Drug-Metabolizing Enzymes: Mechanisms and Functions · 2019-07-08 · Drug-Metabolizing Enzymes: Mechanisms and Functions Current Drug Metabolism, 2000 , Vol. 1, No. 2 109 exhibited

Current Drug Metabolism, 2000, 1, 107-132 107

1389-2000/00 $25.00+.00 © 2000 Bentham Science Publishers Ltd.

Drug-Metabolizing Enzymes: Mechanisms and Functions

Salah A. Sheweita*

Department of Bioscience and Technology, Institute of Graduate Studies and Research, 163Horreya Ave., PO Box 832, Alexandria University, Egypt

Abstract: Drug-metabolizing enzymes are called mixed-function oxidase ormonooxygenase and containing many enzymes including cytochrome P450, cytochromeb5, and NADPH-cytochrome P450 reductase and other components. The hepaticcytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in themetabolism of many drugs and xenobiotics with each cytochrome isozyme respondingdifferently to exogenous chemicals in terms of its induction and inhibition. For example,Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them intoreactive 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 ofcytochrome 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. Thecarcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolitesto 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-glucuronyltransferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rateof activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizingenzymes. The balance of detoxification and activation reactions depends on the chemical structure of theagents, 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 enzymesinvolved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus theintroduction of specific xenobiotics may change the operating level and the existence of other chemicals. Themechanisms of modification of drug-metabolizing enzyme activities and their role in the activation anddetoxification of xenobiotics and carcinogens have been discussed in the text.

1. DRUG-METABOLIZING ENZYMES

Monooxygenase is involved in the oxidation ofa wide range of substrates at the expense ofmolecular oxygen since one atom of the molecularoxygen enters the substrate and the other formswater, such a reaction being known as a mono-oxygenase or mixed-function oxidase reaction [1].The main components of the mixed functionoxidases (MFO) enzymes system are thecytochrome P-450 isoenzymes [2]. The name wasgiven because the reduced form binds with carbonmonoxide to give a complex with maximumabsorption at 450 nm (3,4). Costas and Dennis in1987, indicated that the cytochrome P-450 acts asthe terminal oxygenases of the mixed-functionoxidase systems of bacteria, yeast, plants, insects,fishes and other vertebrates. MFO catalyzes the

*Address correspondence to this author at the Department of Bioscience andTechnology, 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]

oxidation, and reduction of numerous endogenousand exogenous substances of widely diversechemical structure [5]. In addition, they are alsoinvolved in the biosynthesis of cholesterol, steroidhormones, bile acids and the oxidative metabolismof fatty acids, lipophilic drugs and other chemical(6-8). Many forms of cytochrome P-450 have beenisolated from both rodents and human tissues, andthey have been classified into 17 familiesaccording to homologies of their amino acidssequences [9,10].

Another member of the hepatic monooxygenasesystem is NADPH-cytochrome P-450 reductase,which was firstly observed in whole liver byHorecker (1950) [11] and also in microsomes byStrittmater and Velic in 1956 [12]. The prostheticgroup was identified as FAD (13-15). In additionto cytochrome P-450 and NADPH-cytochrome P-450 reductase, the mixed-function oxidasecontains also cytochrome b5 and NADH-cytochrome b5 reductase. The possible role of both

108 Current Drug Metabolism, 2000, Vol. 1, No. 2 Salah A. Sheweita

in the cytochrome P-450-dependent reactions iswell known now than before (16-19].

1.1 FACTORS AFFECTING THEACTIVITY OF DRUG-METABOLIZINGENZYMES

1.1.1 Organs

Lung

Extrahepatic tissues have received relativelyless attention than liver because of their low levelsof mixed function oxidase activity [20]. Theethoxyresourfin O-deethylase (EROD) activitywas lower in the lung than in the liver of rats [21].Low levels of EROD activity were also detected inrabbit lung [22]. The lower EROD activity in lungcompared to liver was confirmed usingmonoclonal antibodies against cytochromeP4501A1 [23]. Pulmonary levels of cytochromeP450 1A1 were found to be < 3% of the totalmicrosomal cytochromes P-450 using the moresensitive Western blotting technique. ERODactivity was induced after pretreatment of rats with3-methylcholanthrene (MC) and 7,12-dimethyl-benz(a)anthracene, and to a lesser extent by β-naphtoflavone (β-NF) [24-26]. A major form ofpulmonary cytochrome P-450, different from thehepatic proteins, has been purified from rats afterMC treatment, which catalyzed the oxidation ofbenzo (a) pyrene to various phenols, diols, andquinines [27,28].

Similarly, the pulmonary levels of totalhemoprotein and aryl hydrocarbon hydroxylaseactivity were increased after pretreatment ofrabbits with MC [29]. The extent of induction inthe lung of rabbit was low compared with that seenin the liver [29]. Moreover, tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyl(PCB) increased the pulmonary EROD activityand cytochrome P450 1A1 isozymes [30-35.].Similarly, the inducibility of cytochrome P-4501A2 in mouse lung by MC was studied using amonoclonal antibody raised against the rat hepaticcytochrome, which cross-reacted with the maurinepulmonary cytochrome P450 1A1. In MC-inducedmice, cytochrome P450 1A was present in lungand hepatic parenchyma cells, but this isoenzymewas not detected in untreated or PB-induced lungs.Treatment of hamster with MC, β-NF, or PCBstimulated the activity of aryl hydrocarbonhydroxylase [AHH] in lung, whereas hepaticlevels were not changed [36-39]. Induction ofAHH activity by these agents may partly explain

why the hamster is more susceptible to tumors ofthe respiratory tract than other animals [40].

Kidney

The cytochrome P-4501A isozymes weredetected in kidney but at levels markedly lowerthan those seen in liver of rats using monoclonalantibodies recognizing MC-induced cytochromes[41,42]. The lower activity of cytochrome P4501A in kidney was induced after treatments of ratswith either PAH, β-NF, or 2-AAF [43,44]. WithTCDD as inducing agent, immuno quantificationshowed a marked increase in cytochromeP4501A1, which accounted for 30% of total ratkidney cytochrome P-450. Similarly, agents suchas alcohol induced cytochrome P450 2E1 in thekidney [45].

1.1.2 Immunological Aspects

Monoclonal antibodies allowed rapididentification and quantification of cytochromesbelonging to the same gene family [46]. Ninemonoclonal antibodies have been raised againstcytochrome P4501A1 and reacting with sixdistinct epitopes, one of them was shared withcytochrome P4501A2 [46,47]. CytochromeP4501A1 was detected at low levels in the liver ofrats and at relatively higher levels in rabbit andguinea pig livers, whereas a protein that relate tocytochrome P4501A was present in all animals[47]. Using the monoclonal antibodies,cytochrome P450 1A isozymes were detected inrat, hamster, guinea pig, rabbit, and “responsive”mice, but not in “non-responsive” mice afterinduction with MC. Similarly, isosafrole inducedcytochrome P4501A2 in all animals, but onlycytochrome P4501A1 in the rabbit and hamsteronly [47].

1.1.3 Age

It has been established that the activities ofMFO are very low at birth but increase rapidly inadult and then subsequently decline in adult in allanimal species including man [48-52]. Forexample, the cytochrome P450 1A mediated 2-hydroxylation of biphenyl was present in neonatalrat and rabbit livers but this isozyme was notdetected during adulthood [53,54]. Also,cytochrome P-450 1A1 mediated O-deethylationof EROD was relatively higher in the neonatal ratreaching a maximum 2 weeks after birth and thendeclined with age [55]. These observations werefurther 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-oldanimals [56].

1.1.4 Nutrition

Nutrition and diet may modulate the levels ofcytochrome P-450 isoenzymes, resulting inchanges in the metabolic fate of xenobiotics [57-63]. The diet-mediated effects may be due tochemicals inherent in the diet, to contaminants orfood additives, or to compounds generated duringthe process of cooking [64]. Some types of foodhave high contents of natural xenobiotics, whichare potent inducers of the mixed-function oxidasesystem, such as saffron. Rats maintained on a dietcontaining cruciferous vegetables, such as sproutsand cabbage, probably because of their highcontent of indoles, exhibited both high levels ofintestinal mixed-function oxidase activity [64].Similar effects were observed in humansmaintained on such diet [65,66]. Indeed, indole-3-acetonitrile, indole-3-carbinol, and 3,3’-di-indoylmethanes present in cruciferous vegetableshave been identified as naturally occurringinducers of hepatical and intestinal arylhydrocarbon hyrdoxylase [AHH], and of otherenzyme activities [67]. Liver and intestinal ERODactivities have been induced in rats by feedingcabbage-containing diet [68].

1.1.5 Inducing Agents and Mechanism ofInduction

The administration of drugs or otherxenobiotics may lead to an increase in theactivities of various liver isozymes, which areresponsible for the metabolism of foreigncompounds [69-75]. If the increase in the activityof a drug-metabolizing enzyme is due to anincreased level of the enzyme, then the process isknown as induction and the agent is called aninducer (76). Inducers have been traditionallyclassified either as phenobarbital (PB) or 3-methy-lcholanthrene (3-MC), based on the cytochrome P-450 isozymes that are increased (76). Inducers ofboth the PB and 3-MC type increase the totalamount of cytochromes. Although PB-treated ratsshowed elevated microsomal cytochrome P-450levels, while their synthesized hemoprotein hadthe same absorption maximum in its reducedcarbon monoxide-difference spectrum at 450 nmas microsomal cytochrome P-450 from untreatedanimals (25,77). However, the biochemical andphysical changes observed after 3-MC treatmentwere postulated to be due to the induced synthesis

of a new hemoprotein, which shows maximumabsorption in its reduced carbon monoxide-difference spectrum at 448 nm (77).

