Metabolism of chemical carcinogens

F. Peter Guengerich

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638B Medical Research Building I, 23rd Avenue South at Pierce, Nashville, Tennessee 37232-146, USA


    Abstract
 Top
 Abstract
 Introduction
 Highlights of metabolism...
 Current and future issues...
 References
 
The transformation of chemicals is important in carcinogenesis, both in bioactivation and detoxification. Major advances in the past 20 years include appreciation of the migration of reactive electrophiles, the ability of Phase II conjugating enzymes to activate chemicals, understanding of the human enzymes, the realization that DNA modification can result from endogenous chemicals, and the demonstration that cancers can result from the metabolism of chemicals to non-covalently bound products. Pathways of transformation in which major insight was gained during the past 20 years include nitropolycyclic hydrocarbons, polycyclic hydrocarbons and their diols, vinyl halides and dihaloalkanes. Advances in analytical methods and recombinant DNA technology contributed greatly to the study of metabolism of chemical carcinogens. Major advances have been made in the assignment of roles of individual enzymes in reactions. The knowledge developed in this field has contributed to growth in the areas of chemoprevention, molecular epidemiology and species comparisons of risk. Some of the areas in which future development relevant to carcinogen metabolism is expected involve pathways of transformation of certain chemicals, regulation of genes coding for many of the enzymes under consideration and genomics.

Abbreviations: GSH, glutathione; P450, cytochrome P450; PBPK, physiologically-based pharmacokinetic (models).


    Introduction
 Top
 Abstract
 Introduction
 Highlights of metabolism...
 Current and future issues...
 References
 
The discussion of the metabolism of carcinogens will be focused largely on the enzymes involved in the activation and detoxification of these chemicals. The basis of chemical reactivity of activated carcinogens with DNA will not be discussed per se. Most of the basic enzymatic transformations of chemical carcinogens were already known in 1980 (13). However, most of the enzyme systems were not well characterized and very little information existed regarding individual enzymes within groups.


    Highlights of metabolism research, 1980–2000
 Top
 Abstract
 Introduction
 Highlights of metabolism...
 Current and future issues...
 References
 
General concepts
Many of the general concepts regarding bioactivation, detoxification and genotoxicity had already been developed by Miller and others (4,5). However, at least four major new concepts regarding metabolism were developed during the past 20 years.

(i) `Reactive intermediates' do have finite stability and can travel limited distances to alkylate DNA. In the 1970s a view had developed that `activated carcinogens' were so reactive that they could not diffuse very far. This view led to the hypothesis that only nuclear enzymes could be involved in the activation of carcinogens (6). Subsequent work showed that products reactive with DNA could be generated in hepatocytes and be trapped outside the cells, e.g. with polycyclic hydrocarbons, nitrosamines and vinyl halides as the substrates (79). Furthermore, i.p. injection of a benzo[a]pyrene diol epoxide into pre-weanling mice generated lung tumors (10), arguing that distribution could be widespread even with a compound having a 30 s half-life.
(ii) `Phase II' enzymes involved in conjugates are not only protective but also activate chemical carcinogens. An example is glutathione (GSH) transferase, which activates 1,2-dihaloethanes (11,12). These enzymes can also activate other chemicals (13,14). Examples of roles of bioactivation are also known for N-acetyltransferase (15), UDP-glucuronosyl transferase (16), sulfotransferase (17) and other Phase II reactions. During the past 20 years evidence has been obtained for roles of kinases in activation of chemical carcinogens (18).
(iii) Humans generally form the same DNA (and RNA and protein) adducts as animal models. Twenty years ago this was still a hypothesis but has now been clearly demonstrated in many cases (19). Further review is beyond the scope of this review and more relevant to another (20). The point is that the same metabolic pathways are also important in humans and animals; generally the major differences are quantitative.
(iv) DNA adducts can be generated by the metabolism of `endogenous' chemicals. Key examples here are the generation of DNA adducts from products of lipid peroxidation (21,22), estrogens (23,24) and some other `endogenous' materials.
(v) Metabolism of chemicals to unreactive, non-genotoxic products can be an important issue in tumorigenesis, at least in animal models. A classic example is the oxidation of 2,2,4-trimethylpentane to an alcohol, which is stable but is complexed with {alpha}2u-globulin to produce male rat kidney tumors (25).

Development of pathways of metabolism of carcinogens
Many of the pathways we accept today were already established by 1980. For instance, the bay-region diol epoxide pathway for polycyclic hydrocarbons, the N-hydroxylation of arylamines followed by addition of a leaving group, and the {alpha}-hydroxylation of N-nitrosamines were generally accepted pathways (26). However, some reactions had not been established yet. One important group of carcinogens, the heterocyclic amines, has been studied extensively only in the past 20 years, but the pathways of metabolism are largely identical to those established for aryl amines (1). Some of the newer pathways for carcinogen metabolism include the following.

Nitropolycyclic hydrocarbons
These are of considerable interest because of their unusually high bacterial mutagenicity (27) and potential activity in some animal tumor models (28). Activation involves both diol epoxide pathways and reduction to aryl hydroxylamines (29,30). Redox cycling can occur with some of the nitro compounds, at least monocyclic, to yield nitro anion radicals and superoxide (31). P450s are involved in the oxygenation reactions but a number of redox-active enzymes can participate in activation (and detoxification) of nitro groups via reduction (32,33).

Oxidation of polycyclic hydrocarbon diols
One transformation that was not recognized until the 1980s was the oxidation of trans-dihydrodiols of aromatic hydrocarbons to o-catechols by dihydrodiol dehydrogenase [EC 1.3.1.20] (34). These enzymes are members of an aldo-keto reductase superfamily and also have activities toward hydroxy steroids. The oxidation suppresses the formation of carcinogenic dihydrodiol epoxides; conversely, the catechols may oxidize (enzymatically or non-enzymatically) to o-quinones and cause damage by reaction with macromolecules or through generation of reactive oxygen species (35,36).

Vinyl halides
In 1980 the metabolism of vinyl halides was understood only in terms of epoxidation. Studies in this laboratory with trichloroethylene (37) and vinylidene chloride (38) established stepwise oxidation and 1,2-shifts as an explanation for the products. This mechanism, with hydride migration, is generally viewed as a part of the oxidation of terminal olefins (with an aldehyde product) (39,40). Reactive haloacyl halides are produced (41); the relevance of these and the epoxides themselves to genotoxicity remains to be established.

Dihaloalkanes
In 1978 Rannug reported the GSH-dependent activation of 1,2-dichloroethane (11). This pathway is now well-established, with an episulfonium ion intermediate (42) and several characterized DNA adducts (43). The general pathway has been extended to dihalomethanes, although very limited information is available about DNA adducts (44). The same pathway appears to apply to trihalomethanes (45).

