title: Radical cations as precursors in the metabolic formation of quinones from benzo[a]pyrene and 6-fluorobenzo[a]pyrene. Fluoro substitution as a probe for one-electron oxidation in aromatic substrates.
abstract: Three classes of products are formed when benzo[a]pyrene (BP) is metabolized by cytochrome P-450: dihydrodiols, phenols and the quinones, BP 1,6-, 3,6- and 6,12-dione. These products have been thought to arise from attack of a catalytically-activated electrophilic oxygen atom. In this paper we report chemical and biochemical experiments which demonstrate that BP quinones arise from an initial one-electron oxidation of BP to form its radical cation. BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-chlorobenzo[a]pyrene (6-ClBP), and 6-bromobenzo[a]pyrene (6-BrBP) were metabolized by uninduced and 3-methylcholanthrene-induced rat liver microsomes in the presence of NADPH or cumene hydroperoxide (CHP) as cofactor. BP and 6-FBP produced similar metabolic profiles with induced microsomes in the presence of NADPH or 2 mM CHP. With NADPH both compounds produced dihydrodiols, phenols and quinones, whereas with CHP, they yielded only quinones. Metabolism of BP and 6-FBP was also similar with uninduced microsomes and 2 mM CHP, yielding the same BP quinones. With uninduced microsomes in the presence of NADPH, BP produced all three classes of metabolites, whereas 6-FBP afforded only quinones. At a low concentration of CHP (0.10 mM), BP was metabolized to phenols and quinones, whereas 6-FBP gave only quinones. 6-ClBP and 6-BrBP were poor substrates, forming metabolites only with induced microsomes and NADPH. One-electron oxidation of BP by Mn(OAc)3 occurred exclusively at C-6 with predominant formation of 6-acetoxyBP and small amounts of BP quinones. In the one-electron oxidation of 6-FBP by Mn(OAc)3, the major products obtained were 6-acetoxyBP, a mixture of 1,6- and 3,6-diacetoxyBP, and BP quinones. Reaction of BP and 6-FBP radical cation perchlorates with water produced the same BP quinones. Conversely, electrophilic substitution of 6-FBP with bromine or deuterium ion afforded C-1 and/or C-3 derivatives with retention of the fluoro substituent at C-6. These results indicate that metabolic formation of BP quinones from BP and 6-FBP can only derive from their intermediate radical cation.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68105-1065.
authors.forename: E L
authors.initials: EL
authors.lastname: Cavalieri
authors.forename: E G
authors.initials: EG
authors.lastname: Rogan
authors.forename: P
authors.initials: P
authors.lastname: Cremonesi
authors.forename: P D
authors.initials: PD
authors.lastname: Devanesan
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000378:metabolism*; D001580:Benzopyrenes / Q000378:metabolism*; D005461:Fluorine; D005609:Free Radicals; D066298:In Vitro Techniques; D008297:Male; D008345:Manganese / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010472:Perchlorates; D011809:Quinones / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D001580:Benzopyrenes; D005609:Free Radicals; D010472:Perchlorates; D011809:Quinones; D005461:Fluorine; D001564:Benzo(a)pyrene; D008345:Manganese; C012323:6-fluorobenzo(a)pyrene; C018003:benzo(a)pyrene-3,6-quinone; C007164:cumene hydroperoxide