title: The impact of individual cytochrome P450 enzymes on oxidative metabolism of benzo[a]pyrene in human livers.
abstract: Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after metabolic activation by cytochrome P450 (CYP) enzymes. In this study human recombinant CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5) were expressed in Supersomes™ together with their reductases, NADPH:CYP oxidoreductase, epoxide hydrolase and cytochrome b5 , to investigate BaP metabolism. Human CYPs produced up to eight BaP metabolites. Among these, BaP-7,8-dihydrodiol and BaP-9-ol, which are intermediates in BaP-derived DNA adduct formation, were mainly formed by CYP1A1 and 1B1, and to a lesser extent by CYP2C19 and 3A4. BaP-3-ol, a metabolite that is a 'detoxified' product of BaP, was formed by most human CYPs tested, although CYP1A1 and 1B1 produced it the most efficiently. Based on the amounts of the individual BaP metabolites formed by these CYPs and their expression levels in human liver, we determined their contributions to BaP metabolite formation in this organ. Our results indicate that hepatic CYP1A1 and CYP2C19 are most important in the activation of BaP to BaP-7,8-dihydrodiol, whereas CYP2C19, 3A4, and 1A1 are the major enzymes contributing to the formation of BaP-9-ol. BaP-3-ol is predominantly formed by hepatic CYP3A4, while CYP1A1 and 2C19 are less active.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Šulc
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Indra
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Moserová
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London, United Kingdom.|NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King's College London in Partnership with Public Health England, London, United Kingdom.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011817:Rabbits
chemical_list: D018736:DNA Adducts; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System
keywords: benzo[a]pyrene; cytochrome P450; human liver; metabolism