058-1066. [189] Wang J.S.; Groopman J.D. (1999) Mutat. Res., 424(12), 167-81. [190] Swenson, D.H.; Lin, J.K.; Miller, E.C. and Miller, J.A. (1977) Cancer Res., 37(1 ), 172-181.

[169] Conney, A. H. (1982) Cancer Res., 42, 4875-4917. . [170] Gooderham, N.J. and Mannering, G. J. (1985) Cancer Res., 45,1569-1572. [171] Nordqvist, M.; Thakker, D.R.; Levin, W.; Yagi, H.; Ryan, D.E.; Thomas, P.E.; Conney, A.H.; and Jerina, D.M.(1979) Mol. Pharmacol., 16, 643-655. [172] Wood, A.W.; Chang, R.L.; Levin, W.; Yagi, H.; Thakker, D.R.; Van Bladeren, P.J.; Jerina, D.M.; and Conney, A.H.(1983) Cancer Res., 43,12 Pt 1 .

[191] Robertson I.G.; Zeiger E. and Goldstein J.A. (1983) Carcinogenesis, 4, 193-196. [192] Lin, J.K.; Kennan, K.A.; Miller, E.C. and Miller, J.A. (1978) Cancer Res., 38: 2424-2428. [193] Sun, J.D. and Dent, J.G. (1980) Chem. Biol. Interact., 32(1-2), 41-61. [194] Wang H.; Dick R.; Yin H.; Licad-Coles E.; Kroetz D.L.; Szklarz G.; Harlow G.; Halpert J.R.; Correia M.A. (1998) Biochem., 37(36), 12536-45.

[173] Blount, W. P. (1961) Turkeys, 9, 52-56. [174] Asplin, F. S. and Carnag han, R. B. (1961) Vet. Record, 73(46), 1215-1218. [175] Sargent, K.; Allcroft, R. and Carnag han, R. B. (1961) Vet. Record, 73, 865-867. [176] Hueper, W. C. and Payne, W. W. (1961) J. NatI. Cancer Inst., 27, 1123-1126. [177] Wood, E. M. and Larson, C. P. (1961) Arch. Pathol., 71, 471-479. [178] Ghittino, P. and Ceretto, F. (1962) Tumori., 48, 393395. [179] Wolf, H. and Jackson, E. W. (1963) Science, 142, 470-678. [180] Nesbitt, B. F.; O'Kelly, J.; Sargent, K. and Sheridan, A. (1962) Nature, 195, 1062-1063. . [181] Hartley, R. D.; Brenda, F. and O'Kelly, J. (1963) Nature, 198, 1056-1058. [182] Gurtoo, H.L.; and Dave, C.V. (1975) Cancer Res., 35(2), 382-389. [183] Williams, D.E. and Buhler, D.R. (1983) Cancer Res., 43, 14752-14756. [184] Ueng Y.F.; Shimada T.; Yamazaki H.; Peterguengerich F. (1998) J. Toxicol. Sci. Suppl., 2, 132-5. [185] Neal G.E.; Eaton D.L.; Judah D.J.; Verma A. (1998) Toxicol. Appl. Pharmacol., 151(1), 152-8. [186] McDonagh P.D.; Judah D.J.; Hayes J.D.; Lian L.Y.; Neal G.E.; Wolf C.R.; Roberts G.C. (1998) Biochem. J., 339 ( Pt 1), 95-101. [187] Garner, R.C.; Miller, E.C.; Miller, J.A.; Garner, J.V.; and Hanson, R.S. (1971) Biochem. Biophys. Res. Commun., 45, 774-778. .

