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J. Biol. Chem., Vol. 279, Issue 23, 23847-23850, June 4, 2004

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Minireview

Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer^*

Daniel W. Nebert, Timothy P. Dalton, Allan B. Okey, and Frank J. Gonzalez¶

From the Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and ^¶Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20814

	ABSTRACT

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor (AHR). The CYP1 enzymes are responsible for both metabolically activating and detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines present in combustion products. Many substrates for CYP1 enzymes are AHR ligands. Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven. Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation. Intact animal data contradict pharmaceutical company policies that routinely test drugs under development; if a candidate drug shows CYP1 inducibility, further testing is generally discontinued for fear of possible toxic or carcinogenic effects. In the future, use of "humanized" mouse lines, containing a human AHR or CYP1 allele in place of the orthologous mouse gene, is one likely approach to show that the AHR and the CYP1 enzymes in human behave similarly to that in mouse.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
Classical cancer studies in the 1930s showed that coal tar applied to a rabbit's ear causes papillomas followed by tumors. The active ingredients in coal tar were determined to be polycyclic aromatic hydrocarbons (PAHs)¹ such as benzo[a]pyrene (BaP). The parent PAH at first was thought to be the carcinogen and an enzyme that metabolized PAHs thought to be beneficial in detoxification (1). It was subsequently shown that PAHs, metabolized to reactive intermediates, bind covalently to nucleic acids and proteins to form adducts (2); thus, the concept of "metabolic activation" by PAH-metabolizing enzymes was born.

Mammalian cell cultures were found to have BaP hydroxylase (aryl hydrocarbon hydroxylase) activity that becomes highly induced within 12–24 h upon exposure to various PAHs (3). This paradigm for studying the response of cultured cells to PAH treatment has led to a wealth of knowledge concerning transcription, translation, and signal transduction pathways (4–6).

Some inbred mouse strains are "sensitive" to the PAH inducer, whereas others are not (7). Breeding sensitive C57BL/6 (B6) with resistant DBA/2 (D2) mice revealed that resistance was inherited largely as an autosomal recessive trait (8). When 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) was realized to be at least 30,000 times more potent than PAHs as an inducer of BaP hydroxylase, B6 and D2 mice were treated with dioxin, and the effective dose for 50% induction (ED₅₀) was shifted 15-fold to the right in the resistant D2 compared with the sensitive B6 mouse (Fig. 1). These data (proven years later when the genes were cloned) suggested that the Cyp1a1 gene, which encodes BaP hydroxylase, has an identical amino acid sequence in both B6 and D2 mice; however, the Ahr gene, which encodes the AHR that regulates CYP1A1 induction, has amino acid differences responsible for high affinity (in B6) and poor affinity (in D2) receptor that binds dioxin or PAHs (reviewed in Refs. 10 and 11).

View larger version (18K): [in this window] [in a new window]   FIG. 1. Dose-response curve for hepatic CYP1A1 induction by TCDD in B6 and D2 mice. The enzyme activity was determined 3 days after treatment with the indicated doses of TCDD; dosage on the abscissa is logarithmic scale. (Redrawn and modified from Ref. 9, with permission obtained from Elsevier.)

	PAH-induced CYP1 and Cancer Studies in Humans

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
Following reports of the mouse high affinity/low affinity AHR paradigm and relationship of high CYP1 inducibility and cancer (12), a CYP1 inducibility assay was developed in mitogen-activated PAH-treated human lymphocytes (which are transformed 55 h later into lymphoblasts) in culture (13), and an association was shown between high CYP1 inducibility and bronchogenic carcinoma (14). Following improvements in the assay (15), many laboratories have found that the distribution of CYP1 inducibility was generally skewed to the left (Fig. 2), i.e. more individuals displayed low CYP1 inducibility and fewer showed high CYP1 inducibility. Studying cigarette smokers, more than a dozen laboratories independently found correlations between the high CYP1 inducibility phenotype and cancer of the lung, larynx, or oral cavity (tissues in direct contact with cigarette smoke) compared with no correlation between the high inducibility phenotype and cancer of the renal pelvis, ureter, or urinary bladder (tissues distant from incoming cigarette smoke) (reviewed in Ref. 10).

View larger version (17K): [in this window] [in a new window]   FIG. 2. Maximally induced CYP1 enzyme activity per unit of NADH-cytochrome c reductase activity in mitogen-activated 3-methylcholanthrene-treated lymphocytes from 47 unrelated individuals. Environmental factors, such as the number of cigarettes smoked at the time the blood was drawn, do not influence this assay that specifically determines the CYP1-inducibility phenotype. (Redrawn from Ref. 16, with permission obtained from University of Chicago Press.)

