Inducibility of cytochrome P450 1A1 and chemical carcinogenesis by benzo[a]pyrene in AhR repressor-deficient mice

AhR repressor (AhRR) is an AhR-related bHLH-PAS transcription factor. It is known to repress AhR transcription activity in a competitive manner. To examine AhRR functions in mice, we produced AhRR-deficient mice by gene knockout. AhRR(−/−) mice were born in normal Mendelian proportions, grew well, and were fertile. AhR(−/−) mice exhibited higher levels of Cyp1a1 (Cytochrome P450 1A1) mRNA induction in the skin, stomach and spleen than wild-type mice, while expression of Cyp1a1 mRNA was not significantly altered in the liver, lung, heart or other tissues, suggesting that “super-induction” of Cyp1a1 mRNA expression in AhRR(−/−) mice occurs in a tissue specific manner. AhRR(−/−) mice displayed a delayed response to skin carcinogenesis caused by benzo[a]pyrene. Since CYP1A1 is involved in the metabolic activation and detoxification of chemical carcinogens, these results suggest that overexpression of CYP1A1 shifts the balance of the metabolic activities in the skin of AhRR(−/−) mice in favor of the detoxification of carcinogens.