[195] Ishii, K.; Maeda, K.; Kamataki, T. and Kato, R. (1986) Mutat. Res., 174, 85-88. [196] Garner, R.C. (1975) Biochem. Pharmacol., 24(16), 1553-1556. [197] Martin, C.N. and Garner, R.C. (1977) Nature, 267, 863-865. [198] .Essigmann, J.M.; Croy R.G.; Bennett, R.A. and Wogan, G.N. (1982) Drug Metab. Rev., 13, 581-602. [199] Essigmann, J.M.; Donahue, P.R.; Story, D.L.; Wogan, G.N. and Brunengraber, H. (1980) Cancer Res., 4, 4085-4091. [200] Preussmann, P. (1984) In N-nitroso compounds, Occurrence, biological effects and relevance to human cancer ( I. K. O'Neil, R. C. Von Borstll, C. T. Miller, J. Long, and H. Bartsch Eds.) International Agency for Research on Cancer, IARC Sci. Publ. no. 57, Lyon. [201] Bartsch, H. and Montesano, Carcinogenesis, 5, 1381-1393.

R.

(1984)

[202] Brunnemann K.D.; Prokopczyk B.; Djordjevic M.V.; Hoffmann D. (1996) Crit. Rev. Toxicol., 26(2), 12137. [203] Hecht, S.S. (1998) Chem. Res. Toxicol., 11(6), 559603. [204] Schuller, H.M. (1997) Mutat. Rer., 380(1-2), 13-8. [205] Tricker, A.R. (1996) Eur. J. Cancer Prev. Suppl., 1, 95-9. [206] Hoffmann, D.; Rivenson, A. and Hecht, S.S. (1996) Crit. Rev. Toxicol., 26(2), 199-211. [207] Izquierdo-Pulido, M.; Barbour, J.F. and Scanlan, R.A. (1996) Food Chem. Toxicol., 34(3), 297-9 .

128


Salah A. Sheweita

[208] Lijinsky, W.E.; Conrad, J. and Van De Bogart, R. (1972) Nature, 239: 165-174.

[228] Yang, C.S.; Yoo, J-SH, Ishizaki, H.; Hong, J. (1990) Drug Metaboism Rev., 22, 147-159.

[209] Elespuru, R.K. and Lijinsky, W. (1973) Food and Cosm. Toxicol., 11, 807-817.

[229] Shields, P.G.; Ambrosone, C.B.; Graham, S.; Bowman, E.D.; Harrington, A.M.; Gillenwater, K.A.; Marshall, J.R.; Vena, J.E.; Laughlin, R.; Nemoto, T. and Freudenheim, J.L.(1996) Mol. Carcinog., 17(3), 144-50.

[210] Preuss, R. and Eisenbrand, G. (1984) In Chemical carcinogens, 2nd ed, (Searle, C. E. Ed.) ACS Monograph Series No. 182, Am. Chem. Socit., Washington, DC. [211] Wang, Y.; Ichiba, M.; Iyadomi, M.; Zhang, J. and Tomokuni, K. (1998) Ind. Health, 36(4), 337-46. [212] Volmer, D.A.; Lay, J.O.; Billedeau, M. and Vollmer, D.L. (1996) Rapid. Commun. Mass Spectrom., 10(6), 715-20. [213] Tricker, A. R.; Mostafa, M. H.; Spiegelhalder, B. an. Preussman, R. (1989) Carcinogenesis, 1, 547-552.

[230] Nakagawa, T.; Sawada, M.; Gonzalez, F.J.; Yokoi, T. and Kamataki, T. (1996) Mutat. Res., 360(3), 181-6. [231] Zerilli, A.; Lucas, D.; Dreano, Y.; Picart, D. and Berthou, F. (1998) Alcohol Clin. Exp. Res., 22(3), 652-7. [232] Tu, Y.Y. and Yang, C.S. (1985) Arch. Biochem. Biophys., 242, 32-40. [233] Yoo, J.S.H. and Yang, C.S. (1985) Cancer Res., 45, 5569-5574.

[214] Mostafa,, M.H.; Helmi, S.; Badawi, A. F.; Tricker, A. R, Spiegelhalder, B. and Preussman, R.. (1994) Carcinogenesis, 15:619-625.

[234] Yoo, J.S.H.; Ning, S.H.; Patten, C. and Yang, C.S. (1987) Cancer Res., 47, 992-998.