View larger version (12K): [in this window] [in a new window]   FIG. 3. Probit analysis of placenta cytosolic samples from 115 unrelated patients. The dissociation constant, Kd, for each patient was determined by Scatchard plot using five concentrations of radiolabeled [3H]TCDD (Renehan, E., Manchester, D. K., Parker, N. B., Wong, J. M. Y., Giannone, J. V., Bush, L., Endrenyi, L., Harper, P. A., and Okey, A. B., unpublished data). A low Kd value by Scatchard analysis would be consistent with the high affinity B6 curve in Fig. 1 and the high CYP1/reductase ratio in Fig. 2.

	CYP1A1

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
Basal CYP1A1 expression is negligible. High levels of CYP1A1 mRNA, protein, and enzyme activity are detectable following induction by PAHs; in fact, many of the inducers are in turn metabolized by CYP1A1. Inducible CYP1A1 activity is ubiquitous, located in virtually every tissue of the body including endothelial cells of blood vessels, epithelial cells of the skin and gastrointestinal tract, fetus, and embryo (reviewed in Ref. 6). Of 12 mutations in and near the human CYP1A1 gene,² no variant exhibits differences in BaP hydroxylase activity.

Among Japanese, a mutated MspI site, 450 bp downstream of the last exon (CYP1A1*2A allele), is associated with increased risk of cigarette smoking-induced lung cancer, especially when combined with the glutathione S-transferase mu (GSTM1*0) null mutation (23). An I462V mutation, often associated with the MspI mutation, was reported to have increased BaP hydroxylase activity (23); however, two independent studies showed that cDNA-expressed BaP hydroxylase activity in vitro is not different between the CYP1A1*1 wild-type and CYP1A1*2A, *2B, or *2C allelic products (24, 25). Similar associations (between the CYP1A1*2 alleles and lung cancer in cigarette smokers) were found in other laboratories in Japan (26–28) and China (29, 30) but not in Caucasians, African Americans, or Eastern Mediterraneans (10). In Asian populations but not in Caucasian or African populations, the CYP1A1*2 allelic series might therefore be in linkage disequilibrium with a different mutation involved in cigarette smoking-induced cancer. The human CYP1A2 gene might be a candidate because it is located only 23.3 kb from the CYP1A1 gene (31). Dozens of other clinical studies of the CYP1A1 polymorphism and various types of toxicity or cancer have also been reported.

	CYP1A2

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
CYP1A2 metabolizes some drugs plus many environmental aromatic amines: N-heterocyclic amines found in charcoal-grilled food (such as 2-amino-3-methylimidazo[4,5f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP)) and arylamines such as 2-acetylaminofluorene and 4-aminobiphenyl (ABP). Substantial constitutive CYP1A2 activity occurs in mammalian liver. The human CYP1A2 gene is PAH-inducible in liver, gastrointestinal tract, nasal epithelium, and brain. Although there are >60-fold differences in hepatic CYP1A2 between individuals (10), there have been no mutations shown unequivocally to account for the striking interindividual differences in levels of expression. At least 14 mutations in and near the human CYP1A2 gene have been described to date with three showing decreases in enzyme activity and one showing increases in inducibility.²

	CYP1B1

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
CYP1B1 metabolizes numerous PAHs as well as many N-heterocyclic amines, arylamines, amino azo dyes, and several other carcinogens (21). Unlike CYP1A1, CYP1B1 often shows substantial constitutive levels. CYP1B1 expression is high in vascular endothelial cells, breast, prostate, uterus, epithelial lining of the head and neck, various types of tumors, adrenal cortex, and many other tissues. That the highest BaP hydroxylase activity in the first trimester occurs in human adrenal cortex (32) presumably reflects constitutive CYP1B1 expression. Large interindividual differences in CYP1B1 (and CYP1A1) protein levels have been reported in human lung (33) although what is constitutive and what is inducible CYP1B1 is difficult to distinguish among smokers, non-smokers, and ex-smokers. To date, at least 22 mutations in and near the human CYP1B1 gene have been reported although none have yet been shown via cDNA expression assays to cause decreased enzyme activity.² Many of these mutations are associated with an inborn-error-of-metabolism (primary congenital glaucoma), suggesting that development of the anterior chamber of the eye during embryogenesis might require metabolism of an important endogenous substrate by CYP1B1 (34). CYP1B1 appears to be largely responsible for PAH-induced immunotoxicity (35).

