title: 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.
abstract: 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.
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
authors.forename: Liupeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Tong Ren Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People's Republic of China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Ma
authors.affiliation: KG Pharma Limited, Foshan, 528000, People's Republic of China.
authors.forename: Suxing
authors.initials: S
authors.lastname: Zhang
authors.affiliation: KG Pharma Limited, Foshan, 528000, People's Republic of China.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Zhang
authors.affiliation: KG Pharma Limited, Foshan, 528000, People's Republic of China.
authors.forename: Peizhen
authors.initials: P
authors.lastname: Ye
authors.affiliation: Jiangsu Tripod Preclinical Research Laboratories, Pukou Economic Development Zone, Nanjing, People's Republic of China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Xing
authors.affiliation: Jiangsu Tripod Preclinical Research Laboratories, Pukou Economic Development Zone, Nanjing, People's Republic of China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xi
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, NY, 12201-0509, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luan
mesh_terms: D000074408:Aldo-Keto Reductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D000074408:Aldo-Keto Reductases; D001094:Arachidonate 5-Lipoxygenase
keywords: benzo[a]pyrene; cytochrome P450; mutagenicity; oxidoreductase