title: Metabolic activation of PCBs to quinones: reactivity toward nitrogen and sulfur nucleophiles and influence of superoxide dismutase.
abstract: Polychlorinated biphenyls (PCBs) may undergo cytochrome P-450-catalyzed hydroxylations to form chlorinated dihydroxybiphenyl metabolites. When the hydroxyl groups are ortho or para to each other, oxidation to a quinone may be catalyzed by peroxidases present within the cell. In order to study the reactivity of PCB-derived quinones, selected chlorophenyl 1,2- and 1,4-benzoquinones were synthesized and characterized, including their reduction potentials against a saturated calomel electrode. Two quinones, 4-(4'-chlorophenyl)-1,2-, and 4-(3',4'-dichlorophenyl)-1,2-benzoquinone, were obtained via the oxidation of the corresponding dihydroxybiphenyls with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Six 1,4-benzoquinones were synthesized via the Meerwein arylation: 2-(2'-chlorophenyl)-1,4-, 2-(3'-chlorophenyl)-1,4-, 2-(4'-chlorophenyl)-1,4-, 2-(2',5'-dichlorophenyl)-1,4-, 2-(3',4'-dichlorophenyl)-1,4-, and 2-(3',5'-dichlorophenyl)-1,4-benzoquinone. As a model study, the rate of reactivity of 2-(4'-chlorophenyl)-1,4-benzoquinone toward the nitrogen nucleophiles glycine, L-arginine, L-histidine- and L-lysine was determined under pseudo-first-order conditions at pH 7.4. The rate constants ranged from 0.45 to 0.75 min-1 M-1. Higher rates were obtained under conditions of higher pH. Two reaction products were identified as the 5- and 6-ring addition products in the ratio of 1:4. In contrast, the reaction of 2-(4'-chlorophenyl)-1,4-benzoquinone with the sulfur nucleophiles glutathione or N-acetyl-L-cysteine was instantaneous. The major product of the reaction of glutathione with 2-(4'-chlorophenyl)-1,4-benzoquinone was also the 6-ring addition product. The hydroquinone thioether could be enzymatically reoxidized to the quinone thioether. Also, the influence of atmospheric oxygen and superoxide dismutase on the rates of the following horseradish peroxidase/H2O2-catalyzed oxidations was investigated: 3,4-dichloro-2',5'-dihydroxybiphenyl to 2-(3',4'-dichlorophenyl)-1,4-benzoquinone and 3,4-dichloro-3',4'-dihydroxybiphenyl to 4-(3',4'-dichlorophenyl)-1,2-benzoquinone. While the presence or absence of atmospheric oxygen did not alter the rates of the oxidation reactions, the presence of superoxide dismutase significantly increased the rates of both oxidation reactions, having the greater effect on the oxidation of the 1,4-hydroquinone. These data show that PCB-derived quinones react with both nitrogen and sulfur nucleophiles of the cell and may explain, in part, the toxic effects of individual PCBs and PCB formulations, such as glutathione depletion, oxidative stress, and cell death.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington 40536, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Amaro
authors.forename: G G
authors.initials: GG
authors.lastname: Oakley
authors.forename: U
authors.initials: U
authors.lastname: Bauer
authors.forename: H P
authors.initials: HP
authors.lastname: Spielmann
authors.forename: L W
authors.initials: LW
authors.lastname: Robertson
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D000603:Amino Acids, Sulfur / Q000737:chemistry / Q000378:metabolism; D016227:Benzoquinones / Q000138:chemical synthesis / Q000378:metabolism; D001713:Biphenyl Compounds / Q000138:chemical synthesis; D002384:Catalysis; D006735:Horseradish Peroxidase / Q000378:metabolism; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D009584:Nitrogen / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism; D011809:Quinones / Q000138:chemical synthesis* / Q000378:metabolism; D013053:Spectrophotometry; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism
chemical_list: C101063:4-(3',4'-dichlorophenyl)-1,2-benzoquinone; C101062:4-(4'-chlorophenyl)-1,2-benzoquinone; D000596:Amino Acids; D000603:Amino Acids, Sulfur; D016227:Benzoquinones; D001713:Biphenyl Compounds; D011809:Quinones; D011078:Polychlorinated Biphenyls; D006735:Horseradish Peroxidase; D013482:Superoxide Dismutase; D009584:Nitrogen