	AHR

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
The AHR is a ligand-activated transcription factor that controls several dozen genes (5, 11),³ including up-regulation of all three CYP1 genes (6). Ligands for the AHR include dioxin, PAHs, polyhalogenated aromatic hydrocarbons, indoles and tryptophan-derived endogenous ligands, and benzoflavones found especially in cruciferous plants (37). The AHR gene exists in all vertebrates and even in Caenorhabditis elegans (11). The AHR participates in cell cycle control and apoptosis that is cell type- or tissue-specific (6). To date, at least nine mutations in and near the human AHR gene (17, 38, 39)⁴ and a staggering 2,213 mutations in and near the mouse Ahr gene spanning 16 kb from 13 inbred strains (40) have been reported.

The Ahr(–/–) knockout mouse exhibits lowered viability and fertility and defects in liver development (41–43). The Ahr(–/–) mouse lacks constitutive and inducible CYP1 expression and is resistant to TCDD-induced toxicity (44), topical BaP-induced skin tumors (43), and benzene-induced hemotoxicity (45). The Ahr(–/–) mouse generated in Japan (46) appears to have high constitutive CYP1A2 levels in liver but not lung.

	Paradoxical Effects of CYP1A1 and CYP1A2

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
Historically, the role of CYP1A1 in BaP-induced toxicity was demonstrated in the Hepa-1c1c7 hepatoma cell line. Mouse Hepa-1 cells retain several differentiated liver functions, including albumin synthesis commonly lost in culture (4–6). BaP-treated Hepa-1 cells grew only rarely as resistant variants; such colonies were used to complement the "resistance" phenotype in other colonies, which led to the discovery of at least three complementation groups (5). These were ultimately defined as the genes encoding Cyp1a1, Ahr, and the dimerization partner of AHR, the AHR nuclear translocator, Arnt. Thus, CYP1A1 activates BaP to become toxic, and the AHR and ARNT are necessary for Cyp1a1-inducible expression; these experiments showed that CYP1A1 is a primary determinant for BaP toxicity. Because these experiments were conducted in hepatoma cells, it was presumed that hepatic CYP1A1 is likely to be responsible for BaP-mediated toxicity in the intact animal.

Cyp1a1(–/–) (47), Cyp1a2(–/–) (48), and Cyp1b1(–/–) (49) knockout mice are viable and able to reproduce. Cyp1a2(–/–) mice exhibit increased toxicity from drugs that are predominantly CYP1A2 substrates (48, 50). When Cyp1a1(–/–) mice were given oral BaP (125 mg/kg/day), however, all Cyp1a1(–/–) mice die within 30 days whereas Cyp1a1(+/+) mice survived the year long experiment; BaP-DNA adducts are unexpectedly much higher in the gastrointestinal tract, liver, spleen, and marrow of Cyp1a1(–/–), and immunotoxicity occurs compared with that in wild-type mice (51). BaP pharmacokinetic studies suggested that adducts accumulate to high levels in Cyp1a1(–/–) mice despite much lower rates of BaP metabolism in the genetic absence of CYP1A1. The Cyp1a2(–/–) mouse also shows paradoxical responses. Metabolic activation of the human urinary bladder carcinogen ABP by CYP1A2 in vitro causes enhanced ABP-DNA adducts and toxicity, yet Cyp1a2(–/–) mice treated with topical ABP show increased adducts in the liver and urinary bladder (52) (metabolism in the absence of CYP1A2). A similar contradiction was seen in ABP-induced hepatocellular carcinomas and preneoplastic foci (53) and ABP-induced methemoglobinemia (54). Further paradoxical responses were observed with the food mutagens IQ and PhIP on DNA adducts in liver, kidney, mammary gland, and colon (55) and the effect of PhIP on the incidence of several types of malignancies (56).

To our knowledge, the Cyp1b1(–/–) mouse has not shown any such inconsistent effects. As might be predicted from in vitro studies, the Cyp1b1(–/–) mouse exhibits increased protection against 7,12-dimethylbenzo[a]anthracene (DMBA)-induced lymphomas (49), DMBA-induced marrow toxicity and pre-leukemia (57), and dibenzo[a,l]pyrene-induced tumors (58). Hence, if CYP1B1 is not present to activate these environmental chemicals, less toxicity or neoplasia is seen.