The hepatic microsomal and nuclearcytochromes P-450 are antigenically similar [78],and also 3-methylcholanthrene (MC)-induces bothof them [79]. Nuclear cytochromes P-450 areinduced by many known compounds of themicrosomal cytochromes, such as pregnenalone16α-carbonitrile (PCN), phenobarbitone (PB), β-naphthoflavone (β-NF), and the chlorinatedbiphenyl mixture, Aroclor 1254 [80]. However,the mitochondrial mixed-function oxidases differfrom the microsomal and nuclear enzymes in theelectron donor system, the mitochondrial formsbeing able to operate with adrenodoxin,ferredoxin, or the microsomal cytochrome P-450reductase, while the microsomal and nuclear formsfunction only in the presence of the reductase [81].Despite intensive research, the induction processitself is poorly understood and the precisemechanisms of induction of mixed functionoxidase by xenobiotics still complex and not yetfully elucidated.

Inducers of the cytochromes P-450 stimulatethe synthesis of new isozymes by enhancing theirrates of transcription. This mechanism appears tobe common to all cytochrome P-450 proteins butdoes not extrude the presence of additionalalternative mechanism.

Nebert and his colleagues have contributedenormously to the elucidation of the complexprocess involved in the induction of thecytochromes P-450 [82]. The aromatichydrocarbon (Ah) receptor has been demonstratedin the hepatic cytosol of mice, which binds avidlybut noncovalently with the inducing agent which isassociated with the induction of cytochromes P-450 [83,84]. This hydrophobic receptor appears tobe composed of two subunits but contains onlyone binding site [85,86] and the binding appears toinvolve one or more sulfhydryl groups whoseintegrity is essential [87]. It appears that the parentchemical rather than an intermediate or metabolitethat interacts with the receptor [88]. In addition tothe legend binding, a DNA-binding domain existson the receptor [89,90]. The inducer-receptorcomplex translocated into the nucleus wereassociated with structural genes leading toincreased transcription and synthesis of the Ahreceptor protein and the cytochrome P-450apoproteins, which in the cytosol interact withheme to form the P-450 holoenzymes [91]. A goodcorrelation exists between the amount of complex


translocated into the nucleus and the amount ofP450 mRNA induced [91]. Interaction of theinducing agent with the receptor increases theaffinity of the receptor for DNA [89]. Manyendogenous compounds, including steroidhormones, failed to interact with the receptor, andthere is considerable evidence indicating that noneof the characterized steroid receptors is similar tothe Ah receptor [92,93].

It has been suggested that inducers may affectthe initiation of protein synthesis and eventranslation central factors [94]. Phenobarbitone hasbeen reported to increase C14-leucine incorporationinto proteins by rat liver polyribosomes [95]. Theincreased RNA and protein synthesis as well as thestabilization and decreased degradation of thesecomponents has been implicated in the inductionof drug metabolizing activity [96].

Induction of cytochrome P-450 is a verycomplex process and may be mediated by severalprocesses. Manen and his coworkers (1978) havesuggested that the cyclic AMP is the intracellularmediator of monooxygenase induction [97]. Theincreased synthesis of cytochrome P-450apoprotein produces an increased demand forheme [98]. The mechanism of monooxygenaseinduction might be also due to enhancing of delta-aminolevulinic acid (δALA) synthetase, the initialand rate-limiting step in the biosynthesis of theheme moiety of cytochrome P450s. It has beenreported earlier that the activity of δALAsynthetase was increased after a relatively shortperiod of rat treatments with some heavy metals[99]; or may be due to inhibition of hemeoxygenase, the first and rate-limiting enzyme inheme degradation [100], since P450s arehemoproteins.

1.1.6 Inhibitors

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

450 both in vivo and in vitro. Mercurials such asmersalyl [107]; p-chloromercuribenzoate [108];alkylating agents such as N-ethylinaleimide andN-nitrosamines have been used as inhibitors ofmany different metabolic transformationsmediated by the mixed-function oxidase system[109,110]. Bioactivation of xenobiotics by MFO isa complex series of reactions and interference ofinhibitors with any of them may represent apossible mechanism of inhibition [111]. Inhibitorsof cytochrome P-450 isozymes have been used asa tool in studying the multiple forms of theseisozymes, and provide a valuable technique forcharacterizing the nature of cytochrome P450.Various disease conditions such as malignancy,diabetes mellitus, malnutrition, schistosomalinfection, malarial infection and other infections,can produce structural and biochemical changes inthe liver capable of decreasing the levels ofhepatic cytochrome P-450 and microsomal protein[112-116].

Flavonoids are a class of dietaryphytochemicals that modulate various biologicalactivities. Four hydroxylated flavone derivatives(3-hydroxy-, 5-hydroxy-, 7-hydroxy-, and 3,7-dihydroxy flavone) were potent inhibitors of Cyp1A1, and 1A2 [117]. Treatment of mice witholeanolic acid resulted in a significant decrease ofP4502E1-dependent p-nitrophenol and anilinehydroxylase [118]. The protective effects ofoleanolic acid against the carbon tetrachloride-induced hepatotoxicity may be due to blocking ofcarbon tetrachloride bioactivation, which ismediated by P4502E1 [118]. Trans-1, 2-dichloroethylene was a more potent inhibitor ofCyp2E1 than cis-1,2-dichloroethylene based onboth in vivo and in vitro studies [119]. In anotherstudy, trans 1, 2-dichloroethylene yielded maximalinactivation of P450 2E1 than other P450isozymes including 1A2, 2A1, 2B1, 2C6, 2C11,2D1 and 3A after 24h of treatment [120]. Thelevels of hepatic P450 2B1/2, 2C11, and 3A1/2were decreased, whereas P450 2E1 expression wasnot affected after treatment of rat with acriflavine,a protein kinase c inhibitor [121]. Moreover,organophosphates are still widely used worldwideand cause thousands of intoxication every year.Repetitive exposure to subclinical doses ofparathion to rabbits for one week caused markedinhibition of cytochrome P450 [122].

The inhibitory effects of neurotransmitters,precursors, and metabolites on Cyp 1A2 enzymeactivity were studied in human liver microsome[123]. Two indoleamines, serotonin andtryptamine showed an inhibitory effect on the


activity of phenacetin O-deethylase [123]. Othersubstances, which were either poor or partialinhibitors of Cyp1A2 were dopamine, L-tyrosine,adrenaline, indole-3-acetic acid, L-tryptophan, and5-hydroxyindole acetic acid [123].

1.2 MECHANISMS OF DRUG OXIDATIONBY MIXED-FUNCTION OXIDASE SYSTEM

The wide substrate specificity of themicrosomal mixed-function oxidases is due largelyto the multiplicity of the constitutive and induciblecytochromes P-450, which display different, butoften overlapping substrate specificity. The mixed-function-oxidase is primarily concerned withdetoxication involving the formation of morepolar, readily excretable metabolites [124].Paradoxically, however, the same microsomalmixed-function oxidase system can affect theformation of more toxic and reactiveintermediates, a process known as "metabolicactivation or bioactivation" [125,126]. A likelyexplanation of this paradox is that the activationprocess may be attributed entirely to one or morespecific gene families of the cytochrome P-450proteins, while other gene families catalyzeoxygenation which lead to detoxification. Thus theamount of a reactive intermediate formed is theresult of these two competing processes, that isactivation and detoxication catalyzed by differentgene families of the hemoprotein [127]. As suchnot only the cellular levels but also the cytochromeP-450 isoenzyme population, will determinewhether a chemical will be activated ordeactivated and subsequently eliminated [125,126,128,129].

It is well known that cytochrome P-450 acts asa terminal oxidase for the electron transportsystem of mixed-function oxidase, which isimplicated in the biotransformation of manyxenobiotics [130]. The two important cofactorshave been realized to be the absolute requirementfor such microsomal mediated reactions: namely,molecular oxygen and NADPH. Absolute demandfor 02 was demonstrated through the incorporationof heavy oxygen (1802) into 3,4-dimethyl phenol[131]. Requirement of NADPH in microsomaldrug oxidation has also been demonstrated byimmunological studies with antibodies againstNADPH-cytochrome P-450 reductase [132] aswell as with purified components of thecytochrome P-450.

Initially, a substrate binds to the apoproteinmoiety of the ferric (Fe3+) hemoprotein to form

ferric substrate complex. This complex thenundergoes a one-electron reduction by acceptingthis electron from NADPH via the flavoproteinenzyme, NADPH cytochrome P-450 reductase,which converts heme iron to the ferrous (Fe2+)state. This Fe2+complex reacts with molecularoxygen to produce an oxygenated hemoprotein-substrate complex (02-Fe2+-substrate). Theoxycytochrome P-450 complex undergoes afurther one electron reduction. Although the originof the second electron is not well established,several studies have suggested that this reductionmay be mediated via NADH-cytochrome b5reductase and cytochrome b5 [17-19]. Thiscomplex is then subjected to intra-molecularrearrangement and one atom of oxygen is insertedinto substrate producing oxidized metabolites andthe other atom for water formation. Finally, thehemoprotein product complex dissociated to giveproduct and free enzyme, allowing the cycle to berepeated.

1.3 FUNCTIONS OF MIXED-FUNCTIONOXIDASE SYSTEM

There are many different forms of cytochromeP-450 such as P-448 and 446 are present inmammalian cells [33,46]. One of the mostimportant differences between the cytochromes P-448 and other families of the hemoproteins, fromthe point of view of chemical toxicity and diseaseetiology, their is contrasting role in the metabolicactivation and detoxication of toxic chemicals andcarcinogens [79,133-135]. Cytochrome P450 1Afamily almost always metabolically activateschemicals to reactive intermediates, that iselectrophiles, which are resistant to subsequentconjugation and interact with intracellularmacromolecules and nucleophiles, giving rise totoxicity and carcinogenicity [126]. In contrast, thephenobarbital-cytochromes P-450 (Cyp P-4502B1/2) direct the overall oxidative metabolism ofchemicals toward subsequent conjugation anddetoxication. The reason for this markeddifference is that the cytochrome P-450 1A familyaccepts large planar molecules, which they areable to oxygenate in conformationally hinderedpositions giving rise to epoxides and otheroxygenated metabolites that are poorly acceptablesubstrates for epoxide hydrolase and otherconjugating enzymes [126]. However, the PB-cytochromes P-450 generally oxygenate globularmolecules in unhindered positions to fromepoxides and other oxygenated products which arereadily acceptable substrates for epoxide hydrolaseand other conjugates, thereby resulting indetoxication.