[215] Hecht, S.S. (1997) Proc. Soc. Exp. Biol. Med., 216(2) 181-91.

[235] Hong, J. and Yang, C.S. (1985) Carcinogenesis, 6, 1805-1809.

[216] Amin, S.; Desai, D.; Hecht, S.S.; Hoffmann, D. (1996) Crit. Rev. Toxicol., 26(2), 139-47.

[236] Lorr, N.A.; Miller, K.W.; Chung, H.R. and Yang, C.S. (1984) Toxicol. Appl. Pharmacol., 73, 423-431.

[217] Bellec, G.; Goasduff, T, Dreano, Y.; Menez, J.F.; Berthou, F. (1996) Cancer Lett., 100(1-2) 115-23.

[237] Magee, P. (1989) Cancer Surv., 8, 207-239. [238] Wolf, C.R.; (1990) Cancer Surv., 9, 437-474.

[218] Le Marchand, L.; Sivaraman, L.; Pierce, L.; Seifried ,A.; Lum, A.; Wilkens, L.R.; Lau, A.F. (1998) Cancer Res., 58(21), 4858-63. [219] Mochizuki, M.; Suzuki, E. and Okada, M. (1997) Yakugaku Zasshi, 117(10-11), 884-94. [220] Wu, X.; Amos, C.I.; Kemp, B.L.; Shi, H.; Jiang, H.; Wan, Y. and Spitz, M.R. (1998) Cancer Epidemiol Biomarkers Prev., 7(1), 13-8. [221] Arcos, J.C.; Davies, D.L.. Brown, C.E. and Argus, M. E. (1977): Z. Krebsforsch., 89, 181-199. [222] Hecht, S.S. (1999) Mutat Res., 424(1-2), 127-42. [223] Petruzzelli, S.; Tavanti, L.M.; Celi, A. and Giuntini, C. (1996) Am. J. Respir. Cell. Mol. Biol., 15(2), 21623. [224] Koppang, N.; Rivenson, A.; Dahle, H.K. and Hoffmann, D. (1997) Cancer Lett., 111(1-2) 167-71. [225] Mostafa, M.H.; Ruchirawat, M. and Weisburger. E. K. (1981) Biochem. Pharmacol., 3, 2007-2011. [226] Encell, L.; Foiles, P.G.; Gold, Carcinogenesis, 17(5), 1127-34.

B.

(1996)

[227] Wong, P.P.; Beaune, P.; Kaminsky, L.S.; Dannan, G.A.; Kadlubar, F.F.; Larrey, D.; Guengerich, F. P. (1983) Biochem., 22, 5375-5383.

[239] Orrenius, S.; Thor, H. and Jerstrom, B. (1980) In: Environmental chemicals, enzyme function and human diseases. Ciba Foundation Symposium no. 76. Exverpta Medica, Amsterdam. [240] Carrière, V.; Berthou, F.; Baird, S.; Belloc, C.; Beaune, P. and de Waziers, I. (1996) Pharmacogenetics, 6(3), 203-11. [241] Clayson, D.B. and Garner, R.C. (1976) In Chemical carcinogenesis. (Searle, C. E.; ed. ) Am. Chem. Soci, ACS Monograph, 173, Lyon, France. [242] Pfau, W.; Martin, F.L.; Cole, K.J.; Venitt, S.; Phillips, D.H.; Grover, P.L. and Marquardt, H. (1999) Carcinogenesis, 20(4), 545-51. [243] Masson, H.A.; Ioannides, C.; Gorrod, J.W. and Gibson, G.G. (1983) Carcinogenesis, 4(12),15831586 . [244] Turesky, R.J.; Constable, A.; Fay, L.B. and Guengerich, F.P. (1999) Cancer Lett., 143(2), 109-12. [245] International Labor Office (1921): Cancers among workers in aniline factories. Studies and reports, series F, No.1, P.2-26. Geneva. [246] IARC (1972) IARC monograph on the evaluation of carcinogenic risk to man, Vol.1, Lyon, France.



