[Sex- and species-differences on xenobiotic-induced toxicity: differences in constitutive and xenobiotic-mediated expression of cytochrome P450 1A subfamily enzymes (CYP1As)].

Cytochrome P450 1A subfamily enzymes (CYP1As) are important molecules in the metabolic activation of carcinogens such as polycyclic aromatic hydrocarbons and heterocyclic amines and are induced by their substrate exposure. There are species, sex, and organ differences in the induction of CYP1As, and susceptibilities to carcinogens are closely related to the constitutive and carcinogen-induced levels of CYP1As in target organs of experimental rodents. In this study, we investigated the induction of CYP1As and their species or sex differences after treatment with various chemicals using experimental animals and cultured cell lines. We found that: 1) newly established reporter cell lines, HepG2-A10 and KanR2-XL8, can be used for determining of activation of the aryl hydrocarbon receptor (AhR), a key transcription factor in the expression of CYP1As; 2) monocyclic aromatic amine (2-methoxy-4-nitroaniline) induced hepatic CYP1As in rats but not in other rodents in an AhR-independent manner; 3) androgen suppressed the constitutive expression or heterocyclic aromatic amine (Trp-P-1)-dependent induction of these enzymes in pigs and mice; and 4) nicardipine, a dihydropyridine calcium channel blocker, increased hepatic CYP1A expression in rats and augmented 3-methylcholanthrene-mediated induction of CYP1As and DNA-adduct formation in HepG2 cells. These findings indicate that there are species or sex differences in the induction of hepatic CYP1As via AhR-independent and unexplained transcriptional mechanisms. The elucidation of these mechanisms will aid in finding new predictors or developing new prevention strategies for chemical-induced carcinogenesis.