Detoxification of benzo[a]pyrene primarily depends on cytochrome P450, while bioactivation involves additional oxidoreductases including 5‐lipoxygenase, cyclooxygenase, and aldo‐keto reductase in the liver

Cytochrome P450s are involved in detoxification and activation of benzo[a]pyrene (BaP) with unclear balance and unknown contribution of other oxidoreductases. Here, we investigated the BaP and BaP-induced mutagenicity in hepatic and extra-hepatic tissues using hepatic P450 reductase null (HRN) gpt mice. After 2-week treatment (50 mg/kg, i.p. 4 days), BaP in the liver and lung of HRN-gpt mice were increased. BaP promoted gpt mutant frequency (MF) in HRN-gpt mice liver. MF of gpt in the lung and Pig-a in hematopoietic cells induced by BaP in HRN-gpt mice were increased than in gpt mice. BaP-7,8-diol-9,10-epoxide (BPDE)-DNA adducts in vitro was analyzed for enzymes detection in BaP bioactivation. Specific inhibitors of 5-lipoxygenase, cyclooxygenase-1&2, and aldo-keto reductase resulted in more than 80% inhibition rate in the DNA adduct formation, further confirmed by Macaca fascicularis hepatic S9 system. Our results suggested the detoxification of BaP primarily depends on cytochrome P450, while the bioactivation involves additional oxidoreductases.