Among the various classes of xenobioticsknown to be selectively activated by thecytochromes P-450 1A, with the formation ofreactive intermediates, are the polycyclic aromatichydrocarbons (PAH), the aromatic amines andamides, the planar polyhalogenated biphenyls andother halogenated polycyclics, azo compounds,mycotoxins, and paracetamol [128,129,136].However, there are a few known instances wherePB-induction increases chemical toxicity, or thePB-cytochromes P-450 specifically metabolizechemicals via toxic pathways, and these includethe activation of cyclophosphamide, and thetoxicity of bromobenzene and carbontetrachloride.

1.3.1 Metabolism of Endogenous Substrates

The cytochromes P-450 2C11 catalyze specificsteroid hydroxylation from livers of both rats andrabbits [17,49,137-139]. The PB-cytochromes P-450 and cytochromes P-450 1A can hydroxylatesteroids, but generally do so at rates well belowthose occurring in crude microsomes, indicatingthat steroids are unlikely to be the primaryendogenous substrates of these cytochromes.However, even in the hydroxylation of steroids,PB-cytochromes P-450 and MC-cytochromes P-448 again show distinct differences in regionselectivity with virtually no overlap [139]. In the2-hydroxylation of 17β-estradiol, cytochromeP4501A2 is markedly more active than any othercytochrome P-450 protein [140]. Differences inthe sites of oxygenations by the MC-cytochromesP-448 and PB-cytochromes P-450 are also seenwith the endogenous substrate arachidonic acid[30]. Cytochrome P-448 proteins from livers ofrats 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 gaveprimarily four epoxides [141,142]. A cytochromeP-450 protein catalyzing the epoxidation ofarachidonic acid has been isolated from humanliver [142]. Interestingly, this protein had highcatalytic activity toward 7-ethoxyresorufin and itmight be related to cytochromes P-450 1A family[142].

1.3.2 Metabolic Activation of ChemicalCarcinogens

The concept that some types of cancer might becaused by environmental factors traces back to theobservation of the English physician Pott in thelate 18th century that human scrotal cancer in Great

Britain was associated with the occupation ofpatients as chimney sweeps [143]. Since that time,people in other occupations have beendemonstrated to have certain risk of developingcancer at some sites. Overall, however,occupational cancers are relatively rare events thataffect only limited numbers of individuals. Thebulk of human cancers were until recentlyconsidered to stem from unknown elements. It wasprimarily the examination of internationalincidence rates of various types of cancer, and thefact that the incidence depends in part on the siteof residence, that led to the concept that manytypes of human cancer are caused, mediated, ormodified by environmental factors [144-147].

Chemical carcinogens are defined operationallyby their ability to induce tumors. Four types ofresponse have generally been accepted as evidenceof tumorigenicity: (1) an increased incidence ofthe tumor types occurring in controls; (2) theoccurrence of tumors earlier than in controls; (3)the development of types of tumors not seen incontrols; (4) an increased multiplicity of tumors inindividual animals. Chemicals capable of elicitingone of these tumorigenic responses are therebyclassified as carcinogens. They comprise a highlydiverse collection, including organic and inorganicchemicals, solid-state materials, hormones, andimmunosuppressants. In order to draw attention tothe differences in properties of the diverse agentsthat can be considered as carcinogenic,Weisburger and Williams have developed aclassification based on the mechanistic mode ofaction of carcinogen [146], which separate theminto eight classes. These in turn can be dividedinto two general categories based on their abilityto damage DNA [146]. Carcinogens that undergocovalent reactions with DNA are categorized asgenotoxic, and those lacking this property aredesignated as epigenetic, the eight classes havebeen divided between these two categories [147].The genotoxic category contains those agents thatfunction as electrophilic reactants, a property ofcarcinogens originally postulated by Miller andMiller in 1976 [148]. In addition, carcinogenicchemicals that give rise to DNA damage throughformation of free radicals derived from their ownmolecular structure or from altered cellularmacromolecules, would be considered genotoxic.The second broad category, designated asepigenetic carcinogens, comprises thosecarcinogens for which no evidence of directinteraction with material exists or DNA [148].Within this broad definition of carcinogens, manystructural types of chemicals are included such asthose in the class of the direct acting carcinogens


[146-148]. They do not require the participation ofenzymes from the host organism to generate thekey reactive intermediate of the ultimatecarcinogens. However, they do not generallypersist in the environment because of their highreactivity.

The second class of genotoxic carcinogens,termed procarcinogens, is comprised of organicchemicals that are active only after metabolicconversion by the host. This class include most ofthe known chemical carcinogens, and in contrastto direct-acting carcinogens can exist in theenvironment in a relatively stable condition untiltaken in by an exposed individual and activatedthrough biotransformation [147,148].

1.3.2.1 Polycyclic Aromatic Hydrocarbons

Polycyclic aromatic hydrocarbons areubiquitous in the environment and some of themare believed to cause cancer in man [149-151].Benzo[a]pyrene is present as a component of thetotal content of polynuclear aromatic compoundsin the environment. Human exposure tobenzo[a]pyrene occurs primarily through thesmoking of tobacco, inhalation of polluted air andby ingestion of food and water contaminated bycombustion effluents [145]. Benzo [a] pyrene hasbeen shown to be carcinogenic to experimentalanimals [153-158]. It has produced tumors in all ofanimal species following different administrationsincluding oral, skin and intratracheal routes. It hasboth a local and a systemic carcinogenic effect. Insub-human primates, there is convincing evidenceof the ability of benzo(a)pyrene to produce localsarcomas following repeated subcutaneousinjections and lung carcinomas followingintratracheal instillation. It is also an initiator ofskin carcinogenesis in mice, and it is carcinogenicin single-dose experiments and following prenatalexposure [159].

Polycyclic aromatic hydrocarbons (PAH) notonly induce the cytochromes P-448 but also arepreferentially metabolized by these enzymes. Thecytochrome P450 system participates in thebioactivation of polycyclic aromatic hydrocarbons(PAHs) and other carcinogens to their reactiveintermediates [160-163]. An important and veryextensively studied member of the polycyclicaromatic hydrocarbons is benzo(a)pyrene which ismainly metabolized by cytochrome P450-dependent aryl hydrocarbon hydroxylase intovarious derivatives, among which are electrophilicepoxides [147,157]. Solublized, purifiedCytochrome P450 2A1 preparations were moreefficient than the PB-cytochromes P-450 in

converting benzo(a)pyrene and (±)-trans-benzo(a)pyrene -7,8-dihydrodiol, the precursor ofthe ultimate carcinogen, into mutagens [29,68].Similarly hepatic microsomal preparations formMC-treated animals are markedly more efficientthan similar preparations from PB-induced animalsin activating benzo(a)pyrene to mutagens and inconverting it to the 7,8-diol-9,10-epoxide [38].

Pretreatment of rats with PB increased theformation of the 4,5-diol of benzo(a)pyrene buthad little or no effect on the 7,8-and 9,10-diolformation; the formation of all three diols was,however, induced by pretreatment with β-NF andMC, the least effect being seen with the 4,5 diol[161]. The MC-induced type increased in benzo(a) pyrene mutagenesis [160,164]. Intraperitonealpretreatment of mice with MC increased theformation of benzo(a)pyrene 7,8-diol in both lungand liver, while no such effect was seen followingtreatment with phenobarbital [159]. Furthermore,pretreatment of mice by intratracheal instillation ofbenzo(a)pyrene increased markedly the covalentbinding of the carcinogen to lung DNA [165].Supporting these findings are immunologicalstudies which showed that the metabolic activationof benzo(a)pyrene to mutagens was markedlyinhibited by antibodies to cytochrome P4501A1but was unaffected by antibodies againstcytochrome P-450 2E1 [166]. Similarly, amonoclonal antibody against MC inducedcytochromes P-448 inhibited the conversion ofbenzo(a) pyrene 7,8 diol to mutagens by livermicrosomes from MC-induced responsive micewhile no effect was seen with an antibody to PB-induced microsomes [167]. Finally, goodcorrelation has been obtained between rat livercytochrome P450 1A content determined by theethoxyresourfin O-deethylase (EROD) assay andthe activation of benzo(a)pyrene to mutagens inthe Ames test by rat liver microsomes [167]. Thealcohol-inducible cytochrome P-450 isoenzymes(P450 2 E1) appear not to catalyze the activationof PAH [168]. The carcinogenic potency and theextent of binding of these metabolites, epoxides,with DNA and proteins are correlated with theinduction of cytochrome P-450-dependent arylhydrocarbon hydroxylase activity [169,170]. Thepreferential activation of PAH by cytochromes P-448 is not confined to benzo(a)pyrene.Cytochromes P-448 also convert MC, 6-aminochrysene, benzo(a)anthracene, dibenzo(a,h)anthracene, dibenze(a,c) anthracene, and manyother bay-region-containing PAH to highlymutagenic species [166,171,172].