Development of analytical methods
Although many of the basic methods existed in 1980, the past two decades have seen an explosion of capability in two major areas.

Analytical chemistry
The first area involves chromatography and spectroscopy. HPLC has been developed as a necessary technique in the area. Capillary electrophoresis and other new separation techniques have potential. NMR and mass spectrometry were already very important in 1980 but today both methods have much greater resolution and sensitivity and are coupled on-line with HPLC. Other spectroscopic methods such as fluorescence (46) have been applied to DNA adduct studies. 32P-post-labeling was developed as a method of DNA adduct analysis by Randerath (47) and has been integrated into metabolic studies, although this method may ultimately be replaced by mass spectrometry methods.

Recombinant DNA technology
These approaches were in their infancy in 1980. In 1982 the first P450 cDNA sequence was published (48), and the characterization of the enzymes involved in carcinogen metabolism would have been impossible without these methods. Scarce proteins can be identified, characterized, and produced in large amounts.

As an aside, it should be emphasized that human tissue samples are now much more readily available than in 1980 and have been invaluable in extending work from animal models to humans.

Characterization of roles of individual enzymes in carcinogen metabolism
By 1980 many of the general concepts about the significance of enzymes in carcinogen metabolism had been developed, at least in principle. For instance, enzymes such as P450 were known to be inducible (49), enzymatic differences could be used to explain variable susceptibility of individual animals to carcinogens (50), and some evidence for P450 polymorphism as a risk factor in lung cancer had been presented (51). Enzymology had been used successfully to address issues regarding the existence of multiple enzyme forms within some multi-gene families (5256).

Protein chemistry and, later, molecular biology techniques were developed to characterize the enzymes involved in carcinogen metabolism, both in terms of the enzymology and also regulation of gene expression. This work was done with experimental animal models and, most importantly, with humans. Today there is a reasonably good understanding of many individual enzymes (e.g. individual P450s, GSH transferases, etc.) in terms of their concentrations in various human tissues, the extent of variability among humans, and the involvement of these enzymes in particular steps in metabolism of chemical carcinogens (57). The approaches are used rather routinely and many have been relatively straightforward, although the overall significance of a particular reaction to tumorigenesis may not always be clear. In the past few years, animals in which particular enzymes have been `knocked out' have been used in cancer studies to define the roles of individual proteins in the overall processes of toxicity and carcinogenesis (58,59).

Inter-individual variation in the enzymes involved in carcinogen metabolism is now extensively studied. To date there has been impressive success in the application of information about human P450s in the development of new drugs in the pharmaceutical industry (57). There is optimism that such approaches will also be productive in the prediction of cancer risks due to inter-individual variations in enzymes. The National Institute of Environmental Health Sciences has begun an Environmental Genome Project, in which the long-term goal is to associate risks with polymorphisms of the genes involved in carcinogen metabolism, as well as others (60). The overall appreciation, characterization and organization of information about individual genes has developed dramatically since 1980.

Development of approaches to chemoprevention
Chemoprevention is discussed in another article in this issue (61). The strategy of inducing `Phase II' conjugating enzymes was already in place before 1980 (62), but knowledge about the regulation of conjugating enzymes (63) and the inhibition of P450s (6466) has been integrated. Also of interest, however, are reports that some of the chemopreventive agents can increase the toxicity, or at least DNA adduct formation, by inducing the conjugating enzymes (67,68).

Development of in vitro genotoxicity assays
These cellular systems are very useful both in basic studies on roles of enzymes in activation/detoxification and in practical work on new chemicals, etc. The majority of the major systems used today was done before 1980. During the past decade many improvements in the systems have been made, particularly in terms of integration with enzyme systems of mammalian origin.

Purified enzymes and human microsomes have been added to Salmonella typhimurium-based systems, both in the classic Ames' reversion assay (69) and an SOS response-based colorimetric assay (70), in order to define roles of individual enzymes. Another approach is to express individual enzymes, or sets of enzymes, and reporter genes within cells. Such approaches have been utilized with mammalian cells (71) and bacteria (72). Both S.typhimurium and Escherichia coli-based systems with P450s have been used (7375).

Development of predictions for humans based upon species comparisons
One of the problems with in vitro results obtained in some of the systems described above is that the relevance of metabolism in different tissues may be difficult to relate to in vivo problems, e.g. cancer. One approach is the use of PBPK models, which have been developed mainly in the past 20 years. A common strategy is to: (i) define specific enzymatic steps of major relevance to bioactivation and detoxification; (ii) identify the most important tissues, in terms of metabolism and as targets for tumor development; (iii) collect data on rates of all relevant enzymatic transformations in vitro, with tissues of interest both from humans and experiment models; (iv) if possible (i.e. with reasonably weak cancer suspects such as industrial solvents), validate the model in humans with low exposures; and (v) on the basis of comparisons and predictions about the effective concentration of the activated carcinogen delivered at the target site in humans and animals, compare the risk of concentrations of the chemical to humans to those known to produce tumors in the experimental animal models (76,77). This strategy has been used with information about lung and liver measurements of CH2Cl2 metabolism by P450 2E1 and GSH transferase T1 (78), and as a consequence the Environmental Protection Agency revised its exposure limit upwards.


    Current and future issues in metabolism of chemical carcinogens
 Top
 Abstract
 Introduction
 Highlights of metabolism...
 Current and future issues...
 References
 
Although much progress has been made in the past 20 years and the field has matured, there are a number of remaining challenges that must be considered. These involve the general significance of the field and the basis for development of related areas, such as genomics.

Relevant pathways need to be established for more chemicals
Despite all of the knowledge of pathways obtained in the past half-century or more (79), the reactions remain to be established in many cases. Some notable examples include the GSH conjugation of trihalomethanes found in drinking water (45) and the oxidation products of trichloroethylene, at least those that are involved in reactions with macromolecules (9) [a separate issue is the contribution of an alternate, GSH-dependent pathway to activation (80,81)]. Even after many years of research on polycyclic hydrocarbons, controversies exist about the contribution of a radical pathway (82,83) and suggestions of `poly' oxidized products have been proposed (84). Another issue involves the chemical characterization of the DNA adducts generated by oxidations of several compounds by peroxidases (e.g. myeloperoxidase, cyclooxygenase, etc.) (85).

