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

Xianai Wu; Ananya Pramanik; Michael W Duffel; Eugene G Hrycay; Stelvio M Bandiera; Hans-Joachim Lehmler; Izabela Kania-Korwel

doi:10.1021/tx200360m

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

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

Xianai Wu, Ananya Pramanik, Michael W Duffel, Eugene G Hrycay, Stelvio M Bandiera, Hans-Joachim Lehmler and Izabela Kania-Korwel

Chemical research in toxicology, Vol.24(12), pp.2249-2257

12/19/2011

DOI: 10.1021/tx200360m

PMCID: PMC3243785

PMID: 22026639

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Abstract

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

Details

Title: Subtitle: 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is Enantioselectively Oxidized to Hydroxylated Metabolites by Rat Liver Microsomes
Creators: Xianai Wu - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Ananya Pramanik - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Michael W Duffel - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Eugene G Hrycay - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Stelvio M Bandiera - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Hans-Joachim Lehmler - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Izabela Kania-Korwel - Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC, Canada V6T1Z3
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.24(12), pp.2249-2257
DOI: 10.1021/tx200360m
PMID: 22026639
PMCID: PMC3243785
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Grant note: P42 ES013661-06 || ES / National Institute of Environmental Health Sciences : NIEHS P30 ES005605-19 || ES / National Institute of Environmental Health Sciences : NIEHS P30 ES005605-15 || ES / National Institute of Environmental Health Sciences : NIEHS R01 ES017425-01A1 || ES / National Institute of Environmental Health Sciences : NIEHS P42 ES013661-05 || ES / National Institute of Environmental Health Sciences : NIEHS P30 ES005605-18 || ES / National Institute of Environmental Health Sciences : NIEHS R01 ES017425-02 || ES / National Institute of Environmental Health Sciences : NIEHS P30 ES005605-16 || ES / National Institute of Environmental Health Sciences : NIEHS P30 ES005605-17 || ES / National Institute of Environmental Health Sciences : NIEHS P42 ES013661-03 || ES / National Institute of Environmental Health Sciences : NIEHS P30 ES005605-20 || ES / National Institute of Environmental Health Sciences : NIEHS R01 ES017425-01A1S1 || ES / National Institute of Environmental Health Sciences : NIEHS P42 ES013661-01A1 || ES / National Institute of Environmental Health Sciences : NIEHS P42 ES013661-04 || ES / National Institute of Environmental Health Sciences : NIEHS P42 ES013661-02 || ES / National Institute of Environmental Health Sciences : NIEHS
Language: English
Date published: 12/19/2011
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984001096202771

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