1.3.2.2 Naturally Occurring Carcinogen(Aflatoxin B1)

Until the early 1950s it was thought thatvirtually all-organic chemicals were man-made.However, in the beginning of 1955 it wasincreasingly realized that some chemicalcompounds elaborated by certain plants arecarcinogenic. The demonstration in the early1960s of the potent carcinogenicity of aflatoxinsrevealed that carcinogens are also found amongmetabolites of certain molds and microorganisms[173]. Thus, nature itself contributes a fair share tothe cancer causing substances in the environment,the naturally occurring carcinogen [173].

Aflatoxins were discovered in England in 1960when a Brazilian peanut meal was used as aprotein supplement to poultry diets caused theacute deaths of more than 100,000 young turkeysfrom liver damage or turkey X disease [174]. Atthe same time, an outbreak of turkey X likedisease in ducklings occurred in Kenya followingthe ingestion of African peanut meal [175].Symptoms similar to turkey X disease were alsoreported in outbreaks in other form or domesticanimals fed peanut meals. Coincidentally, anepizootic of liver cancer in hatchery-rearedrainbow trout occurred in the United States andEurope in 1960 [176-178]. A commercial troutfeed contaminated cottonseed meal was eventuallyfound to be associated with the trout hepatomaproblem. The magnitude of the problem inspiredintensive research efforts by investigatorsthroughout the world [179]. The toxic agent inpeanut meal was narrowed down to a mixture ofaflatoxins produced by a common mold,Aspergillus flavus, as secondary metabolites [175].The mixture could be separated into fourcomponents by thin layer chromatography; thesewere designated BI, B2, G1, and G2 according totheir fluorescent colors (B1 for blue, G1 for green)and relative mobility in the chromatogram[180,181].

1.3.2.2.1 Metabolism and Mechanism ofAction of Aflatoxin B1

Aflatoxin B1 is actively metabolized in a varietyof animal species. Epoxidation of the 2,3 doublebond of AFB1 is now generally accepted to be thekey metabolic reaction eliciting the carcinogenicand mutagenic effects of the mycotoxin [182].That the 2,3-double bond is a critical structuralrequirement for carcinogenicity and mutagenicityhas been pinpointed by structure-activityrelationship studies on a variety of structuralanalogs of AFB1 [183,184]. Moreover, quantummechanical calculations have shown that the 2,3-

double bond is the most reactive site in themolecule [185,186]. Although attempts to isolatethe putative reactive intermediate, AFB1-2, 3-oxide, have been unsuccessful because ofinstability, its formation can be deduced from itsreaction products with cellular constituents and itshydrolysis products. Aflatoxin B1 binds covalentlyto nucleic acids after in vitro metabolic activationby liver microsomes [182,187-189] as well as invivo studies [183,190]. The major acid hydrolysisproducts of AFB1-DNA adducts were identified as2,3-dihydro-2- (N7-guanyl)-3-hydroxyaflatoxin B1and 2,3-dihydro-2- (2,6-diamino-4-oxo-3, 4-dihydro-pyrimid -5-ylformamido)-3-hydroxy aflat-oxin B1 indicating the involvement of AFB1-2, 3-oxide [189]. In the absence of exogenousnucleophiles, 2,3-dihydro-2,3-dihydroxy-aflatoxinB1, an expected hydrolysis product of AFB1-2,3-oxide, is a major metabolite in the incubation ofAFB1 with rat, hamster, and trout liver microsomes[184,191,192]. The relative importance of eachindividual pathway varies substantially, dependingon the animal species and the experimentalconditions. Essentially, the initial metabolism ofAFB1 involves three principal types of reactions:(a) hydroxylation, (b) epoxidation, and (c) ketoreduction. The former two reactions believed to becarried out principally by a microsomal mixed-function oxidase system, the latter by a cytosolicNADPH-dependent reductase. In most animalspecies, the hydroxylated AFB1 metabolites mayundergo phase II metabolism by conjugating withgulcuronic acid or sulfate [193]. The activation ofthis mycotoxin to mutagenic and carcinogenicproducts, involving epoxidation of the 2,3-doublebond and possibly other oxygenation, appears tobe catalyzed by the cytochromes P-448 andpossibly other forms of the cytochromes[184,194]. A comparison of 5 purified ratcytochrome P-450 proteins in the activation ofaflatoxin B1 into mutagens showed thatcytochrome P4501A2 and a sex-related male formwere the best efficient. Although a significantactivity was also seen with cytochromes P-4501A1 and P-4501A2 [195], other workers whofurther showed that although PB-uninducableforms have activated this mycotoxin, havedocumented the high efficiency of cytochromeP450 3A4 [196]. The hepatic microsomal enzymesystem that catalyzes the 2,3-epoxidation of AFB1exhibits the typical characteristics of a mixed-function oxidase. Pretreatment of animals withPhenobarbital (but not with 3-methylcholanthrene)greatly enhances the in vitro formation of adductsof AFB1 with nucleic acids, suggesting theinvolvement of a cytochrome P-450-dependentsystem. However, somewhat inconsistent results


have been obtained from reconstitution experi-ments using purified cytochromes. In two of thesestudies purified hepatic cytochrome P450 1Aspecies obtained from polychlorinated biphenyl- or3-methylcholanthrene-treated rats were moreeffective than purified Phenobarbital-inducedcytochrome P-450 2B1/2 in catalyzing theformation of a reactive intermediate that binds toDNA or exerts a mutagenic effect [195,196]. In athird study, purified Phenobarbital-induced ratliver cytochrome P-450 was more active than β-naphthoflavone-induced cytochrome P450 3A4 incatalyzing the formation of AFB1-DNA adduct[197-199].

1.3.2.3 N-Nitrosamines

N-nitrosoamines are an important class ofenvironmental carcinogens, and their potential roleas causative agents in the carcinogenesis of somehuman neoplastic diseases has been extensivelyreviewed [200-206]. There are two potentialsources of human exposure to nitrosamines.Firstly, certain dietary items are known to containnitrosoamines [207]. Secondly, A more importantsource of nitrosamines is almost certainly fromingested amines and nitrite. The nitrite can comefrom foods containing nitrite, such as cured meatand fish, or be present in saliva and enter thestomach in that way. Nitrosotable amines can be ofenormous variety. A majority of drugs andmedicines are nitrosotable amines; manyagricultural chemicals are nitrosotable aminocompounds, and many constituents of foodthemselves, as well as food additives, are amines ofthis type [208-212]. The amino acid proline is oneexample of naturally occurring nitrosotableamines, although it gives rise to a non-carcinogenic nitroso derivative. More recentstudies have shown that the urinary levels ofnitrosamines are higher in Egyptian schistosomalpatients than those of the controls [213,214].

1.3.2.3.1 Bioactivatlon of N-nitrosoCompounds

N-nitrosourea and related compounds(nitrosoamides, nitrosoguanidine, nitrosourethans,nitrosocyanamides ) are chemically reactive, anddecompose at physiological pH to formelectrophilic alkylating agents. N-nitrosamines, onthe other hand, are stable at neutral pH, andrequire metabolic transformation in vivo in orderto exert their carcinogenic effects [215-220]. Thisdifference explains why nitrosourea tend toproduce tumors at or near the site of application,

whereas nitrosamines produce tumors in tissuesremote from the site of administration.

Nitrosamines are potent carcinogens for avariety of animal species and metabolic activationis known to be required for their carcinogenecity.Dimethylnitrosamine (DMN) has been usedfrequently as a prototype compound in studyingthe metabolism of nitrosamines [217]. It is knownthat the metabolism of DMN can be mediated by aliver microsomal fraction which requires NADPHand molecular oxygen. There are two enzymespecies responsible for the N-demethylation ofdimethylnitrosamine (DMN) through an oxidativeN-demethylation reaction, namely DMN-N-demethylases I and II (which can operate at ~ 4mM and ~200 mM of DMN respectively)[69,221]. It was found that following the N-demethylation of dimethylnitrosamine (DMN), adiazonium ion is produced leading ultimately tothe formation of carbonium ion that methylatesDNA [222-224]. It was suggested that thecarcinogenic effects of alkylating agents areproportional to the activities of their activatingenzymes in the liver [225,226] since more of theactive metabolites might be produced [226], whenthe demethylases are activated. Therefore, thecarcinogenic effects of carbonium ion resultingfrom activation of N-nitrosodimethylamine mightbe increased toward the liver and probably otherorgans. It has, therefore been postulated that thereaction involves oxidative demethylation toeliminate formaldehyde, which has been identifiedas a product, and carbonium ion, which alkylatesaccessible nucleophiles, including nucleic acids,proteins and water.

1.3.2.3.2 Role of Cytochrome P450 2E1 in theActivation of N-Nitrosamines

Among six purified human cytochrome P450forms, the alcohol-induced P450 2E1 was the mostefficient in catalyzing the demethylation anddenitrosation of dimethylntrosamine (DMN) [227-231]. Moreover studies with purified rat liver P450isozymes demonstrated that Cyp2E1 is moreactive than other forms in catalyzing themetabolism of dimethylnitrosamine [231,232].Other P450 forms such as phenobarbital-inducibleP450b showed substantial activities only at highsubstrate concentrations of dimethylnitrosamine,suggesting high Km values [69,231,233]. Theseobservations are consistent with the concept thatthe multiple Km values for dimethylnitrosamineN-demethylase found in microsomes are due to thecatalytic activity of multiple forms of P450 [229].


The key role of dimethylnitrosamine N-demethylase in the activation of dimethyl-nitrosamine has been demonstrated in severaldifferent system: [1] cytochrome P450 2E1 wasmore efficient than other forms in the activation ofdimethylnitrosamine to a mutagen in Chinesehamster [233]; [2] some of the previously reportedspecies and age difference in DMN have beeninterpreted on the basis of the quantity of P4502E1 present in the hepatic microsomes of rats andhamasters of different age [234]; and [3]pretreatment of rats with ethanol or acetoneincreased DMN-induced methylation of DNA invivo and in vitro and potentiated hepatotoxicity[235,236].