[247] IARC (1987): IARC monograph on the evaluation of carcinogenic risk to humans, suppl. 7, volumes 1 -42, Lyon, France.

[267] Miller, J.A. and Miller, E.C. (1975) International Agency for Research on Cancer, PP.153-176, Lyon, France.

[248] IARC (1990): IARC monograph on the evaluation of carcinogenic risk to humans, Vol.48, Lyon, France.

[268] Cheo, D.L.; Burns, D.K.; Meira, L.B.; Houle, J.F.; Friedberg, E.C. (1999) Cancer Res., 59(4), 771-5.

[249] Aström, A. and DePierre, Carcinogenesis, 6(1), 113-122.

(1985)

[269] King, C.M.; Traub, N. R.; Lortz, Z.M. and Thissen, M.R. (1979) Cancer Res., 39(9), 3369-72.

[250] Goldstein, J.A.; Weaver, R. and Sundheimer, D.W. (1984) Cancer Res., 44(9), 3768-3771.

[270] Sakakibara, Y.; Yanagisawa, K.; Katafuchi, J.; Ringer, D.P.;Takami, Y.; Nakayama, T.; Suiko, M.; Liu, M.C. (1998) J. Biol. Chem., 273(51), 33929-35.

J.W.

[251] Kitamura, S.; Takekawa, K.; Sugihara, K.; Tatsumi, K. and Ohta, S. (1999) Carcinogenesis, 20(2), 34750.

[271] Beland, F.A.; Allaben, W.T. and Evans, F.E. (1980) Cancer Res., 40(3), 834-40.

[252] Hara, E.; Kawajiri, K.; Gotoh, O. and Tagashira, Y. (1981) Cancer Res., 41(1), 253-257.

[272] Chung, J.G.; Chang, H.L.; Lin, W.C.; Yeh, F.T.; Hung, C.F. (1999) J. Appl. Toxicol., 19(1), 1-6.

[253] Rzeszowska-Wolny ,J. and Widak.; P. (1999) Acta. Biochim. Pol., 46(1) 173-80.

[273] Miller, E.C. (1978) Cancer Res., 38(6), 1479-96.

[254] Shibutani, S.; Suzuki, N. and Grollman, A.P. (1998) Biochem., 37(35), 12034-41. [255] Razzouk, C.; Batardy-Grégoire, M. and Roberfroid, M.(1982) Mol. Pharmacol., 21(2), 449-457. [256] Ross JA, Leavitt SA (1998) Mutagenesis, 13(2), 1739.

[274] Igarashi, S.; Yonekawa, H.; Kawajiri, K.; Watanabe, J.; Kimura, T.; Kodama M.; Nagata C.; and Tagashira Y.(1982) Biochem. Biophys. Res. Commun., 14, 164169. [275] Kimura, T.; Kodama, M.; Nagata, C.; Kamataki, T.; and Kato, R. (1985): Biochem. Pharmacol., 1, 33753377.

[257] Thorgeirsson, S.S.; Sanderson, N.; Park, S.S. and Gelboin, H.V. (1983) Carcinogenesis, 4(5), 639-641.

[276] IARC (1972): IARC monographs on the evaluation of carcinogenic risk of chemical to man, Vol.1, Lyon, France.

[258] Cramer, T.W.; Miller, J.A. and Miller, E.C. (1960) J. Blol. Chem., 235, 885-888.

[277] Kadlubar, F.F.; Miller, J.A. and Miller, E.C. (1976) Cancer Res., 36(3), 1196-1206.

[259] Irving, C.C. (1973) in metabolic conjugation and metbolic hydrolysis, (Fishman, W, H.; ed.) Vol.1.. Academic press, New York. pp.53-119.

[278] Miller, E.C.; Kadlubar, F.F.; Miller, J. A.; Pitot, H.C. and Drinkwater, N. R. (1979) Cancer Res., 39(9), 341 1-8.

