title: Identification of catechol and hydroquinone metabolites of 4-monochlorobiphenyl.
abstract: Polychlorinated biphenyls (PCBs) may be metabolically activated to electrophiles, which bind to proteins and nucleic acids. One activation scheme involves the formation of reactive arene oxide intermediates during cytochrome P450-catalyzed hydroxylation. We propose a second activation pathway whereby PCB catechol and hydroquinone metabolites may be oxidized to reactive semiquinones and/or quinones. By employing 4-monochlorobiphenyl (4-MCB) as a model substrate and liver microsomes from rats treated with phenobarbital and 3-methyl-cholanthrene, five monol and three diol metabolites were identified. The major metabolite was 4-chloro-4'-monohydroxybiphenyl, followed by, in decreasing order, 4-chloro-3',4'-dihydroxybiphenyl, unknown B (a monol), 4-chloro-2',3'-dihydroxybiphenyl, 4-chloro-3'-hydroxybiphenyl, 4-chloro-2',5'-dihydroxybiphenyl, unknown A (a monol), and 4-chloro-2'-monohydroxybiphenyl. A trace of a dihydrodiol was detected by GC/MS. To elucidate the source of the diols, 4-MCB and the synthetic monol metabolites 4-chloro-2'-/-3'-/-4'-monohydroxybiphenyls were each employed as substrates in incubations with microsomes from rats treated with phenobarbital, 3-methylcholanthrene, or both inducers. The three diol metabolites were all produced from 4-MCB in incubations with microsomes from 3-methylcholanthrene-treated rats, but incubations with microsomes from phenobarbital-treated rats did not yield detectable amounts of 4-chloro-2',3'-dihydroxybiphenyl. 4-Chloro-2',3'-dihydroxybiphenyl was only found as a product of 4-chloro-2'-monohydroxybiphenyl. The 4-chloro-2',5'-dihydroxybiphenyl was found in extracts of incubations with 4-chloro-2'- and -3'-monohydroxybiphenyls, while the 4-chloro-3',4'-dihydroxybiphenyl was the only product found from 4-chloro-3'- and -4'-monohydroxybiphenyls. No other chlorinated diols were detected by GC/MS. These data suggest that the major route of biosynthesis of the diols was via a second hydroxylation step and not aromatization of dihydrodiols derived from primary arene oxides. We propose a scheme for the in vitro synthesis of the catechol and hydroquinone metabolites, which may be precursors for electrophilic semiquinone or quinone products with the potential for cytotoxic and genotoxic effects.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0305, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: McLean
authors.forename: U
authors.initials: U
authors.lastname: Bauer
authors.forename: A R
authors.initials: AR
authors.lastname: Amaro
authors.forename: L W
authors.initials: LW
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002396:Catechols / Q000378:metabolism*; D006873:Hydroquinones / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001713:Biphenyl Compounds; D002396:Catechols; D006873:Hydroquinones; D011078:Polychlorinated Biphenyls; C034221:catechol; C006983:4-chlorobiphenyl