The ultimate effect of N-nitrosamines willdepend upon the rate of activation and the rate ofdetoxification. As the activated carcinogen reactswith various nucleophilic sites in addition tonucleic acids) and as water is the most plentifulcellular component, reaction with water could beregarded as detoxifying process [237]. Similarly,the trapping of reactive intermediates by proteinand other cellular components also providesprotection against the mutagenic and carcinogeniceffects of N-nitrosamines although not againstsome of the cytotoxic effects of these agents [237].In addition, there are other mechanisms ofmetabolic detoxification of N-nitrosamines byglutathione S-transferases [238], all of which limitthe formation of the highly reactive electrophilicintermediates. Although trapping of reactivemetabolites by glutathione conjugation appears tobe the primary defense mechanism against theharmful effects of reactive intermediates, in somecases the conjugation of an ultimate carcinogenwith glutathione can form genotoxic species [239].

The electrophilic intermediates produced bychemical decomposition of nitrosourea and relatedcompounds, or by metabolic activation ofnitrosamines, react rapidly with cellularnucleophiles. Attention has been focused onreactions with DNA because this is generallyconsidered to be the critical cellular target forcarcinogens during tumor initiation [223,240].Although 7-methylguanine (66.8 %) is the mostabundant modified base in DNA produced bydimethy-lnitrosamine, a variety of other productshave been identified [216,217,240]. These includealkylphosphate triesters (12 %), 1-,3- and 7-methyladenine ( 0.9 %, 2.3%, 0.7%); and 06-methylguanine (6.1%) and unidentified products.Not all DNA lesions have the same biologicalimportance [223,240]. Methylation of the 7-position of guanine shows no correlation with

carcinogenic activity, but several strikingcorrelation have been obtained between tissuesusceptibility to tumor induction and the initialextent of formation and subsequent persistence of06-methyl guanine residue [223,240].

1.3.2.4 Aromatic Amines and Amides

The aromatic amines include some veryimportant industrial chemicals used asintermediates in the manufacture of dyes andpigments for textile, paints, plastics, paper and hairdyes; they also include drugs, pesticides andantioxidants used in the preparation of rubber forthe manufacture of tires and cables [241,242].Studies of bladder cancer among workers in thedyestuff industry and later among rubber workershold an important place in the history ofoccupational bladder cancer. Epidemiologicalstudies of the hazards to workers in the chemicalindustry established that benzidine and 2-naphthylamine are carcinogenic to humans[241,242]. It was shown that rubber workers alsohad increased risk for bladder cancer, attributedlargely to exposure to aromatic amines [241,242].Most aromatic amines are initially activated by N-hydroxylation, mainly in the liver via acytochrome P-450 catalyzed reaction [243,244].

Studies of bladder cancer among workers in thedyestuffs industry, and later among rubberworkers, hold an important place in the history of"occupational" bladder cancer. This evidence ledto the International Labor Organization to declarecertain aromatic amines as human carcinogen[245]. The epidemiological study for the hazardson workers in the chemical industry, establishedthat benzidine and 2-naphthylamine werecarcinogenic to human [245,246]. In another studycarried out at about the same time, it was shownthat rubber workers had also an increased risk forbladder cancer, attributed largely to exposure toaromatic amines. 4-aminobiphenyl was widelyused in the industry at that time, and it was shownshortly afterwards that it caused bladder cancer inhumans [246,247]. The epidemiological findingsubsequently prompted discontinuation ofproduction and prevented widespread use of 4-aminobiphenyl in other countries. Recentepidemiological studies have demonstrated anelevated occurrence of bladder cancer amongworkers exposed to para-chloro-ortho-toluidine.Since it also induced malignant tumors inexperimental animals, this compound and itsstrong acid salts are probably carcinogenic tohuman [248].


1.3.2.4.1 Metabolic Activation of 2-Acetylaminofluorene

Activation of 2-acetylaminofluorene (2-AAF)proceeds through N-hydroxylation which iscatalyzed exclusively by cytochromes P-448 [249-251], confirming previous observations whereantibodies to cytochromes P-448, but not PB-cytochromes P-450, decreased the N-hydroxylation and covalent binding of thecarcinogen [252-254]. Pretreatment of animalswith 2-AAF or MC increases the N-hydroxylationof the amide, and increases the cytochromes P-448content as determined by EROD activity[255,256]. Similarly, rabbit liver microsomescatalyze the N-hydroxylation of 2-AAF.Furthermore, monoclonal antibodies to MC-induced cytochromes P-448 inhibited the N-hydroxylation of 2-AAF [257], and themutagenicity of 2-AAF was inhibited 60% byantibodies to cytochrome P450 3A4 but only 35%by antibodies to cytochrome P-450. N-hydroxylation of acetylaminofluorene occurs tothe greatest extent in the liver and is catalyzed by acytochrome P-450 and NADPH-generating systemin the endoplasmic reticulum [251,258]. A majorfraction of N-hydroxy-AFF is converted to its 0-glucuronide, which is excreted in the bile andurine [259,260,261]. This glucuronide has weakelectrophilic reactivity, but its N-deacetylatedderivative is a potent electrophile, although thelatter compound is not a known metabolite [262].Male Sprague-Dawley rats and male and femalerats of the Fisher strain, all of which are highlysusceptible to hepatic tumor induction, have a highlevel of cytosolic 3'-phosphoadenosine-5'-phosphosulfate (PAPS)-mediated sulfotransferaseactivity for N-hydroxy-AAF in their livers [263-266]. The activity of sulfotransferases in livercytosol under various experimental conditionscorrelates with the extent of covalent binding ofseveral of amines and amides to macromoleculesand with susceptibility of animals to thehepatocarcinogenicity of N-hydroxy-AAF. Thus,the sulfuric acid ester appears to be the majorultimate carcinogenic metabolite of N-hydroxy-AFF in the liver [267,268].

N, 0-acyltransferase, which catalyses thetransfer of the N-acetyl group of N-hydroxy-AAFto the oxygen atom of the correspondinghydroxyamine (formed by N-deacetylation),occurs in a wide variety of tissues in rat and otherspecies [269,270]. The 0-acetyl derivative of N-hydroxy-2-aminofluorene is a very strongelectrophile. Because of the wide tissuedistribution of N, 0-acyltransferase, this metabolicpathway is an alternative mechanism for the

metabolic activation of N-hydroxy-AAF or otherhydroxamic acids in tissues. Since arylaminatedresidues are major products found in rat liver DNAfollowing administration of N-hydroxy-AAF thisacyltransferase may also play a role in theformation of 2-aminofluorene moieties whichbecome attached to DNA [271,272]

The major hepatic nucleic acid adducts in ratliver from N-hydroxy-AFF-treated animals are N-2-(guan-8-yl)-AAF or aminofluorene derivatives.In addition, 3-(guan-N2-yl)-AFF has beenidentified in hepatic DNA. The latter modifiedbase persists much longer in DNA than the firstadduct [253,273].

1.3.2.4.2 Metabolic Activation of N,N-Dimethylaminoazobenzene

The N-hydroxylation of N-methylamino-azobenzene and the metabolic activation of N, N-dimethylaminoazobezene are catalyzed bycytochromes P-448 [274,275]; cytochromeP4501A2 catalyzes the N-hydroxylation of N-methylaminoazobenzene at twice the rate ofcytochrome P4501A1 although the latter is moreactive in ring hydroxylation [26,27,68]. N-methyl-4-aminoazobenzene (MAB) is a proximatecarcinogenic metabolite formed from N, N-dimethylaminoazobenzene through oxidative N-demethylation. This hepatocarcinogen is then N-hydroxylated by a flavoprotein that requiresNADPH, but not cytochrome P-450 [277].Carcinogenicity studies in rats and mice led to theconclusion that N-hydroxy metabolites of MABand other amino azo dyes are proximatecarcinogens [278]. N-hydroxy-MAB is esterifiedby a PAPS-dependent cytosolic system in rat liver[279]; this ester is presumed to be the ultimatecarcinogenic metabolite. Livers of ratsadministered MAB in vivo contained the samenucleic acid and protein-bound adducts that areformed on incubation of the synthetic benzoic acidester of N-hydroxy-MAB with nucleophiles invitro [280]; the nucleic acid adducts are N-(guan-8-yl)-MAB derivatives [280]. Protein-boundcysteine derivatives are formed in vivo and theseamino acid adducts have been characterized. Thesusceptibilities of the livers of the rat and severalrodent species correlate with the capacities ofthese tissues to form N-hydroxy-MAB and thesulfate ester of this product [277,279]. Thus theaddition of sulfate ester to the diet of rats enhancesthe induction of liver tumors by the related aminoazo dye, 3'-methyl-N,N-dimethyl-4-aminoaz-obenzene [281].


The cleavage of azo bonds, catalyzed by theenzyme azo reductase, may lead to detoxificationof certain carcinogenic and mutagenic azo dyes,such as N,N-dimethyaminoazobenzene. In otherinstances, such a reaction may activate azocompound [282].

1.4 ENZYMES OF CARCINOGENINACTIVATION

1.4.1 Glutathione and other Amino AcidsConjugation

Glutathione (GSH) is present in most plant andanimal tissues from which the human diet isderived. GSH can function as an antioxidant,maintain ascorbate in a reduced and functionalform, directly react with and inactivate toxicelectrophiles in the diet, and can be broken downto yield cysteine [283]. Studies have shown thatdietary GSH enhances metabolic clearance ofdietary peroxidized lipids and decreases their netabsorption [284] and that consumption of foodhigh in GSH content is associated with about a50% reduction in risk of oral and pharyngealcancer [285]. Therefore, an improved under-standing of the distribution of GSH in foods andthe factors affecting GSH absorption anddistribution can be expected to provide the basisfor improved food selection and preparation toreduce risk of chronic diseases.