[260] Mojarrabi, B. and Mackenzie, P.I. (1998) Biochem. Biophys. Res. Commun., 247(3), 704-9.

[279] Kadlubar, F.F.; Miller, J.A. and Miller, E.C. (1976) Cancer Res., 36(7 PT 1 ), 2350-9.

[261] Shibutani, S. and Grollman, A.P. (1997) Mutat. Res., 376(1-2), 71-8.

[280] Un, J.K.; Schmall, B.; Sharpe, I.D.; Miura, I.; Miller, J.A. and Miller, E.C. (1975) Cancer Res., 35(3), 83243.

[262] Irving, C.C. (1979) in carcinogenesis: identification and mechanism of action. (Griffin, C. and Shaw, C. R. Eds.),. Raven press, New York. PP.211-227.

[281] Btunck, J. M. and Crowther, C. E. (1975) Euro. J. Cancer, 11(1 ), 23-31.

[263] DeBaun, J.R.; Miller, E.C. and Miller, J.A. (1970) Cancer Res., 30(3), 577-95.

[282] Clayson, D.B. and Garner, R.C. (1976) In Chemical carcinogenesis. (Searle, C. E.; Ed.) Am. Chem. Soci, ACS Monograph, 173,Washington DC, PP.366-461. .

[264] Irving, C.C. (1975) Cancer Res., 35(11 Pt 1 ), 295961.

[283] Winkler, B. S. (1987) Biochim. Biophys. Acta., 925(3), 258-64.

[265] Glatt, H.; Bartsch, I.; Christoph, S.; Coughtrie, M.W.; Falany, C.N.; Hagen, M.; Landsiedel, R.; Pabel, U.; Phillips, D.H.; Seidel, A.; Yamazoe, Y. (1998) Chem. Biol. Interact., 109(1-3), 195-219.

[284] Kowalski, D.P.; Feeley, R.M. and Jones, D.P. (1990) J. Nutr., 120(9), 1115-21.

[266] Sticha, K.R.; Bergstrom, C.P.; Wagner, C.R.; Hanna, P.E. (1998) Biochem. Pharmacol., 56(1), 47-59.

[285] Flagg, E.W.; Coates, R.J.; Jones, D.P.; Byers, T.E.; Greenberg, R.S.; Gridley, G.; McLaughlin, J. K.; Blot, W. J.; Haber, M. and Preston-Martin S. (1994) Am. J. Epidemiol., 139(5), 453-65.

130


Salah A. Sheweita

[286] Mester, A. and Anderson, M. E. (1983). Rev. Biochm., 52, 711-720.

[306] Gopalan, P.; Jensen, D.E. and Lotikar, P.D. (1994) Cancer Lett., 64, 225-233.

[287] Arrick, B. A. and Nathan, C.F. (1984) Cancer Res., 44, 4224-4228.

[307] Lotlikar, P.D.; Insetta, S.M.; Lyons, P.R. and Jhee, E.C. (1980). Cancer Lett., 9,143-149.

[288] .Chasseud, L. F. (1979) Adv. Cancer Res., 45, 12341245.

[308] Kramer, R. A.; Zakher, J. and Kim, G. (1988) Science, 241, 694-697.

[289] Orrenius, S. and Moldeus, P. (1984) Trends Pharmacol. Sci., 5, 432-438.

[309] Farner, P. B.; Neumann, H, G. and Henschler, D. (1987) Arch. Toxicol., 60, 251-260. .

[290] Muzio, G.; Marengo, B.; Salvo, R.; Semeraro, A.; Canuto, R.A. and Tessitore, L. (1999) Free Radical Biol. Med., 26(9-10), 1314-20.

[310] Roy, D. and Snodgrass, W. (1990) J. Pharmacol. Exp. Ther., 252, 895-899.

[291] Rossi, L.; Moore, G. A.; Orrenius, S. and O’Brien, P. J. (1988) Arch. Biochem. Biophys., 251, 25-35. [292] Stenius, U.; Warholm, M. Rannug, A.; Walles, S. Lundbreg, I.and Hogberg, J, (1989) Carcinogenosis, 10, 593-599.

