title: Effects of thiol antioxidants on the atropselective oxidation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) by rat liver microsomes.
abstract: Chiral polychlorinated biphenyl (PCB) congeners, such as PCB 136, are atropselectively metabolized to various hydroxylated PCB metabolites (HO-PCBs). The present study investigates the effect of two thiol antioxidants, glutathione and N-acetyl-cysteine (NAC), on profiles and chiral signatures of PCB 136 and its HO-PCB metabolites in rat liver microsomal incubations. Liver microsomes prepared from rats pretreated with phenobarbital were incubated with PCB 136 (5 μM) in the presence of the respective antioxidant (0-10 mM), and levels and chiral signatures of PCB 136 and its HO-PCB metabolites were determined. Three metabolites, 5-136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol), 4-136 (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol), and 4,5-136 (2,2',3,3',6,6'-hexachlorobiphenyl-4,5-diol), were detected in all incubations, with 5-136 being the major metabolite. Compared to microsomal incubations without antioxidant, levels of 4,5-136 increased with increasing antioxidant concentration, whereas levels of PCB 136 and both mono-HO-PCBs were not affected by the presence of either antioxidant. PCB 136, 4-136, and 5-136 displayed significant atropisomeric enrichment; however, the direction and extent of the atropisomeric enrichment was not altered in the presence of an antioxidant. Because 4,5-136 can either be conjugated to a sulfate or glucuronide metabolite that is readily excreted or further oxidized a potentially toxic PCB 136 quinone, the effect of both thiol antioxidants on 4,5-136 formation suggests that disruptions of glutathione homeostasis may alter the balance between both metabolic pathways and, thus, PCB 136 toxicity in vivo.
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, University of Iowa Research Park, #221 IREH, Iowa City, IA, 52242-5000, USA.
authors.forename: Xianai
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, University of Iowa Research Park, #221 IREH, Iowa City, IA, 52242-5000, USA. hans-joachim-lehmler@uiowa.edu.
authors.forename: Hans-Joachim
authors.identifier: http://orcid.org/0000-0001-9163-927X
authors.initials: HJ
authors.lastname: Lehmler
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D013438:Sulfhydryl Compounds; D011078:Polychlorinated Biphenyls; D005978:Glutathione; C010498:2,3,6,2',3',6'-hexachlorobiphenyl
keywords: Biotransformation; Cytochrome P450 enzymes; Enantioselective; Glutathione; Hepatic microsomes; NAC; PCB 136