Glutathione (GSH) one of the most abundantintracellular thiols, aids in the protection of cellsfrom the lethal effects of toxic and carcinogeniccompounds [286,287]. It has shown to be animportant determinant of cellular sensitivity to awide variety of drugs and other cytotoxiccompounds [288-290]. Both oxidation-reductionreactions may eventually result in GSH depletioneven though the former type of reaction primarilyleads to glutathione oxidation and should beeffectively compensated by glutathione reductaseactivity [291]. GSH depletion is often associatedwith cytotoxicity, and there are some indicationsthat conjugation reactions can be more detrimentalto the cell than redox cycles [292, 293]. It thusseems possible that GSH depletion may promotetumor development through a mechanism thatinvolves cytotoxicity and other different ways[294, 295]. The cytosolic glutathione-S-transferaseand GSH play an important role in thedetoxification of many environmental chemicalsincluding mutagens and carcinogens [296-300].Their main function is the conjugation of GSH to avariety of electrophilic compounds. Recent studieshave demonstrated that GSH and GST reduced the

covalent binding of epoxides of well knownchemical carcinogens, e.g. aflatoxin B1 and benzo[a]pyrene, with DNA [301-305]. It has beenreported that such DNA-binding was found to beeffective in decreasing the hepatocarcinogenesiscaused by these compounds [306,307].

Glutathione conjugates are not excreted per sebut rather undergo further enzymatic modificationof the peptide moiety resulting in the urinary orbiliary excretion of cysteinyl-sulfur substituted, n-acylcysteines, more commonly referred tomercapturic acids [295]. Mercapturic acidformation is initiated by glutathionase conjugationfollowed by removal of the glutamate moiety byglutathionase and subsequent removal of glycineby a peptidase enzyme, the latter two enzymesbeing present in both liver, gastrointestinal tractand kidney. In the final step, the amino group ofcysteine is acetylated by a hepatic n-acetylaseresulting in formation of the mercapturic acidderivative. This latter acetylation reaction isreversible and deacetylases can reform the aminometabolite [308].

It is clear that glutathione conjugation serves asa protective mechanism whereby potentially toxic,electrophilic metabolites, are detoxified either asglutathione conjugates or mercapturic acids [306-308]. However, it is becoming increasinglyrecognized that glutathione conjugation is notexclusively a detoxification reaction and thatcertain xenobiotics are toxicologically activated bythis conjugation route, either as such or as a resultof further processing of the glutathione conjugate.Therefore, cellular levels of glutathione are animportant determinant of xenobiotic toxicity[292,293,307].

The covalent binding of electrophilicmetabolites to DNA has been extensively studiedas primary mechanism of triggering mutagenic orcarcinogenic events. Some studies havesuccessfully identified the target amino acids towhich drug metabolites bind during the covalentinteractions with proteins. In general, the mostreactive target sites in proteins include thenucleophilic centers of cysteine, methionine,histidine and tyrosine [309]. Thiol sulfurrepresents a particularly potent nucleophilic site ina protein. Ample evidence suggests that proteinsulfhydryl groups may be important sites for attackby electrophilic drug metabolites resulting incovalent binding. Sulfhydryl blocking agents oftendecreases the covalent binding of drug to proteinthiols [310,311]. Exposure of Chinese hamster topotassium chromate leads to the formation of


stable complexes between DNA and amino acids([312]. Cysteine, glutamic acid, and histidine werethe major amino acids crosslinked to DNA inchromate-treated hamster [312]

1.4.2 Glutathione-S-Transferase (GST)

The glutathione-S-transferase enzymes aresoluble proteins predominantly found in thecytosol of hepatocytes and catalyze theconjugation of a variety of compounds with theendogenous tripeptide, glutathione. Cytosolicglutathione S-transferases can be divided into fourfamilies, termed alph (α), mu (µ), Pi(π), and theta(φ), having different but sometimes overlappingsubstrate specificities [298,302,313-315].Glutathione S-transferases are subjected toactivation by endogenous disulfides and byvarious intermediates that form during themetabolism of drugs and other foreign compounds[316]. Individual variation in the expression ofGST isozymes is well documented [317]. Forexample, the levels of GSTα class isozymes canvary markedly between individuals [318], and inthe case of GSTµ class, as a consequence ofgenetic polymorphism, about 45% of individualsdo not express GSTµ subunits [319]. Suchvariation in expression of GST isozymes maypredispose individuals to the toxic effects ofenvironmental carcinogens. A number of studiesdemonstrating that high levels of GSTπ inneoplastic nodules in several rat models ofhepatocarcinogenesis have prompted investi-gations of GSTπ levels in human tumors. Thepredominant form in most human tumorsinvestigated was class GSTπ and comparison ofmatched pairs of normal and tumor tissuesrevealed high levels in stomach, colon, bladder,cervix and lung tumors [320-323]. GSTπ serves asa marker for hepatotoxicity in rodent system [324],and also plays an important role in carcinogendetoxification. Therefore, inhibition of GSTactivity and depletion of GSH levels mightpotentiate the deleterious effects of manyenvironmental toxicants and carcinogens.Glutathione-S-transferases (GSTs) have thecapacity to detoxify electrophilic xenobiotics bycatalyzing the formation of glutathione (GSH)conjugates. GSTs are also engaged in theintracellular transport of variety of hormones,endogenous metabolites, and drugs, by virtue oftheir capacity to bind these substances [325]. Aseries of carcinogens drugs, metabolites, andrelated compounds were analyzed for binding toGST [326]. Broad specificity of binding is evident,but relative affinities are not determined by

lipophilicity alone. This is exemplified by thestriking differences between 2,3-benzo(a)anthracene, which was bound with high affinity,and 1,2-benzo(a)anthracene, which was classifiedas non-binding. Distinct structural requirementsemerged from these results [326]. Steric factorsappear to dictate binding; the polysubstitutedanthracenes such as the dibenzanthracenes, pyrene,chrysene and other polycyclic aromaticcompounds were bound. Similarly, dibenz(a,j)acridine was bound whereas acridine and acridineorange were not bound [306]. It is well known thatparasites and heavy metals caused marked changesin GST activity, and GSH levels [327-329].

Inducers of GSTs are generally considered asprotective compounds against cancer, acting asblocking agents. The human diet contains manycompounds that inhibit various steps of thecarcinogenic process [330]. The coffee specificditerpenses cafestol and kahweol have beenreported to be anti-carcinogenic in several animalmodels. It has been postulated that this activitymay be related to their ability to the induction ofglutathione S-transferase π class [331]. GSTπ wasinduced in the stomach by coumarin and α-angelicalactone and in the pancrease by flavone[332]. Several dietary compounds have beendemonstrated to reduce gastrointestinal cancerrates in both human and animals. For example,sulforaphane, indole-3-carbinol, D-limonene andrelafen induced GSTα levels in small intestine andlivers, GSTµ levels in stomach and small intestine,GSTπ levels in stomach and small and largeintestine [333]. Aqueous extracts of either green orblack tea were administered to rats as the soledrinking fluid for 4 weeks. Hepatic GST activityand UDP-Glucuronyl transferase were induced[333].

On the other hand, many different chemicalcompounds and dietary items were found to inhibitthe expression and the activity of GST isozymes.Trivalent antimony was a potent inhibitor ofglutathione S-transferases from humanerythrocytes [335]. Based on this inhibitioncharacteristics and the preferential accumulation oftrivalent antimony in mammalian erythrocytes, forexample, during therapeutic treatment ofLeishmaniasis, antimony levels in erythrocytesmay be high enough to depress GST activity,which might compromise the ability oferythrocytes to detoxify electrophilic xenobiotics[335]. Animals treated with acriflavine, a proteinkinase c inhibitor, and allyl disulfide showedcomplete blockage of GST gene expression asearly as 12 h of treatment [299]. Analogues of


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

1.4.3 Glutathione Reductase

Glutathione reductase from several tissuesources has been extensively characterized. Itscatalytic mechanism, amino acid sequence and itsthree dimensional crystal structure have beendetermined [339,340]. But little is known aboutthe physiological regulation of its activity. Therole of glutathione reductase is to maintain thecellular level of reduced glutathione. Its substratesand/or products in vivo do not regulate glutathionereductase activity. However, there have beenseveral reports hinting at the in vivo inhibition ofthe enzyme by GSH. No details of the inhibitionwere provided in these early reports [341,342].The first such detailed report on the inhibition ofglutathione reductase by GSH appeared in theliterature [343]. In that study, GSH was shown tobe a non-linear, non-competitive inhibitor ofglutathione reductase [343]. The inhibition ofglutathione reductase by GSH appear to be a widespread phenomenon that should hereafter beconsidered in any treatment of GSH metabolism orhomeostasis on the enzymes from human platelets,bovine intestinal mucosa, yeast and E. coli wereall 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 ininhibition patterns for glutathione reductase byGSH reported here is, to the best of knowledge,the first example of an observed functionaldifference in the generally highly conservedglutathione reductase enzyme. Physiologically, theconsideration of this inhibition has importantconsequences because normal levels of GSH canregulate the enzyme [343]. Presumably, theenzyme will be inhibited by GSH under normalcellular conditions and will therefore be less ableto convert oxidized form (GSSG) to reduced form(GSH), providing a concentration of GSSG to bemaintained at higher than other wise expectedconcentration [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 N-glucuronides, are rapidly excreted following theirformation in the body and that these metabolites

are not active or reactive [344,345]. The resultingacyl glucuronides were found to be electrophiles,reacting with sulfhydryl group. Conjugation withD-glucuronic acid represents the major route forelimination and detoxification of drugs andendogenous compounds possessing a carboxylicacid function [346,347]. Carcinogens and theirreactive metabolites may also be metabolized byalternative routes (e.g., by conjugation or byhydroxylase activities) to relatively harmlessintermediates that can be eliminated from thebody, although in some cases these may be furthertransformed into highly reactive chemical species[348,349]. As with the enzymes of carcinogenactivation those responsible for inactivation mayplay pivotal roles in the determination of the targettissue specificity of a particular carcinogen. It hasalso been suggested that the sulfation of certainchemical carcinogens could lead to more toxicconjugates, which can cause cell necrosis [350-352]. A major fraction of the N-hydroxyderivatives of aromatic amines is converted to theglucuronide, which is then excreted in the bile andurine [350]. However, the glucuronide also may behydrolyzed to release the free N-hydroxyarylamine, which is a potent electrophile [353].

