Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity

Eric Uwimana; Brianna Cagle; Coby Yeung; Xueshu Li; Eric V Patterson; Jonathan A Doorn; Hans-Joachim Lehmler

doi:10.1093/toxsci/kfz150

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Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity

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Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity

Eric Uwimana, Brianna Cagle, Coby Yeung, Xueshu Li, Eric V Patterson, Jonathan A Doorn and Hans-Joachim Lehmler

Toxicological sciences, Vol.171(2), pp.406-420

10/2019

DOI: 10.1093/toxsci/kfz150

PMCID: PMC6760323

PMID: 31268529

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Abstract

Polychlorinated biphenyls (PCBs) have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB neurotoxicity. Only limited information is available regarding the atropselective metabolism of these congeners in humans and their atropselective effects on neurotoxic outcomes. Here we investigate the hypothesis that the oxidation of 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) and their effects on dopaminergic cells in culture are atropselective. Racemic PCB 132 was incubated with pooled or single donor HLMs, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite was either 2,2′,3,4,4′,6′-hexachlorobiphenyl-3′-ol (3′-140), a 1,2-shift product, or 2,2′,3,3′,4,6′-hexachlorobiphenyl-5′-ol (5′-132). The PCB 132 metabolite profiles displayed interindividual differences and depended on the PCB 132 atropisomer. Computational studies suggested that 3′-140 is formed via a 3,4-arene oxide intermediate. The second eluting atropisomer of PCB 132, first eluting atropisomer of 3′-140, and second eluting atropisomer of 5′-132 were enriched in all HLM incubations. Enantiomeric fractions of the PCB 132 metabolites differed only slightly between the single donor HLM preparations investigated. Reactive oxygen species and levels of dopamine and its metabolites were not significantly altered after a 24 h exposure of dopaminergic cells to pure PCB 132 atropisomers. These findings suggest that there are interindividual differences in the atropselective biotransformation of PCB 132 to its metabolites in humans; however, the resulting atropisomeric enrichment of PCB 132 is unlikely to affect neurotoxic outcomes associated with the endpoints investigated in the study.

biotransformation

reactive oxygen species

1,2-shift

enantiomers

dopamine metabolism

arene oxide

cytochrome P450 enzymes

Exposure Sciences

Details

Title: Subtitle: Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity
Creators: Eric Uwimana - Department of Occupational and Environmental Health, College of Public Health, University of Iowa Research Park, University of Iowa, Iowa City, Iowa 52242-5000
Brianna Cagle - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242
Coby Yeung - Department of Chemistry, College of Arts and Sciences, Stony Brook University, Stony Brook, New York 11794–3400
Xueshu Li - Department of Occupational and Environmental Health, College of Public Health, University of Iowa Research Park, University of Iowa, Iowa City, Iowa 52242-5000
Eric V Patterson - Department of Chemistry, College of Arts and Sciences, Stony Brook University, Stony Brook, New York 11794–3400
Jonathan A Doorn - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa Research Park, University of Iowa, Iowa City, Iowa 52242-5000
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.171(2), pp.406-420
DOI: 10.1093/toxsci/kfz150
PMID: 31268529
PMCID: PMC6760323
NLM abbreviation: Toxicol Sci
ISSN: 1096-6080
eISSN: 1096-0929
Publisher: Oxford University Press
Grant note: ; ; ; CHE-1609669; CHE-1229354 / ; ; ; CHE-1662030 / ; ; ES05605; ES013661; ES027169; ES029035 / ; ; ;
Language: English
Date published: 10/2019
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984001085202771

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