Basic enzymology
Understanding mechanistic details of one transformation is critical in making predictions about others. Much remains to be understood about most of the enzymes under consideration here (for recent review on the enzymes of interest, see ref. 86). The questions relate to both structure and catalysis (which are not unrelated). With some of the enzymes, the availability of crystal structures has facilitated progress (87,88); more are needed. Enzymology issues with practical implications include the question of whether P450s can catalyze 1-electron oxidation of polycyclic aromatic hydrocarbons (82). This hypothesis seems reasonable but has been difficult to address (89). The meaning of Km in most of the enzymatic transformations is not well understood (9092); what does this value mean when incorporated into PBPK models (93)?

Genomics
Genomics is a popular field today, and in the area of carcinogen metabolism there is much anticipation that genetic differences in the enzymes of interest will be associated with major differences in cancer risk. Two major issues must be addressed in the course of a massive study. The first is the identification of the major allelic variants of the genes (that code for the enzymes under consideration). This effort will require large-scale sequencing efforts. In some enzyme families not all of the individual genes have been identified yet (94,95).

The second issue is functional analysis. One approach to assessing the significance of genetic variations is to go directly to epidemiological correlations. However, the danger of going directly to such associations in the absence of basic scientific information has been demonstrated in the work with P450 2D6 (96,97). A logical approach is development of functional analysis systems, in which allelic variants of enzymes can be expressed and examined for parameters relevant to metabolism of relevant carcinogens. (For further discussion of the complexity and relevant issues, see ref. 60.)

Regulation of expression of enzymes
In a sense, most of the progress made in the regulation of the enzymes of interest has been made in the past 20 years, primarily because of the development of useful methodology. Today, much is known about the systems, but even more questions remain. In many cases, even the primary responsive elements (receptors) remain to be identified and fully characterized [e.g. antioxidant response element system (98100)]. Recent progress in the characterization of barbiturate and other drug-binding receptors has been promising (101,102). However, as work has proceeded with the elucidation of elements involved in gene regulation, so has the appreciation of the complexity of the systems. As an example, consider the Ah locus. The Ah receptor has now been extensively characterized but the list of involved partners continues to grow (103107) and definition of the role of each component remains challenging.

A need exists for more understanding of mechanisms of regulation of enzymes involved in carcinogen metabolism. Just as important is an understanding of the influence of modulation on carcinogenesis and toxicity. For instance, we are still not in a position to provide an explanation for the carcinogenicity and toxicity of dioxins (108). Without such understanding, efforts to compare risk among species (e.g. humans) are deficient (109). Does induction of Ah-linked genes really imply increased risk from a chemical? Although regulatory agencies are concerned because of the example of dioxin, the answers still remain equivocal or, at the least, dependent upon the particular model under investigation (110,111). Concerns also exist about the significance of induction by barbiturates and peroxisome proliferators to carcinogenesis (112).

Relevance to biomarkers and molecular epidemiology
The basic question is whether high or low activity of a particular enzyme is related to a change in risk. This type of work has become popular and there is good precedent for success in the paradigms of drug metabolism and P450 (57). Programs such as the Environmental Genome Project have been set up to evaluate the contribution of gene polymorphisms to various risks. Many issues need to be addressed, and there is considerable room for innovative approaches. These include better technology for high-throughput screening and also `functional genomics' (i.e. approaches to determining the effect of a genetic change on the enzymatic or other function of the involved proteins) (60,113,114). Another issue in this area is that of tissue localization and relevance to exposure. For instance, we have made the point that the epoxidation of aflatoxin B1 in the small intestine should be considered a detoxification event, in that it diverts the mycotoxin (from the liver) to cells that are readily sloughed (115). The issue of tissue localization is a problem in that it shifts the field to measurement of RNA and proteins, which must be excised from humans in order to make analyses. A related issue with polymorphisms is with genes that are not expressed in target tissues. Consideration of distribution kinetics of carcinogens and active metabolites and PBPK modes is needed (vide supra).

Assays with mixtures
Almost all of the experiments in the chemical carcinogenesis literature have been done with single compounds. This reductionist approach is not inappropriate and is certainly commended for understanding basic mechanisms. However, real exposure situations all involve mixtures and the approaches to dealing with these are difficult. As an example from our own research, consider work on the genotoxicity of tobacco smoke condensate components (116). The work was difficult because of the extremely inhibitory effect of tar components on P450 enzymes. What does this mean in terms of issues with smoking? The literature contains considerations of strategies. More insight will be needed in this area, particularly as scientists try to relate work on carcinogen metabolism to molecular epidemiology and practical human issues.

General relevance of carcinogen metabolism to cancer
This issue was addressed in a 1988 review (2). There is ample evidence in experimental animal models that altered carcinogen metabolism can have dramatic effects on tumor incidence (111,117). The concept that enzyme differences in humans can alter xenobiotic disposition and effects has very good precedence in the pharmaceutical industry, as mentioned earlier. Therefore, there is great hope that similar effects will be seen with cancer. However, the epidemiology results to date have not been strong. Although the association of P450 2D6 with lung cancer has been studied for many years, neither consistent epidemiology nor an experimental basis of a causal relationship have resulted (96,97,118). Similar problems have been encountered with GSH transferases M1 and P1 (119,120). Although there have been some reports of altered cancer incidence related to P450s 1A1 and 1B1 (121,122), the results cannot be interpreted in terms of any dramatic experimental differences between the allelic gene products (123125). The evidence regarding N-acetyltransferase may be more compelling (126,127). One of the major problems in doing epidemiology studies of this type is assessment of the actual chemical exposure, whether an endogenous or xenobiotic chemical. Linking variations in enzyme expression and catalytic activity to the endpoint of human cancer (128) will remain a challenge for at least part of the next 20 years.


    Notes
 
Email: guengerich{at}toxicology.mc.vanderbilt.edu


    Acknowledgments
 
I would like to dediacte this article to Prof. James A.Miller, who, with his late wife Elizabeth, really developed this area (4,49,79). I also thank Dr Fred Kadlubar for his comments on the manuscript. Work in the author's laboratory was supported in part by funds from the USPHS (R35 CA44353 and P30 ES00267).


