2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is Enantioselectively Oxidized to Hydroxylated Metabolites by Rat Liver Microsomes

摘要: Developmental exposure to multiple ortho-substituted polychlorinated biphenyls (PCBs) causes adverse neurodevelopmental outcomes in laboratory animals and humans by mechanisms involving the sensitization of Ryanodine receptors (RyRs). In case PCB 136, RyR is enantiospecific, with only (-)-PCB 136 being active. However, role enantioselective metabolism developmental neurotoxicity poorly understood. The present study employed hepatic microsomes from phenobarbital (PB)-, dexamethasone (DEX)- corn oil (VEH)-treated male Sprague-Dawley rats investigate hypothesis that atropisomers are enantioselectively metabolized P450 enzymes potentially neurotoxic, hydroxylated metabolites. results demonstrated time- isoform-dependent formation three metabolites, 5-OH-PCB (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) major metabolite. increased activity 2B microsomal preparation, which consistent rat 2B1. minor metabolite 4-OH-PCB (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol) was produced a currently unidentified enzyme. An enantiomeric enrichment observed incubations due preferential (+)-PCB corresponding atropisomer. displayed an atropisomer formed 136; however, this did not affect parent because Although 5- time, OH-PCB metabolites resulted constant enrichment, especially at later incubation times. These observations demonstrate chiral signatures PCBs their wildlife but also suggest neurotoxic such as may play PCBs.