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. Environ. Mol. Mutagen. 57:229–235, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.

Differentiation‐associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic‐metabolizing activity of “luminal” muscle‐invasive bladder cancers

“…This may be due to the tissue‐specific nature of extra‐hepatic CYP activity (reviewed in Ref. ) and the role of other CYPs that might metabolize BaP in human urothelium. This conclusion is supported by the efficacy of TMS inhibition which reduced EROD activity to 14%, BaP‐7,8‐dihydrodiol formation only to 46%, BaP‐tetrol formation to 35%, and BaP‐DNA adduct formation to 21% relative to ITE‐induced cells; suggesting that other enzymes not inhibited by TMS may play a role in BaP metabolism by the urothelium.…”

Modulation of benzo[a]pyrene–DNA adduct formation by CYP1 inducer and inhibitor

“…AhR modulators influence BaP adducts through CYP1A1/1B1 gene induction (a), reduction (b), and/or inhibition of enzyme activity (c). A recent report showed that impact of individual cytochrome P450 enzymes including CYP1A1 and 1B1 in BaP metabolism [51]. The report showed that CYP1A1 and 1B1 also generate products of detoxification such as 3-hydroxy-BaP.…”

Development and Uses of Offline and Web-Searchable Metabolism Databases - The Case of Benzo[a]pyrene

“…1) and has been subject of extensive research over time and extensively discussed in research papers, reviews, and the references cited the published papers. In the present discussion, we refer to some recently published reports [28,29,30]. As presented in Tables 1–6 and Fig.…”

“…It was reported that B[ a ]P-7,8-dihydrodiol and B[ a ]P-9-ol, which are precursors of B[ a ]P toxic metabolites, are mainly formed by CYP1A1, 1B1, and (to a lesser extent) by CYP2C19 and CYP3A4. In contrast, the formation of B[ a ]P-3-ol is most efficiently catalyzed by CYP1A1 and 1B1, but CYP2B6, 2C9, 2C19, and 3A4 also partially contribute to its production [30]. The enzymes converting B[a]P to toxic species might be strongly induced or inhibited by many different chemical agents, including the compound itself (Tables 1 and 2) through the action of the aryl hydrocarbon receptor (AhR) [31].…”