    References
 Top
 Abstract
 Introduction
 Highlights of metabolism...
 Current and future issues...
 References
 

  1. Kadlubar,F.F. and Hammons,G.J. (1987) The role of cytochrome P-450 in the metabolism of chemical carcinogens. In Guengerich,F.P. (ed.) Mammalian Cytochromes P-450. CRC Press, Boca Raton, FL, Vol. 2, pp. 81–130.
  2. Guengerich,F.P. (1988) Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res., 48, 2946–2954.[ISI][Medline]
  3. Jakoby,W.B. (1980) Enzymatic Basis of Detoxification. Academic Press, New York, Vols 1 and 2.
  4. Miller,J.A. (1970) Carcinogenesis by chemicals: an overview. G.H.A. Clowes Memorial Lecture. Cancer Res., 30, 559–576.[ISI][Medline]
  5. Ames,B.N., Durston,W.E., Yamasaki,E. and Lee,F.D. (1973) Carcinogens are mutagens: A simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl Acad. Sci. USA, 70, 2281–2285.[Abstract]
  6. Bresnick,E. (1979) Nuclear activation of polycyclic hydrocarbons. Drug Metab. Rev., 10, 209–223.[ISI][Medline]
  7. Shen,A.L., Fahl,W.E. and Jefcoate,C.R. (1980) Metabolism of benzo(a)pyrene by isolated hepatocytes and factors affecting covalent binding of benzo(a)pyrene metabolites to DNA in hepatocyte and microsomal systems. Arch. Biochem. Biophys., 204, 511–523.[ISI][Medline]
  8. Umbenhauer,D.R. and Pegg,A.E. (1981) Alkylation of intracellular and extracellular DNA by dimethylnitrosamine following activation by isolated rat hepatocytes. Cancer Res., 41, 3471–3474.[Abstract]
  9. Miller,R.E. and Guengerich,F.P. (1983) Metabolism of trichloroethylene in isolated hepatocytes, microsomes, and reconstituted enzyme systems containing cytochrome P-450. Cancer Res., 43, 1145–1152.[Abstract]
  10. Kapitulnik,J., Wislocki,P.G., Levin,W., Yagi,H., Jerina,D.M. and Conney,A.H. (1978) Tumorigenicity studies with diol-epoxides of benzo[a]pyrene which indicate that (±)-trans-7ß,8{alpha}-dihydroxy-9{alpha},10{alpha}-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene is an ultimate carcinogen in newborn mice. Cancer Res., 38, 354–358.[Abstract]
  11. Rannug,U., Sundvall,A. and Ramel,C. (1978) The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. I. Activation through conjugation with glutathione in vitro. Chem. Biol. Interact., 20, 1–16.[ISI][Medline]
  12. Ozawa,N. and Guengerich,F.P. (1983) Evidence for formation of an S-[2-(N7-guanyl)ethyl]glutathione adduct in glutathione-mediated binding of 1,2-dibromoethane to DNA. Proc. Natl Acad. Sci. USA, 80, 5266–5270.[Abstract]
  13. Monks,T.J., Anders,M.W., Dekant,W., Stevens,J.L., Lau,S.S. and van Bladeren,P.J. (1990) Glutathione conjugate mediated toxicities. Toxicol. Appl. Pharmacol., 106, 1–19.[ISI][Medline]
  14. Anders,M.W. and Dekant,W. (1998) Glutathione-dependent bioactivation of haloalkanes. Annu. Rev. Pharmacol. Toxicol., 38, 501–537.[ISI][Medline]
  15. Grant,D.M., Josephy,P.D., Lord,H.L. and Morrison,L.D. (1992) Salmonella typhimurium strains expressing human arylamine N-acetyltransferases: metabolism and mutagenic activation of aromatic amines. Cancer Res., 52, 3961–3964.[Abstract]
  16. Kaderlik,K.R., Mulder,G.J., Turesky,R.J., Lang,N.P., Teitel,C.H., Chiarelli,M.P. and Kadlubar,F.F. (1994) Glucuronidation of N-hydroxy heterocyclic amines by human and rat liver microsomes. Carcinogenesis, 15, 1695–1701.[Abstract]
  17. Boberg,E.W., Miller,E.C., Miller,J.A., Poland,A. and Liem,A. (1983) Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1'-sulfoöxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1'-hydroxysafrole in mouse liver. Cancer Res., 43, 5163–5173.[Abstract]
  18. Lin,D.-X., Lang,N.P. and Kadlubar,F.F. (1995) Species differences in the biotransformation of the food-borne carcinogen 2-amino-1-methyl-6-phenylimazo[4,5-b]pyridine by hepatic microsomes and cytosols from humans, rats, and mice. Drug Metab. Dispos., 23, 518–524.[Abstract]
  19. Kaderlik,K.R. and Kadlubar,F.F. (1995) Metabolic polymorphisms and carcinogen–DNA adduct formation in human populations. Pharmacogenetics, 5, S108–S117.[ISI][Medline]
  20. Poirier,M., Santella,R.M. and Weston,A. (2000) Carcinogen macromolecular adducts and their measurement. Carcinogenesis, 21, 353–359.[Abstract/Free Full Text]
  21. Marnett,L.J., Hurd,H.K., Hollstein,M.C., Levin,D.E., Esterbauer,H. and Ames,B.N. (1985) Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat. Res., 148, 25–34.[ISI][Medline]
  22. Chung,F.L., Chen,H.J.C. and Nath,R.G. (1996) Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts. Carcinogenesis, 17, 2105–2111.[Abstract]
  23. Bolton,J.L., Pisha,E., Zhang,F. and Qiu,S. (1998) Role of quinoids in estrogen carcinogenesis. Chem. Res. Toxicol., 11, 1113–1127.[ISI][Medline]
  24. Cavalieri,E.L., Stack,D.E., Devanesan,P.D., Todorovic,R., Dwivedy,I., Higginbotham,S., Johansson,S.L., Patil,K., Gross,M.L., Gooden,J.K., Ramanathan,R., Cerny,R.L. and Rogan,E.G. (1997) Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc. Natl Acad. Sci. USA, 94, 10937–10942.[Abstract/Free Full Text]
  25. Borghoff,S.J., Short,B.G. and Swenberg,J.A. (1990) Biochemical mechanisms and pathobiology of {alpha}2u-globulin nephropathy. Annu. Rev. Pharmacol. Toxicol., 30, 349–367.[ISI][Medline]
  26. Searle,C.E. (1984) Chemical Carcinogens. American Chemistry Society, Washington, DC.
  27. Rosenkranz,H.S. and Mermelstein,R. (1985) The genotoxicity, metabolism and carcinogenicity of nitrated polycyclic aromatic hydrocarbons. J. Environ. Sci. Health, C3, 221–272.