[311] Boelsterli, U. A. (1993) Drug Metab. Rev., 25(4), 395-451. [312] Zhitkovich, A.; Voitkun, V. and Costa, M. (1995) Carcinogenesis, 16(4)907-913. [313] Mannervik, B. (1985) Advanced Enzymol., 57, 357417.

[293] Kappus, H. (1986) Biochem. Pharmacol., 35,1-6. [294] Murray, G. I.; Burke, M. D. and Ewen, S. W. (1987) Br. J. Cancer, 55: 605-609.

[314] Boyer, T. D. and Kenney, W. C. (1985). In Biochemistry, pharmacology and toxicology, (D. Zakin and D. A. Vessey, Eds.), John Wiley and Sons Inc.; New York, pp. 297-363.

[295] Calcult, G. and Connors, T. A. (1963) Biochem. Pharmacol., 12, 839-841.

[315] Buetler, T.M. (1998) Hepatology, 28(6), 1551-60.

[296] Batist, G.; Tulpule, A.; Sinha, B. K.; Katki, A. G.; Myers, C. E. and Cowan, K. H. (1986). J. Biol. Chem., 33, 15544-15549.

[316] Morgenstern, R.; and Depierre, J. W. (1988) In:glutathione conjugation (Sies, H. and Kettere, B. Eds), New York Academic Press, pp. 157-174.

[297] Hu, X.; Pal, A.; Krzeminski, J.; Amin, S.; Awasthi, Y.C.; Zimniak, P. and Singh, S.V. (1998) Carcinogenesis, 19(9), 1685-9.

[317] Board, G.G.; Coggan, M.; Johnson, P.; Ross, V.; Suzuki, J.; and Webb, G. (1990) Pharmacol. Ther., 48, 357-369.

[298] Whalen, R.; Boyer, T.D. and Semin, J. (1998) Liver Diseases, 18(4), 345-58.

[318] Howie, A. F.; Forrester, L. M.; Glancey, M. J.; Schlager, J.; Powis, G.; Beckett, G.; Hayes, J. and Wolf, C. (1990) Cacinogenesis, 11, 451-458.

[299] Kim, D.J.; Lee, K.K.; Hong, J.T, (1998) Arch. Pharm. Res., 21(4), 363-9. [300] Hirose, M.; Futakuchi, M.; Tanaka, H, Orita, S.I.; Ito, T.; Miki, T.; Shirai, T. (1998) Eur. J. Cancer Prev., 7(1), 61-7. [301] Gopalan, P.; Hirumm, S. and Lotikar, P. D. (1994) Cancer Lett., 76, 25-30. [302] Xia, H.; Pan, S.S.; Hu, X.; Srivastava, S.K.; Pal, A.; Singh, S.V. (1998) Arch. Biochem. Biophys., 353(2), 337-48. [303] Said, B.; Matsumoto, D.C.; Hamade, A.K.; andShank, R.C (1999) Biochem. Biophys. Res. Commun., 261(3), 844-7.

[319] Hussey, A. J.; Stockman, P. K.; Beckett, G. J. and Hayes, J. D. (1986) Biochem. Biophys. Acta., 874, 112. [320] Peter, W. H.; Wormskamp, N. G.; and Thies, E. (1990) Carcinogenesis, 11, 1593-1596. [321] Peter, W. H.; Boon, C. E.; Roelof, H. M.; Wobbes, T.; and Kremers, P. G. (1992) Gasteroentrology, 103, 448-454. [322] Tsuchida, S. and Sato, K. (1992) Crit. Rev. Biochem. Mol. Biol., 27, 337-384. [323] Mulder, T. P.; Roelfos, H. M.; Peter, W. H.; Wagenmans, M. J.; Sier, C. F.; and Verspaget, H. W. (1994) Carcinogenesis, 15(10), 2149-2153.