1.4.5 Sulfate Conjugation

Many drugs are oxidized to a variety ofphenols, alcohols or hydroxylamines which canthen serve as excellent substrates for subsequent tosulfates conjugation, forming the readilyexcretable sulfate esters. However, inorganicsulfate is relatively inert and must first beactivated by ATP [263]. For phenolic metabolites,the key enzyme in this sequence issulfotransferase. The sulfotransferase enzymes aresoluble enzymes found in many tissues includingliver, kidney, gut and platelets and catalyze thesulfation of drugs such as paracetamol,isoprenaline and salicylamide and many steroids.It appears that the sulphotransferase exist inmultiple enzyme forms with the steroid sulfatingenzymes being distinct from the sulfotransferasesresponsible for drug conjugation reaction [354-356]. It should be emphasized that sulfateconjugation reactions are not as widespread or asof quantitative importance as glucuronideconjugation reactions, due in part to the limitedbioavailability of inorganic sulfate and hencePAPS. This is particularly true when a drug isactively metabolized to phenolic products or whenhigh body burdens of phenolic drugs are reached(for example, in overdose), resulting in effectivesaturation of this metabolic pathway [357].


1.4.6 N-Acetyltransferase

Xenobiotic-metabolizing enzymes constitute animportant line of defense against a variety ofcarcinogens. The wide variation in carcinogenmetabolism in human has long been regarded as animportant determinant of individual susceptibilityto chemical carcinogenesis. The carcinogenicity ofseveral arylamines and amides for the liver and theurinary bladder has prompted studies on themetabolism of these carcinogens and on theirreactive metabolites, which are catalyzed bymixed-function oxidases in the hepaticendoplasmic reticulum [358]. Distinct genes,designated NAT1 and NAT2 code for N-acetyl-transferase activities in human. NAT1 activityappears to be monomorphically distributed inhuman tissues, while the latter exhibits apolymorphism that allows the detection ofphenotypically slow and rapid metabolizers [359].The NAT2 polymorphism can have a significanteffect on individual susceptibility to aromaticamine-induced cancers. N-Acetylation ofarylamines represents a competing pathway for N-oxidation, a necessary metabolic activation-stepoccurring in the liver. The unconjugated N-hydroxy metabolites can then enter the circulation,and be transported to the urinary bladder lumen,where reabsorption and covalent binding tourothelial DNA can occur [360]. Low activity ofarylamine N-acetyltransferase 2 (slow NAT2acetylator) was consistently associated withurinary bladder cancer risk [361]. Also, NAT2plays a significant role in risk of lung canceramong non-smokers Chinese women [362].

Some studies have shown that meatconsumption is associated with breast cancer risk.Several heterocyclic amines, formed in cooking ofmeats, are mammary carcinogens in laboratorymodels [363,364]. Heterocyclic amines areactivated and rapid NAT2 activity may increaserisk associated with these compounds [363,364],Since NAT2 increased the binding of quinoline, aheterocyclic amine derivative, with DNA by 12fold, while NAT1 increased such binding by 4 fold[364].

1.4.7 Epoxide Hydrolase

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

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

The soluble epoxide hydrolase (sEH) plays asignificant role in the biosynthesis ofinflammatory mediators as well as xenobiotictransformations [366]. Epoxide hydrolase isinduced by most of the xenobiotic inducers of themixed-function oxidase system. Decamethyl-cyclopentasiloxane (D5) is a cyclic siloxane with awide range of commercial applications. Livermicrosomal epoxide hydrolase activity andimmunoreactive protein increased 1.7- and 1.4-fold, respectively, in the D5-exposed group [367].The naturally occurring organosulfur compounds(OSCs) diallyl sulfide (DAS), diallyl disulfide(DADS) and dipropyl sulfide (DPS) were studiedwith respect to their effects on microsomalepoxide hydrolase (mEH). DADS increased themEH levels in the liver, intestine, and kidney,while DAS and DPS moderately induced mEHlevel in the liver [368]. A series of organosulfurcompounds were developed as chemopreventiveactive compounds against hepatotoxicity andcarcinogenicity of aflatoxin B1 [369]. Themechanism of chemoprotection involved in theinhibition of the P450-mediated metabolicactivation of chemical carcinogens andenhancement of electrophilic detoxificationthrough induction of epoxide hydrolase, whichwould facilitate the clearance of activatedmetabolites through conjugation reaction [369]. .Although hydrolysis in most of the cases result indetoxication, in some cases hydrolysis may lead toactivated molecules that may attackmacromolecules (proteins, RNAs, DNAs),resulting in toxicity [370].

On the other hand, the discovery of substitutedureas and carbamates as potent inhibitors werefound to enhance cytotoxicity of trans-stilbeneoxide, which is active as the epoxide, but reducecytotoxicity of leukotoxin, which is activated byepoxide hydrolase to its toxic diol [366]. They alsoreduce toxicity of leukotoxin in vivo in mice andprevent symptoms suggestive of acute respiratorydistress syndrome [366].

Genetic polymorphisms of biotransformationenzymes are in a number of cases a major factorinvolved in the interindividual variability inxenobiotic metabolism and toxicity [371]. Thismay lead to interindividual variability in efficacyof drugs and disease susceptibility. Polymor-phisms in exons 3 and 4 of microsomal epoxidehydrolase in 101 patients with colon cancer andcompared the results with 203 control samples.


The frequency of the exon 3 T to C mutation washigher in cancer patients than in control [372].This sequence alteration changes tyrosine residue113 to histidine and is associated with lowerenzyme activity when expressed in vitro.Therefore, slow epoxide hydrolase activity may bea risk factor for colon cancer [372].

CONCLUSION

This review represents the importance ofcytochrome P450 in the oxidation of xenobioticsand carcinogens. Cytochromes P450 are multigenefamilies with broad substrate specificities. Theexpression of different P450 isozymes isdependent on many endogenous or exogenousfactors. Each P450 isozyme is responsible foroxidation of certain drug into more or less activemetabolites. The toxicity and carcinogenicity ofchemical carcinogens are mainly dependent on thelevel of their activating enzymes and also on thebalance with detoxifying enzymes such asglutathione S-transferase.

ABBREVIATIONS

Cyp = Cytochrome

MFO = Mixed-function oxidase

MC = 3-Methylcholanthrene

PB = Phenobarbitone

β-NF = β-Naphtoflavone

Ah = Aryl hydrocarbon

PAHs = Polycyclic aromatic hydrocarbons

TCDD = Tetrachlorodibenzo-p-dioxin

PCB = Polychlorinated biphenyl

EROD = Ethoxyresourfin O-deethylase

B(a)P = Benzo (a) pyrene

AHH = Aryl hydrocarbon hydroxylase

2-AAF = 2-Acetylaminofluorene

AFB1 = Aflatoxin B1

DMN = Dimethylnitrosamine

PAPS = 3'-Phosphoadenosine-5'-phosphosulfate

MAB = N-Methyl-4-aminoazobenzene

DAB = N, N-Dimethylaminoazobenzene

GSH = Glutathione (reduced form)

GSSG = Glutathione (oxidized form)

GST = Glutathione-S-transferase

GR = Glutathione reductase

NAT = N-Acetyltransferase

EH = Epoxide hydrolase

DAS = Diallyl sulfide

DADS = Diallyl disulfide

DPS = Dipropyl sulfide

REFERENCES

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

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

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

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

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

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

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

[8] Lee, R.F. (1998) Comp. Biochem. Physiol. CPharmacol. Toxicol. Endocrinol., 121(1-3), 173-9.

[9] 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.

[10] 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.

[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.

[14] Wang, L.E.; Yang, M.; and Xie, G. (1997) Wei ShengYen Chiu, 26(4), 217-20.

[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.

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

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

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

[19] Matsusue, K.; Ariyoshi, N.; Oguri, K.; Koga, N, andYoshimura, H. (1996) Chemosphere, 32(3), 517-23 .

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

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

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

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

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

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

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

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

[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.

[29] Ueng, T.H.; and Alvares, A.P. (1982) MolPharmacol., 1, 221-8.

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

[31] Lee, C.A.; Lawrence, B.P.; Kerkvliet, N.I.; andRifkind, A.B. (1998 ) Toxicol. Appl. Pharmacol.,153(1) 1-11.

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

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

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

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

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

[37] Pacheco, M.; and Santos, M.A. (1998) EcotoxicolEnviron Saf.; 40(1-2) 71-6.

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

[39] Koga, N.; Kikuichi, N.; Kanamaru, T.; Kuroki, H.;Matsusue, K.; Ishida, C.; Ariyoshi N, Oguri K, andYoshimura H (1998) Chemosphere, 37(9-12), 1895-904.

[40] Henry, M.C.; Port, C.D.; Bates, R.R.; and KaufmanDG(1973) Cancer Res., 33(7), 1585-92.

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

[42] Cheng, K.C.; Gelbin, H. V.; Song, B.; Parl, S. S.; andFriedman (1984). J. Biol. Chem., 259, 12279-84.

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

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

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

[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.

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


[49] Yamazaki H.; Shaw P.M.; Guengerich F.P.; ShimadaT. (1998) Chem. Res. Toxicol., 11(6), 659-65 .