  28. El-Bayoumy,K. (1992) Environmental carcinogens that may be involved in human breast cancer etiology. Chem. Res. Toxicol., 5, 585–590.[ISI][Medline]
  29. Yamazaki,H., Mimura,M., Oda,Y., Inui,Y., Shiraga,T., Iwasaki,K., Guengerich,F.P. and Shimada,T. (1993) Roles of different forms of cytochrome P450 in the activation of the promutagen 6-aminochrysene to genotoxic metabolites in human liver microsomes. Carcinogenesis, 14, 1271–1278.[Abstract]
  30. Chae,Y.H., Yun,C.H., Guengerich,F.P., Kadlubar,F.F. and El-Bayoumy,K. (1993) Roles of human hepatic and pulmonary cytochrome P450 enzymes in the metabolism of the environmental carcinogen 6-nitrochrysene. Cancer Res., 53, 2028–2034.[Abstract]
  31. Moreno,S.N.J., Schreiber,J. and Mason,R.P. (1986) Nitrobenzyl radical metabolites from microsomal reduction of nitrobenzyl chlorides. J. Biol. Chem., 261, 7811–7815.[Abstract/Free Full Text]
  32. Shimada,T. and Guengerich,F.P. (1990) Inactivation of 1,3-, 1,6-, and 1,8-dinitropyrene by human and rat microsomes. Cancer Res., 50, 2036–2043.[Abstract]
  33. Djuric,Z., Potter,D.W., Heflich,R.H. and Beland,F.A. (1986) Aerobic and anaerobic reduction of nitrated pyrenes in vitro. Chem. Biol. Interact., 59, 309–324.[ISI][Medline]
  34. Wörner,W. and Oesch,F. (1984) Identity of dihydrodiol dehydrogenase and 3 alpha-hydroxysteroid dehydrogenase in rat but not in rabbit liver cytosol. FEBS Lett., 170, 263–267.[ISI][Medline]
  35. Flowers-Geary,L., Bleczinski,W., Harvey,R.G. and Penning,T.M. (1996) Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon o-quinones produced by dihydrodiol dehydrogenase. Chem. Biol. Interact., 99, 55–72.[ISI][Medline]
  36. Smithgall,T.E., Harvey,R.G. and Penning,T.M. (1988) Oxidation of the trans-3,4-dihydrodiol metabolites of the potent carcinogen 7,12-dimethylbenz(a)anthracene and other benz(a)anthracene derivatives by 3a-hydroxysteroid-dihydrodiol dehydrogenase: effects of methyl substitution on velocity and stereochemical course of trans-dihydrodiol oxidation. Cancer Res., 48, 1227–1232.[Abstract]
  37. Miller,R.E. and Guengerich,F.P. (1982) Oxidation of trichloroethylene by liver microsomal cytochrome P-450: evidence for chlorine migration in a transition state not involving trichloroethylene oxide. Biochemistry, 21, 1090–1097.[ISI][Medline]
  38. Liebler,D.C. and Guengerich,F.P. (1983) Olefin oxidation by cytochrome P-450: evidence for group migration in catalytic intermediates formed with vinylidene chloride and trans-1-phenyl-1-butene. Biochemistry, 22, 5482–5489.[ISI][Medline]
  39. Mansuy,D., Leclaire,J., Fontecave,M. and Momenteau,M. (1984) Oxidation of monosubstituted olefins by cytochrome P-450 and heme models: evidence for the formation of aldehydes in addition to epoxides and allylic alcohols. Biochem. Biophys. Res. Commun., 119, 319–325.[ISI][Medline]
  40. Ortiz de Montellano,P.R. (1986) Oxygen activation and transfer. In Ortiz de Montellano,P.R. (ed.) Cytochrome P-450. Plenum Press, New York, pp. 217–271.
  41. Liebler,D.C., Meredith,M.J. and Guengerich,F.P. (1985) Formation of glutathione conjugates by reactive metabolites of vinylidene chloride in microsomes and isolated hepatocytes. Cancer Res., 45, 186–193.[Abstract]
  42. Peterson,L.A., Harris,T.M. and Guengerich,F.P. (1988) Evidence for an episulfonium ion intermediate in the formation of S-[2-(N7-guanyl)ethyl]glutathione in DNA. J. Am. Chem. Soc., 110, 3284–3291.[ISI]
  43. Cmarik,J.L., Humphreys,W.G., Bruner,K.L., Lloyd,R.S., Tibbetts,C. and Guengerich,F.P. (1992) Mutation spectrum and sequence alkylation selectivity resulting from modification of bacteriophage M13mp18 with S-(2-chloroethyl)glutathione. Evidence for a role of S-[2-(N7-guanyl)ethyl]glutathione as a mutagenic lesion formed from ethylene dibromide. J. Biol. Chem., 267, 6672–6679.[Abstract/Free Full Text]
  44. Thier,R., Pemble,S.E., Taylor,J.B., Humphreys,W.G., Persmark,M., Ketterer,B. and Guengerich,F.P. (1993) Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes. Proc. Natl Acad. Sci. USA, 90, 8576–8580.[Abstract/Free Full Text]
  45. Pegram,R.A., Andersen,M.E., Warren,S.H., Ross,T.M. and Claxton,L.D. (1997) Glutathione S-transferase-mediated mutagenicity of trihalomethanes in Salmonella typhimurium: contrasting results with bromodichloromethane and chloroform. Toxicol. Appl. Pharmacol., 144, 183–188.[ISI][Medline]
  46. Marsch,G.A., Jankowiak,R., Small,G.J., Hughes,N.C. and Phillips,D.H. (1992) Evidence of involvment of multiple sites of metabolism in the in vivo covalent binding of dibenzo[a,h]pyrene to DNA. Chem. Res. Toxicol., 5, 765–772.[ISI][Medline]
  47. Randerath,K., Reddy,M.V. and Gupta,R.C. (1981) 32P-labeling test for DNA damage. Proc. Natl Acad. Sci. USA, 78, 6126–6129.[Abstract]
  48. Fujii-Kuriyama,Y., Mizukami,Y., Kawajiri,K., Sogawa,K. and Muramatsu,M. (1982) Primary structure of a cytochrome P-450: coding nucleotide sequence of phenobarbital-inducible cytochrome P-450 cDNA from rat liver. Proc. Natl Acad. Sci. USA, 79, 2793–2797.[Abstract]
  49. Conney,A.H., Miller,E.C. and Miller,J.A. (1956) The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res., 16, 450–459.[ISI]
  50. Nebert,D.W. and Jensen,N.M. (1979) The Ah locus: genetic regulation of the metabolism of carcinogens, drugs, and other environmental chemicals by cytochrome P-450-mediated monooxygenases. Crit. Rev. Biochem., 6, 401–438.[ISI][Medline]
  51. Kellerman,G., Shaw,C.R. and Luyten-Kellerman,M. (1973) Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. N. Engl. J. Med., 298, 934–937.[Abstract]