Thus, in the context of hepatoma cells or in vitro studies, CYP1A1 is the primary determinant of BaP-mediated toxicity and DNA adduct formation and CYP1A2 is the primary determinant of arylamine-mediated toxicity and DNA adduct formation, whereas in the context of the intact animal, CYP1A1 and CYP1A2 can be protective. This dual role has not been seen with CYP1B1. What might explain this difference? In microsomes, 9,000 x g supernatant (S9) fractions, or Hepa-1 cells, an absence of (or loose coupling to) Phase II enzymes (Fig. 4) would result in enhanced adduct formation, oxidative stress, and toxicity. In gastrointestinal epithelial cells or hepatocytes, it is possible that CYP1A1 and CYP1A2 are tightly coupled to Phase II enzymes, resulting in efficient detoxification rather than increases in toxicity. In the genetic absence of CYP1A1 or CYP1A2, other oxidative enzymes (CYP1B1, CYP2, and prostaglandin H synthase for BaP (51); CYP2A and flavin-containing monooxygenases for arylamines (52)) are responsible for adduct formation and toxicity. In immune cells it is possible that CYP1B1 is not tightly coupled to Phase II metabolism or Phase II metabolism is low or absent, resulting in enhanced BaP-DNA adduct formation and toxicity. An additional likely factor is CYP1 enzyme concentration; gastrointestinal and hepatic CYP1A1 and CYP1A2 are very high in the paradoxical systems described above, whereas CYP1B1 content, in relative terms, is not high in immune cells.

View larger version (18K): [in this window] [in a new window]   FIG. 4. Diagram of Phase I oxidative enzymes and Phase II conjugating enzymes that can be geographically subcellularly "tightly coupled" (top) or "loosely coupled" (bottom). R, any CYP1 substrate; RO•, reactive intermediate; RO-Conj, inactive product. Both Phase I enzymes and Phase II enzymes can be membrane-bound, both can be cytosolic, or one can be membrane-bound and the other cytosolic. Phase II metabolism includes glutathione S-transferases, UDP glucuronosyltransferases, and various acetyl-, methyl- and sulfotransferases (6, 10, 21, 59).

Thus, we have come full circle. There was a time when CYP1 enzymes were thought to be primarily beneficial because of detoxification (1). Then, we all became convinced that CYP1 enzymes were detrimental in that they caused toxicity and cancer (2, 4, 10, 12, 59). Now it appears that, in all likelihood, evolution has provided animals with CYP1 enzymes which, on balance, are generally more protective than destructive during environmental insult.

	Generation of "Humanized" Bacterial Artifical Chromosome-transgenic Mouse Lines

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 
"Humanized" hCYP3A4 and hCYP2D6 mouse lines have been developed in which these pharmacologically important human genes were added to the mouse genome; even without the orthologous mouse Cyp3a and Cyp2d genes removed, these lines have proven very useful for numerous pharmacological studies (36). A mouse line containing a human AHR cDNA in place of the mouse Ahr gene has recently been reported (22). Humanized hCYP1A1, hCYP1A2, hCYP1B1, and hAHR mouse lines are now under development in which the human gene replaces the mouse orthologous gene. Two or more human genes might also be combined in developing a mouse line. Such increasingly "humanized" mouse lines will be important in future risk assessment studies of toxicity and carcinogenesis.

	FOOTNOTES

 
^* This minireview will be reprinted in the 2004 Minireview Compendium, which will be available in January, 2005. This work was funded in part by National Institutes of Health Grant P30 ES06096 (to D. W. N. and T. P. D.).

To whom correspondence should be addressed: Dept. of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056. Tel.: 513-558-4347; Fax: 513-558-3562; E-mail: dan.nebert{at}uc.edu.

¹ The abbreviations used are: PAH, polycyclic aromatic hydrocarbon; BaP, benzo[a]pyrene; B6, C57BL/6; D2, DBA/2; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; AHR, aromatic hydrocarbon receptor; IQ, 2-amino-3-methylimidazo[4,5f]quinoline; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine; ABP, 4-aminobiphenyl; DMBA, 7,12-dimethylbenzo[a]anthracene).

² S. Malmebo, M. Ingelman-Sundberg, A. K. Daly, and D. W. Nebert, www.imm.ki.se/CYPalleles.

³ C. A. Bradfield, mcardle.oncology.wisc.edu/bradfield/default.html.

⁴ D. W. Nebert and A. B. Okey, unpublished data.

	ACKNOWLEDGMENTS

 
We thank our colleagues, especially Lucia F. Jorge-Nebert, for critical readings of this manuscript and valuable suggestions.

	REFERENCES

TOP ABSTRACT INTRODUCTION PAH-induced CYP1 and Cancer... CYP1A1 CYP1A2 CYP1B1 AHR Paradoxical Effects of CYP1A1... Generation of "Humanized"... REFERENCES

 

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48. Liang, H. C. L., Li, H., McKinnon, R. A., Duffy, J. J., Potter, S. S., Puga, A., and Nebert, D. W. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 1671–1676[Abstract/Free Full Text]
49. Buters, J. T., Sakai, S., Richter, T., Pineau, T., Alexander, D. L., Savas, U., Doehmer, J., Ward, J. M., Jefcoate, C. R., and Gonzalez, F. J. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 1977–1982[Abstract/Free Full Text]
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