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

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

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

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

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

[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, 4 575-82.

[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.; DesaiD.; 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.; PevicharovaG.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.; WattenbergL.W.; Kuntzman R.; Conney A.H. (1976) J.Pharmacol. Exp. Ther., 198(2), 278-83.

[65] Rikans L.E.; Notley B.A.; (1982) Biochem.Pharmacol., 31(14), 2339-43.

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

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

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

[69] Mostafa, M.H. and Sheweita, S.A. (1992) RamazziniNewsletter, 2, 15-22.

[70] Sheweita, S. A. and Mostafa, M. H. (1996) CancerLett., 106, 243-249.

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

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

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

[74] Chen R.M.; Chou M.W.; Ueng T.H. (1998) ArchToxicol., 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.; andKuntzman, 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.; GuengerichF.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.; UnkilaM.; 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.

[85] Hamnah, R.R.; Lund, J,Pollinge, L.; Gillner, M.; andGustaffson, J.A. (1986) Eur. J. Biochem., 156, 237-243.

[86] Gonzalez F.J.; Fernandez-Salguero P. (1998) DrugMetab Dispos., 26(12), 1194-8.

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

[88] Wroblewski, V.J.; and Olson, J. R.(1988) DrugMetab. Dispos., 16, 43-51 .


[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] Tukey, R.H.; Hannah, R.R.; Negishi, M.; Nebert,D.W.; and Eisen, H.J. (1982) Cell, 31, 275-284.

[92] 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, 615-617.

[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.

[100] Eaton, D. L.; Stacey, N. H.; Wong, K.-L.; andKlaassen, 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.; BlackS.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, 267-274.

[106] Levin, W.; Jacobson, M.; Sernatinger, E.; andKuntzman, R. (1973) Drug. Metab. Dispos., 1, 265-275.

[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.

[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) Cancerlett., 106, 243-249.

[111] Netter, K. J. (1973) Drug Metabol. Dispos., 1, 162-163.

[112] Mostafa, M. H.; Sheweita, S. A.; El-Kowedy, A. H.and Badawi, A. F. (1993) Int. J. Oncology, 2, 695-699.

[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 onCytochrome P450 Biodiversity and Biotechnology”,Strasbourg, France.

[114] Sheweita, S. A.; Safwat A. Mangoura and Adel G. El-Shemi, (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.

[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.; CascianoD.A.; Kadlubar F.F. (1999) Cancer Lett., 143(2), 167-71.

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

[126] Ioannides, C. and Parke, D.V. (1987) BiochemPharmacol., 36, 4192-4197 .


[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.

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

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

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

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

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

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

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

[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.

[143] Pott, P. (1775) Chirugical observation relative to thecataract, the polypus of the nose, the cancer of thescrotum, the different kinds of ruptures, and themodification of the toes and feet. Hawakes, Clarkeand 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) CancerPrev., 34,180-190.

[147] Tricker A.R. (1997) Eur. J. Cancer Prev., 6(3), 226-68.

[148] Miller, E. C. and Miller, J. A. (1976) In Chemicalcarcinogens, (Searle, C. E. Ed.) American ChemicalSociety, Washington, D. C.

[149] Whyatt R.M.; Bell D.A.; Jedrychowski W.; SantellaR.M.; Garte S.J.; Cosma G.; Manchester D.K.; YoungT.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.; GarteS.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 HealthPerspect 106 Suppl 3, 821-6.

[153] Sagami, I.; Ohmachi, T.; Fujii, H.; and Watanabe, M.(1987) Xenobiotica, 17, 189-198.

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

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

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

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

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

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

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

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

[162] Guengerich, F. P. (1991) J. Biol. Chem., 226,10019-10022.

[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.; andGelboin, 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.

[169] Conney, A. H. (1982) Cancer Res., 42, 4875-4917. .

[170] Gooderham, N.J. and Mannering, G. J. (1985) CancerRes., 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.; andConney, A.H.(1983) Cancer Res., 43,12 Pt 1 .

[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, 393-395.

[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.; Peterg-uengerich 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. .

[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(1-2), 167-81.

[190] Swenson, D.H.; Lin, J.K.; Miller, E.C. and Miller,J.A. (1977) Cancer Res., 37(1 ), 172-181.

[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.; KroetzD.L.; Szklarz G.; Harlow G.; Halpert J.R.; CorreiaM.A. (1998) Biochem., 37(36), 12536-45.

[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. andWogan, 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 tohuman cancer ( I. K. O'Neil, R. C. Von Borstll, C. T.Miller, J. Long, and H. Bartsch Eds.) InternationalAgency for Research on Cancer, IARC Sci. Publ. no.57, Lyon.

[201] Bartsch, H. and Montesano, R. (1984)Carcinogenesis, 5, 1381-1393.

[202] Brunnemann K.D.; Prokopczyk B.; Djordjevic M.V.;Hoffmann D. (1996) Crit. Rev. Toxicol., 26(2), 121-37.

[203] Hecht, S.S. (1998) Chem. Res. Toxicol., 11(6), 559-603.

[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 .


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

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

[210] Preuss, R. and Eisenbrand, G. (1984) In Chemicalcarcinogens, 2nd ed, (Searle, C. E. Ed.) ACSMonograph Series No. 182, Am. Chem. Socit.,Washington, DC.

[211] Wang, Y.; Ichiba, M.; Iyadomi, M.; Zhang, J. andTomokuni, 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.

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

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

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

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

[218] Le Marchand, L.; Sivaraman, L.; Pierce, L.; Seifried,A.; Lum, A.; Wilkens, L.R.; Lau, A.F. (1998) CancerRes., 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 EpidemiolBiomarkers 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), 216-23.

[224] Koppang, N.; Rivenson, A.; Dahle, H.K. andHoffmann, 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, B. (1996)Carcinogenesis, 17(5), 1127-34.

[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.

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

[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.

[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. andBerthou, 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.

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

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

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

[237] Magee, P. (1989) Cancer Surv., 8, 207-239.

[238] Wolf, C.R.; (1990) Cancer Surv., 9, 437-474.

[239] Orrenius, S.; Thor, H. and Jerstrom, B. (1980) In:Environmental chemicals, enzyme function andhuman 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 Chemicalcarcinogenesis. (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. andGibson, G.G. (1983) Carcinogenesis, 4(12),1583-1586 .

[244] Turesky, R.J.; Constable, A.; Fay, L.B. andGuengerich, F.P. (1999) Cancer Lett., 143(2), 109-12.

[245] International Labor Office (1921): Cancers amongworkers in aniline factories. Studies and reports,series F, No.1, P.2-26. Geneva.

[246] IARC (1972) IARC monograph on the evaluation ofcarcinogenic risk to man, Vol.1, Lyon, France.


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

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

[249] Aström, A. and DePierre, J.W. (1985)Carcinogenesis, 6(1), 113-122.

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

[251] Kitamura, S.; Takekawa, K.; Sugihara, K.; Tatsumi,K. and Ohta, S. (1999) Carcinogenesis, 20(2), 347-50.

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

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

[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), 173-9.

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

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

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

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

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

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

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

[264] Irving, C.C. (1975) Cancer Res., 35(11 Pt 1 ), 2959-61.

[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.

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

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

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

[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.

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

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

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

[274] Igarashi, S.; Yonekawa, H.; Kawajiri, K.; Watanabe,J.; Kimura, T.; Kodama M.; Nagata C.; and TagashiraY.(1982) Biochem. Biophys. Res. Commun., 14, 164-169.

[275] Kimura, T.; Kodama, M.; Nagata, C.; Kamataki, T.;and Kato, R. (1985): Biochem. Pharmacol., 1, 3375-3377.

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

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

[278] Miller, E.C.; Kadlubar, F.F.; Miller, J. A.; Pitot, H.C.and Drinkwater, N. R. (1979) Cancer Res., 39(9), 3411-8.

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

[280] Un, J.K.; Schmall, B.; Sharpe, I.D.; Miura, I.; Miller,J.A. and Miller, E.C. (1975) Cancer Res., 35(3), 832-43.

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

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

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

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

[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.


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

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

[288] .Chasseud, L. F. (1979) Adv. Cancer Res., 45, 1234-1245.

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

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

[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.

[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.

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

[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.

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

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

[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.

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

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

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

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

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

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

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

[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, 357-417.

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

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

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

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

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

[319] Hussey, A. J.; Stockman, P. K.; Beckett, G. J. andHayes, J. D. (1986) Biochem. Biophys. Acta., 874, 1-12.

[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.

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

[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. andvon 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) CancerLett., 99, 29-34.

[329] Sheweita, S. A. (1998) Inter. J. Toxicol., 17(4), 383-392.

[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. andIoannides, 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.; Dreef-Tramp, 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.

[341] Mannervik, B. (1969) Acta Chem. Scand., 23, 2912-2914.

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

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

[344] Faed, E. M. (1984). Drug Metab. Rev., 15(5-6), 1213-49.

[345] Caldwell, J. (1979) Life Sci., 24(7), 571-8.

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

[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), inmetabolic 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), 195-201.

[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-RychterM.; Lee M.S.; Wang C.Y. (1997) Mutat. Res., 376(1-2), 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.

[360] Kadlubar, F.F.; Dooley, K.L.; Teitel, C. H.; Roberts,D. W.; Benson, R.; Butler, M. A.; Bailey, J. R. andTannenbaum, S. R. (1991) Cancer Res., 51, 4371-4377.

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

[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.

[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.

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


[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.

[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.

[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.

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

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

[370] Hazai E, Róna K, Vereczkey L (1999) Acta. Pharm.Hung., 69(4), 208-12.

[371] Wormhoudt, L.W.; Commandeur, J.N. andVermeulen, N.P. (1999) Crit. Rev. Toxicol., 29(1),59-124.

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