  52. Habig,W.H., Pabst,M.J. and Jakoby,W.B. (1974) Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. J. Biol. Chem., 249, 7130–7139.[Abstract/Free Full Text]
  53. Haugen,D.A., van der Hoeven,T.A. and Coon,M.J. (1975) Purified liver microsomal cytochrome P-450: separation and characterization of multiple forms. J. Biol. Chem., 250, 3567–3570.[Abstract]
  54. Tukey,R.H. and Tephly,T.R. (1981) Purification and properties of rabbit liver estrone and p-nitrophenol UDP-glucuronyltransferases. Arch. Biochem. Biophys., 209, 565–578.[ISI][Medline]
  55. Ryan,D., Lu,A.Y.H. and Levin,W. (1978) Purification of cytochrome P-450 and P-448 from rat liver microsomes. Methods Enzymol., 52, 117–123.[Medline]
  56. Guengerich,F.P. (1978) Separation and purification of multiple forms of microsomal cytochrome P-450. Partial characterization of three apparently homogeneous cytochromes P-450 prepared from livers of phenobarbital- and 3-methylcholanthrene-treated rats. J. Biol. Chem., 253, 7931–7939.[ISI][Medline]
  57. Guengerich,F.P. (1995) Human cytochrome P450 enzymes. In Ortiz de Montellano,P.R. (ed.) Cytochrome P450. Plenum Press, New York, pp. 473–535.
  58. Lee,S.S.T., Buters,J.T.M., Pineau,T., Fernandez-Salguero,P. and Gonzalez,F.J. (1996) Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem., 271, 12063–12067.[Abstract/Free Full Text]
  59. Fernandez-Salguero,P.M., Hilbert,D.M., Rudikoff,S., Ward,J.M. and Gonzalez,F.J. (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol. Appl. Pharmacol., 140, 173–179.[ISI][Medline]
  60. Guengerich,F.P. (1998) The environmental genome project: functional analysis of polymorphisms. Environ. Health Perspect., 106, 365–368.[ISI][Medline]
  61. Sporn,M.B. and Suh,N. (2000) Chemoprevention of cancer. Carcinogenesis, 21, 525–530.[Abstract/Free Full Text]
  62. Benson,A.M., Batzinger,R.P., Ou,S.Y.L., Bueding,E., Cha,Y.N. and Talalay,P. (1978) Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res., 38, 4486–4495.[ISI][Medline]
  63. Davidson,N.E., Egner,P.A. and Kensler,T.W. (1990) Transcriptional control of glutathione S-transferase gene expression by the chemoprotective agent 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) in rat liver. Cancer Res., 50, 2251–2255.[Abstract]
  64. Langouët,S., Coles,B., Morel,F., Becquemont,L., Beaune,P.H., Guengerich,F.P., Ketterer,B. and Guillouzo,A. (1995) Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture. Cancer Res., 55, 5574–5579.[Abstract]
  65. Jiao,D., Smith,T.J., Kim,S., Yang,C.S., Desai,D., Amin,S. and Chung,F.L. (1996) The essential role of the functional group in alkyl isothiocyanates for inhibition of tobacco nitrosamine-induced lung tumorigenesis. Carcinogenesis, 17, 755–759.[Abstract]
  66. Ahn,D., Putt,D., Kresty,L., Stoner,G.D., Fromm,D. and Hollenberg,P.F. (1996) The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes. Carcinogenesis, 17, 821–828.[Abstract]
  67. Kim,D.-H. and Guengerich,F.P. (1990) Formation of the DNA adduct S-[2-(N7-guanyl)ethyl]glutathione from ethylene dibromide: effects of modulation of glutathione and glutathione S-transferase levels and the lack of a role for sulfation. Carcinogenesis, 11, 419–424.[Abstract]
  68. Sherratt,P.J., Manson,M.M., Thomson,A.M., Hissink,E.A.M., Neal,G.E., Vanbladeren,P.J., Green,T. and Hayes,J.D. (1998) Increased bioactivation of dihaloalkanes in rat liver due to induction of class theta glutathione S-transferase T1-1. Biochem. J., 335, 619–630.[ISI][Medline]
  69. McManus,M.E., Burgess,W.M., Veronese,M.E., Huggett,A., Quattrochi,L.C. and Tukey,R.H. (1990) Metabolism of 2-acetylaminofluorene and benzo(a)pyrene and activation of food-derived heterocyclic amine mutagens by human cytochromes P-450. Cancer Res., 50, 3367–3376.[Abstract]
  70. Shimada,T., Iwasaki,M., Martin,M.V. and Guengerich,F.P. (1989) Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA1535/pSK1002. Cancer Res., 49, 3218–3228.[Abstract]
  71. Gonzalez,F.J. (1993) Molecular biology of human xenobiotic-metabolizing cytochromes P450: role of vaccinia virus cDNA expression in evaluating catalytic function. Toxicology, 82, 77–88.[ISI][Medline]
  72. Guengerich,F.P., Gillam,E.M.J. and Shimada,T. (1996) New applications of bacterial systems to problems in toxicology. Crit. Rev. Toxicol., 26, 551–583.[ISI][Medline]
  73. Suzuki,A., Kushida,H., Iwata,H., Watanabe,M., Nohmi,T., Fujita,K., Gonzalez,F.J. and Kamataki,T. (1998) Establishment of a Salmonella tester strain highly sensitive to mutagenic heterocyclic amines. Cancer Res., 58, 1833–1838.[Abstract]
  74. Josephy,P.D., Evans,D.H., Parikh,A. and Guengerich,F.P. (1998) Expression of active human cytochrome P450 1A2, NADPH-cytochrome P450 reductase, and N-acetyltransferase in Escherichia coli: metabolic activation of aromatic amine mutagens. Chem. Res. Toxicol., 11, 70–74.[ISI][Medline]
  75. Kranendonk,M., Mesquita,P., Laires,A., Vermeulen,N.P.E. and Rueff,J. (1998) Expression of human cytochrome P450 1A2 in Escherichia coli: a system for biotransformation and genotoxicity studies of chemical carcinogens. Mutagenesis, 13, 263–269.[Abstract]
  76. Andersen,M.E., Krewski,D. and Withey,J.R. (1993) Physiological pharmacokinetics and cancer risk assessment. Cancer Lett., 69, 1–14.[ISI][Medline]
  77. Bois,F., Krowech,G. and Zeise,L. (1995) Modeling human interindividual variability in metabolism and risk: the example of 4-aminobiphenyl. Risk Anal., 15, 205–213.[ISI][Medline]