[304] Sundberg, K.; Seidel, A.; Mannervik, B.; and Jernström, B. (1998 ) FEBS Lett., 438(3), 206-10.

[324] Sato, K. (1989) Adv. Cancer Res., 52, 205-255.

[305] Guengerich, F.P.; Johnson, W.W.; Shimada, T.; Ueng, Y.F.; Yamazaki, H.; Langouët, S. (1998) Mutat. Res., 402(1-2), 121-8.

[325] Pickett, C. B.; Telakowski-Hopkins, C. A.; Ding, G. J. and Ding, V. D. (1987) Xenobiotica, 17(3), 317-23.


[326] Warholm, M.; Guthenberg, C.; Mannervik, B. and von Bahr, C. (1981) Biochem. Biophys. Res. Commun., 98(2), 512-9. [327] Sheweita, S. A.; Habib, S. L. and Mostafa, M. H. (1997) Biomedical Lett., 56, 119-127. [328] Sheweita, S.A and Mostafa, M.H. (1996) Cancer Lett., 99, 29-34. [329] Sheweita, S. A. (1998) Inter. J. Toxicol., 17(4), 383392. [330] Wattenberg, L. W. (1985) Cancer Res., 45, 1-8. [332] Wim, A.N. and Wilbert, H.M. (1994) Carcinogenesis, 15(9), 1769-1772. [331] Schilter, B.; Perrin, I.; Cavin, C. and Huggett, A. (1996) Carcinogenesis, 17(11), 2377-2384. [333] Van Lieshout, E. M.; Posner, G. H.; Woodard, B. T.; and Peter, W. H. (1998) Biochem. Biophys. Acta., 1379(3), 325-336. [334] Bu-Abbas, A.; Clifford, M. N.; Walker, R. and Ioannides, C. (1998) Food Chem. Toxicol., 36(8), 617-621. [335] Poon, R. and Chu, I. (2000) J. Biochem. Mol. Toxicol., 14(3), 169-176. [336] Ebisawa, T. and Deguch, T. (1991) Biochem. Biophys. Res. Commun., 177, 1252-1257. [337] Mulder, G. J. and Ouwerk-Mahadevan, S. (1997) Chem. Biol. Interact., 105, 17-34. [338] Ouwerk-Mahadevan, S.; VanBoom, J. H.; DreefTramp, M. C.; Meyer, D. J. and Mulder, G. J. (1995) Biochem. J., 308, 283-290. [339] Karplus, P. A.; Pai, E. F. and Schulz, G. E. (1989) Eur. J. Biochem., 178(3), 693-703. [340] Pai, E. F. and Schulz, G. E. (1989) J. Biol. Chem., 258(3) 1752-7.


[347] Bishayee, A.; Roy, S. and Chatterjee, M. (1999) Oncol. Res., 11(1), 41-53. [348] Li, Y.Z.; Li, C.J.; Pinto, A.V. and Pardee, A.B (1999) Mol. Med., 5(4), 232-9. [349] Marini, S.; Longo, V.; Mazzaccaro, A. and Gervasi, P.G. (1998) Xenobiotica, 28(10), 923-35. [350] Irving, C.C. (1973). In W. H. Fishman (ed), in metabolic conjugation and metabolic hydrolysis, Vol. 1. Academic Press, Inc.; New York, . p. 53-119. [351] Siess, M.H.; Le Bon, A.M.; Canivenc-Lavier, M.C. and Suschetet, M. (1997) Cancer Lett., 120(2), 195201. [352] Conner, C.E.; Burchell, B.; Hume, R. (1997) Biochem. Soc. Trans., 25(2), 181S. [353] Kadlubar, F. F.; Unruh, L. E.; Flammang, T. J.; Sparks, D. Mitchum, P. K. and Mulder, G. J. (1981) Chem. Biol. Interact., 33,129-147. [354] Huang C.S.; Chern H.D.; Shen C.Y.; Hsu S.M.; Chang K.J. (1999) Int. J. Cancer, 82(2) 175-9. [355] Malejka-Giganti D.; Ringer D.P.; Vijayaraghavan P.; Kiehlbauch C.C.; Kong. (1997) J. Exp. Mol. Pathol., 64(2), 63-77. [356] King C.M.; Land S.J.; Jones R.F.; Debiec-Rychter M.; Lee M.S.; Wang C.Y. (1997) Mutat. Res., 376(12), 123-8. [357] Windmill K.F.; McKinnon R.A.; Zhu X.; Gaedigk A.; Grant D.M.; McManus M.E. (1997) Mutat. Re., 376(1-2), 153-6. [359] Kadlubar, F.F.; Butler, M. A.; Kaderlik, K. R.; Chou, H. and Lang, P. L. (1992) Environ. Health Persp., 98, 69-74. [358] Kadlubar, F.F.; Miller, J.A. and Miller, E.C. (1976) Cancer Res., 36:1196-1206.

