Atropselective Disposition of 2,2',3,4',6-Pentachlorobiphenyl (PCB 91) and Identification of Its Metabolites in Mice with Liver-specific Deletion of Cytochrome P450 Reductase

04 June 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Cytochrome P450 enzymes oxidize chiral polychlorinated biphenyls (PCBs) to hydroxylated metabolites. Here we investigated the role of an impaired hepatic metabolism in the disposition of PCB 91 (CASRN 68194-05-8) in mice with a liver-specific deletion of the cpr gene (KO mice). KO mice and wild type (WT) mice were exposed to racemic PCB 91. Levels and enantiomeric fractions of PCB 91 and its metabolites were determined in tissues 3-days after PCB exposure. PCB 91 were higher in KO compared to WT mice. The liver of KO mice accumulated PCB 91 due to the high fat content in the liver of KO mice. 2,2',3,4',6-Pentachlorobiphenyl-5-ol was the major metabolite detected in all samples. PCB 91 and its metabolites displayed a genotype-dependent atropisomeric enrichment. These differences in atropselective disposition of PCB 91 and its metabolites are consistent with slower metabolism of PCB 91 in KO than WT mice and the accumulation of the parent PCB in the fatty liver of KO mice.

Keywords

Atropisomers
Chiral
Deconjugation
Distribution
Disposition
Fatty Liver
hydroxylated PCBs
Metabolism
Mouse
2,2',3,4',6-Pentachlorobiphenyl
PCB
PCB 91
PCB conjugates
Neurotoxic

Supplementary materials

Title
Description
Actions
Title
SI PCB91 dispostion study in CPR null mice 06-03-2019
Description
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