  78. Reitz,R.H., Mendrala,A. and Guengerich,F.P. (1989) In vitro metabolism of methylene chloride in human and animal tissues: use in physiologically-based pharmacokinetic models. Toxicol. Appl. Pharmacol., 97, 230–246.[ISI][Medline]
  79. Miller,E.C. and Miller,J.A. (1947) The presence and significance of bound amino azodyes in the livers of rats fed p-dimethylaminoazobenzene. Cancer Res., 7, 468–480.[ISI]
  80. Dekant,W., Koob,M. and Henschler,D. (1990) Metabolism of trichloroethene—in vivo and in vitro evidence for activation by glutathione conjugation. Chem. Biol. Interact., 73, 89–101.[ISI][Medline]
  81. Goeptar,A.R., Commandeur,J.N.M., van Ommen,B., van Bladeren,P.J. and Vermeulen,N.P.E. (1995) Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity. Relevance to the mercapturic acid pathway. Chem. Res. Toxicol., 8, 3–21.[ISI][Medline]
  82. Cavalieri,E.L. and Rogan,E.G. (1990) Radical cations in aromatic hydrocarbon carcinogenesis. Free Rad. Res. Commun., 11, 77–87.[ISI][Medline]
  83. Melendez-Colon,V.J., Smith,C.A., Seidel,A., Luch,A., Platt,K.L. and Baird,W.M. (1997) Formation of stable adducts and absence of depurinating DNA adducts in cells and DNA treated with the potent carcinogen dibenzo[a,l]pyrene or its diol epoxides. Proc. Natl Acad. Sci. USA, 94, 13542–13547.[Abstract/Free Full Text]
  84. Zhang,J.T., Dai,W. and Harvey,R.G. (1998) Synthesis of higher oxidized metabolites of dibenz[a,j]anthracene implicated in the mechanism of carcinogenesis. J. Org. Chem., 63, 8125–8132.[ISI]
  85. Yamazoe,Y., Zenser,T.V., Miller,D.W. and Kadlubar,F.F. (1988) Mechanism of formation and structural characterization of DNA adducts derived from peroxidative activation of benzidine. Carcinogenesis, 9, 1635–1641.[Abstract]
  86. Guengerich,F.P. (1997) Biotransformation, Vol. 3 of Comprehensive Toxicology. Pergamon, Oxford, UK.
  87. Ji,X.H., Johnson,W.W., Sesay,M.A., Dickert,L., Prasad,S.M., Ammon,H.L., Armstrong,R.N. and Gilliland,G.L. (1994) Structure and function of the xenobiotic substrate binding site of a glutathione S-transferase as revealed by X-ray crystallographic analysis of product complexes with the diastereomers of 9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene. Biochemistry, 33, 1043–1052.[ISI][Medline]
  88. Kakuta,Y., Petrotchenko,E.V., Pedersen,L.C. and Negishi,M. (1998) The sulfuryl transfer mechanism. Crystal structure of a vanadate complex of estrogen sulfotransferase and mutational analysis. J. Biol. Chem., 273, 27325–27330.[Abstract/Free Full Text]
  89. Anzenbacher,P., Niwa,T., Tolbert,L.M., Sirimanne,S.S. and Guengerich,F.P. (1996) Oxidation of 9-alkyl anthracenes by cytochrome P450 2B1, horseradish peroxidase, and iron tetraphenylporphin/iodosylbenzene systems. Anaerobic and aerobic mechanisms. Biochemistry, 35, 2512–2520.[ISI][Medline]
  90. Tzeng,H.-F., Laughlin,L.T., Lin,S. and Armstrong,R.N. (1996) The catalytic mechanism of microsomal epoxide hydrolase involves reversible formation and rate-limiting hydrolysis of the alkyl-enzyme intermediate. J. Am. Chem. Soc., 118, 9436–9437.[ISI]
  91. Bell,L.C. and Guengerich,F.P. (1997) Oxidation kinetics of ethanol by human cytochrome P450 2E1. Rate-limiting product release accounts for effects of isotopic hydrogen substitution and cytochrome b5 on steady-state kinetics. J. Biol. Chem., 272, 29643–29651.[Abstract/Free Full Text]
  92. Northrop,D.B. (1998) On the meaning of Km and V/K in enzyme kinetics. J. Chem. Ed., 75, 1153–1157.[ISI]
  93. Andersen,M.E., Clewell,H.J. and Frederick,C.B. (1995) Applying simulation modeling to problems in toxicology and risk assessment—a short perspective. Toxicol. Appl. Pharmacol., 133, 181–187.[ISI][Medline]
  94. Nelson,D.R., Koymans,L., Kamataki,T., Stegeman,J.J., Feyereisen,R., Waxman,D.J., Waterman,M.R., Gotoh,O., Coon,M.J., Estabrook,R.W., Gunsalus,I.C. and Nebert,D.W. (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers, and nomenclature. Pharmacogenetics, 6, 1–42.[ISI][Medline]
  95. Board,P., Coggan,M., Johnston,P., Ross,V., Suzuki,T. and Webb,G. (1991) Genetic heterogeneity of the human glutathione transferases: a complex of gene families. Pharmacol. Ther., 48, 357–369.[ISI]
  96. Ayesh,R., Idle,J.R., Ritchie,J.C., Crothers,M.J. and Hetzel,M.R. (1984) Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature, 312, 169–170.[ISI][Medline]
  97. Shaw,G.L., Falk,R.T., Frame,J.N., Weiffenbach,B., Nesbitt,J.V., Pass,H.I., Caporaso,N.E., Moir,D.T. and Tucker,M.A. (1998) Genetic polymorphism of CYP2D6 and lung cancer risk. Cancer Epidem. Biomarker. Prev., 7, 215–219.
  98. Liu,S. and Pickett,C.B. (1996) The rat liver glutathione S-transferase Ya subunit gene: characterization of the binding properties of a nuclear protein from HepG2 cells that has high affinity for the antioxidant response element. Biochemistry, 35, 11517–11521.[ISI][Medline]
  99. Pinkus,R., Weiner,L.M. and Daniel,V. (1996) Role of oxidants and antioxidants in the induction of AP-1, NF-{kappa}B, and glutathione S-transferase gene expression. J. Biol. Chem., 271, 13422–13429.[Abstract/Free Full Text]
  100. Wasserman,W.W. and Fahl,W.E. (1997) Functional antioxidant responsive elements. Proc. Natl Acad. Sci. USA, 94, 5361–5366.[Abstract/Free Full Text]
  101. Lehmann,J.M., McKee,D.D., Watson,M.A., Wilson,T.M., Moore,J.T. and Kliewer,S.A. (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest., 102, 1016–1023.[Abstract/Free Full Text]
