ROLE OF CYTOCHROME P4501A2 IN CHEMICAL CARCINOGENESIS - IMPLICATIONS FOR HUMAN VARIABILITY IN EXPRESSION AND ENZYME-ACTIVITY

Cytochrome P4501A2 (CYP1A2) has been identified as a key factor in the metabolic activation of numerous chemical carcinogens, including afla toxin B-1, various heterocyclic and aromatic amines, and certain nitro aromatic compounds. In addition, CYP1A2 contributes to the inactivatio n of several common drugs and dietary constituents, including acetamin ophen and caffeine, Two xenobiotic-responsive-element (XRE)-like seque nces and an antioxidant response element (ARE) have been identified in the regulatory region of the CYP1A2 gene; however, the functionality of the ARE remains to be demonstrated. Based on in vivo phenotyping as says, substantial interindividual variability in CYP1A2 activity has b een reported. Some population-based studies have reported either bi- o r tri-modal distributions in CYP1A2 phenotype, suggesting a genetic ba sis for the large interindividual differences in CYP1A2 activity. Howe ver, despite the polymodal distributions reported for CYP1A2 activity, a distinct functional genetic polymorphism in the gene has not been i dentified. Potential mechanisms contributing to the large interindivid ual variability in CYP1A2 activity are discussed, A thorough understan ding of the functions and regulation of the CYP1A2 gene may ultimately lead to new methods for preventing or intervening in the development of certain chemically-related human cancers.