[341] Mannervik, B. (1969) Acta Chem. Scand., 23, 29122914.

[360] Kadlubar, F.F.; Dooley, K.L.; Teitel, C. H.; Roberts, D. W.; Benson, R.; Butler, M. A.; Bailey, J. R. and Tannenbaum, S. R. (1991) Cancer Res., 51, 43714377.

[342] Chung, P. M.; Cappel, R. E. and Gilbert, H. F. (1991) Arch. Biochem. Biophys., 288(1), 48-53.

[361] Brockmller, J.; Cascorbi, I.; Kerb, R.; Sachse, C. and Roots, I. (1998) Toxicol. Lett., 28, 102-103.

[343] Worthington, D. J. and Rosemeyer, M. A. (1976) Eur. J. Biochem., 67(1) 231-8.

[362] Seow, A.; Zaho, B.; Poh, W.T.; The, M.; Eng, P.; Wang, Y. T.; Tan, W.C, Lee, E.J. and Lee, H.P (1999) Carcinogenesis, 20(9): 1877-1881.

[344] Faed, E. M. (1984). Drug Metab. Rev., 15(5-6), 121349. [345] Caldwell, J. (1979) Life Sci., 24(7), 571-8.

[363] Ambrosone, C.B.; Freudenheim, J.L.; Shina, R.; Graham, S.; Marshall, J.R.; Vena, J.E. and Shields, P.G. (1998) Int. J. Cancer, 75(6), 825-850.

[346] Watt, J. A.; King, A. R. and Dickinson, R. G. (1991) Xenobiotica, 21(3), 403-15.

[364] Liu, Y. and Levy, G.N (1998) Cance Lett., 133(1), 115-123.

132


Salah A. Sheweita

[365] Mullen, R.T.; Trelease, R.N.; Duerk, H.; Ar. and, M.; Hammock, B.D.; Oesch, F. and Grant, D.F. (1999) FEBS Lett., 445(2-3), 301-5.

[368] Guyonnet, D.; Siess, M.H.; Le Bon, A.M. and Suschetet, M. (1999) Toxicol. Appl. Pharmacol., 154(1), 50-8.

[366] Goodrow, M.H.; Dowdy, D.; Zheng, J.; Greene, J.F.; Sanborn, J.R. and Hammock, B.D. (1999 ) Proc. Natl. Acad. Sci. USA, 96(16), 8849-54.

[369] Kim, N.D. and Kim, S.G. (1999) Arch. Pharm. Res., 22(2), 99-107.

[367] McKim, J.M. Jr.; Choudhuri, S.; Wilga, P.C.; Madan, A.; Burns-Naas, L.A.; Gallavan, R.H.; Mast, R.W.; Naas, D.J.; Parkinson, A. and Meeks, R.G. (1999) Toxicol. Sci., 50(1), 10-9.

[370] Hazai E, Róna K, Vereczkey L (1999) Acta. Pharm. Hung., 69(4), 208-12. [371] Wormhoudt, L.W.; Commandeur, J.N. and Vermeulen, N.P. (1999) Crit. Rev. Toxicol., 29(1), 59-124.