  102. Honkakoski,P. and Negishi,M. (1997) Characterization of a phenobarbital-responsive enhancer module in mouse P450 Cyp2b10 gene. J. Biol. Chem., 272, 14943–14949.[Abstract/Free Full Text]
  103. Ma,Q. and Whitlock,J.P.Jr (1997) A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. Biol. Chem., 272, 8878–8884.[Abstract/Free Full Text]
  104. Probst,M.R., Fan,C.M., Tessier-Lavigne,M. and Hankinson,O. (1997) Two murine homologs of the Drosphilia single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein. J. Biol. Chem., 272, 4451–4457.[Abstract/Free Full Text]
  105. Carver,L.A. and Bradfield,C.A. (1997) Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J. Biol. Chem., 272, 11452–11456.[Abstract/Free Full Text]
  106. Carver,L.A., LaPres,J.J., Jain,S., Dunham,E.E. and Bradfield,C.A. (1998) Characterization of the Ah receptor-associated protein, ARA9. J. Biol. Chem., 273, 33580–33587.[Abstract/Free Full Text]
  107. Sogawa,K. and Fujii-Kuriyama,Y. (1997) Ah receptor, a novel ligand-activated transcription factor. J. Biochem., 122, 1975–1979.
  108. Hahn,M.E. (1998) Mechanisms of innate and acquired resistance to dioxin-like compounds. Rev. Toxicol., 2, 395–443.
  109. Bradfield,C.A., Gallo,M.A., Gasiewicz,T.A., Greenberg,R.S., Greenlee,W.F., Margolick,J., Mattison,D.R., Munson,P., Neal,R.A., Okey,A.B., Olive,D.L., Poland,A., Rifkind,A.B., Rodricks,J.V., Rozman,K., Safe,S.H., Starr,T.B. and Sutter,T.R. (1994) EPA dioxin reassessment. Science, 266, 1628–1629.[ISI][Medline]
  110. Richardson,H.L., Stier,A.R. and Borsos-Nachtnebel,E. (1952) Liver tumor inhibition and adrenal histologic responses in rats to which 3'-methyl-4-dimethylaminoazobenzene and 20-methylcholanthrene were simultaneously administered. Cancer Res., 12, 356–361.[ISI]
  111. Nebert,D.W. (1989) The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects. Crit. Rev. Toxicol., 20, 153–174.[ISI][Medline]
  112. McClain,R.M. (1994) Mechanistic considerations in the regulation and classification of chemical carcinogens. In Kotsonis,F.N., Mackey,M. and Hjelle,J. (eds) Nutritional Toxicology. Raven Press Ltd, New York, pp. 273–304.
  113. Veber,D.F., Drake,F.H. and Gowen,M. (1997) The new partnership of genomics and chemistry for accelerated drug development. Curr. Opin. Chem. Biol., 1, 151–156.[ISI][Medline]
  114. DeRisi,J.L., Iyer,V.R. and Brown,P.O. (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science, 278, 680–686.[Abstract/Free Full Text]
  115. Guengerich,F.P. and Johnson,W.W. (1999) Kinetics of hydrolysis and reaction of aflatoxin B1 exo-8,9-epoxide and relevance to toxicity and detoxification. Drug Metab. Rev., 31, 141–158.[ISI][Medline]
  116. Shimada,T. and Guengerich,F.P. (1991) Activation of amino-{alpha}-carboline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and a copper phthalocyanine cellulose extract of cigarette smoke condensate by cytochrome P-450 enzymes in rat and human liver microsomes. Cancer Res., 51, 5284–5291.[Abstract]
  117. Boberg,E.W., Liem,A., Miller,E.C. and Miller,J.A. (1987) Inhibition by pentachlorophenol of the initiating and promoting activites of 1'-hydroxysafrole for the formation of enzyme-altered foci and tumors in rat liver. Carcinogenesis, 8, 531–539.[Abstract]
  118. Drakoulis,N., Minks,T., Ploch,M., Otte,F., Heinemeyer,G., Kampf,D., Loddenkemper,R. and Roots,I. (1986) Questionable association of debrisoquine hydroxilator phenotype and risk for bronchial carcinoma. Acta Pharmacol. Toxicol., 59 (Suppl. 5), 220.[Medline]
  119. Alexandrie,A.K., Sundberg,M.I., Seidegärd,J., Tornling,G. and Rannug,A. (1994) Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. Carcinogenesis, 15, 1785–1790.[Abstract]
  120. Brockmöller,J., Kerb,R., Drakoulis,N., Nitz,M. and Roots,I. (1993) Genotype and phenotype of glutathione S-transferase class A isoenzymes A and {Psi} in lung cancer patients and controls. Cancer Res., 53, 1004–1011.[Abstract]
  121. Kawajiri,K., Nakachi,K., Imai,K., Watanabe,J. and Hayashi,S.-I. (1993) The cytochrome P4501A1 gene and cancer susceptibility. Crit. Rev. Oncol. Hematol., 14, 77–87.[ISI][Medline]
  122. Bailey,L.R., Roodi,N., Dupont,W.D. and Parl,F.F. (1998) Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in breast cancer. Cancer Res., 58, 5038–5041.[Abstract]
  123. Zhang,Z.-Y., Fasco,M.J., Huang,L., Guengerich,F.P. and Kaminsky,L.S. (1996) Characterization of purified recombinant human CYP 1A1-Ile462 and Val462: assessment of a role for the rare allele in carcinogenesis. Cancer Res., 56, 3926–3933.[Abstract]
  124. Persson,I., Johansson,I. and Ingelman-Sundberg,M. (1997) In vitro kinetics of two human CYP1A1 variant enzymes suggested to be associated with interindividual differences in cancer susceptibility. Biochem. Biophys. Res. Commun., 231, 227–230.[ISI][Medline]
  125. Hanna,I.H., Roodi,N., Guengerich,F.P. and Parl,F.F. (1999) Pharmacogenetics of human cytochrome P450 1B1. Proc. Am. Assoc. Cancer Res., 40, 50–51.
  126. Philip,P.A., Fitzgerald,D.L., Cartwright,R.A., Peake,M.D. and Rogers,H.J. (1988) Polymorphic N-acetylation capacity in lung cancer. Carcinogenesis, 9, 491–493.[Abstract]
  127. d'Errico,A., Taioli,E., Chen,X. and Vineis,P. (1996) Genetic metabolic polymorphisms and the risk of cancer: a review of the literature. Biomarkers, 1, 149–173.[ISI]
  128. Perera,F.P. and Weinstein,I.B. (2000) Molecular epidemiology: recent advances and future directions. Carcinogenesis, 21, 517–524.[Abstract/Free Full Text]
Received April 6, 1999; accepted May 7, 1999.