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

doi:10.1074/jbc.R400004200

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

Daniel W. Nebert ${ddagger}$ , 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

The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromesP450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatichydrocarbon receptor (AHR). The CYP1 enzymes are responsiblefor both metabolically activating and detoxifying numerous polycyclicaromatic hydrocarbons (PAHs) and aromatic amines present incombustion products. Many substrates for CYP1 enzymes are AHRligands. Differences in AHR affinity between inbred mouse strainsreflect variations in CYP1 inducibility and clearly have beenshown to be associated with differences in risk of toxicityor cancer caused by PAHs and arylamines. Variability in thehuman AHR affinity exists, but differences in human risk oftoxicity or cancer related to AHR activation remain unproven.Mouse lines having one or another of the Cyp1 genes disruptedhave shown paradoxical effects; in the test tube or in cellculture these enzymes show metabolic activation of PAHs or arylamines,whereas in the intact animal these enzymes are sometimes moreimportant in the role of detoxification than metabolic potentiation.Intact animal data contradict pharmaceutical company policiesthat routinely test drugs under development; if a candidatedrug shows CYP1 inducibility, further testing is generally discontinuedfor fear of possible toxic or carcinogenic effects. In the future,use of "humanized" mouse lines, containing a human AHR or CYP1allele in place of the orthologous mouse gene, is one likelyapproach to show that the AHR and the CYP1 enzymes in humanbehave similarly to that in mouse.

^* This minireview will be reprinted in the 2004 Minireview Compendium,which will be available in January, 2005. This work was fundedin part by National Institutes of Health Grant P30 ES06096 (toD. 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.

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