Probing the Role of CYP2 Enzymes in the Atropselective Metabolism of Polychlorinated Biphenyls Using Liver Microsomes from Transgenic Mouse Models

Hans-Joachim Lehmler; Eric Uwimana; Laura E Dean; Nataliia Kovalchuk; Qing-Yu Zhang; Xinxin Ding

doi:10.1021/acs.chemrestox.2c00276

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Probing the Role of CYP2 Enzymes in the Atropselective Metabolism of Polychlorinated Biphenyls Using Liver Microsomes from Transgenic Mouse Models

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Probing the Role of CYP2 Enzymes in the Atropselective Metabolism of Polychlorinated Biphenyls Using Liver Microsomes from Transgenic Mouse Models

Hans-Joachim Lehmler, Eric Uwimana, Laura E Dean, Nataliia Kovalchuk, Qing-Yu Zhang and Xinxin Ding

Chemical research in toxicology, Vol.35(12), pp.2310-2323

12/06/2022

DOI: 10.1021/acs.chemrestox.2c00276

PMCID: PMC9957597

PMID: 36473170

Appears in UI Libraries Support Open Access

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Abstract

Chiral polychlorinated biphenyls (PCB) are environmentally relevant developmental neurotoxicants. Because their hydroxylated metabolites (OH-PCBs) are also neurotoxic, it is necessary to determine how PCB metabolism affects the developing brain, for example, in mouse models. Because the cytochrome P450 isoforms involved in the metabolism of chiral PCBs remain unexplored, we investigated the metabolism of PCB 91 (2,2',3,4',6-pentachlorobiphenyl), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 132 (2,2',3,3',4,6'-hexachlorobiphenyl), and PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl) using liver microsomes from male and female -null, -null, and wild-type mice. Microsomes, pooled by sex, were incubated with 50 μM PCB for 30 min, and the levels and enantiomeric fractions of the OH-PCBs were determined gas chromatographically. All four PCB congeners appear to be atropselectively metabolized by CYP2A(4/5)BGS and CYP2F2 enzymes in a congener- and sex-dependent manner. The OH-PCB metabolite profiles of PCB 91 and PCB 132, PCB congeners with one -chlorine substituent, differed between null and wild-type mice. No differences in the metabolite profiles were observed for PCB 95 and PCB 136, PCB congeners without a -chlorine group. These findings suggest that -null and -null mice can be used to study how a loss of a specific metabolic function (e.g., deletion of or ) affects the toxicity of chiral PCB congeners.

Animals

Chlorine - metabolism

Cytochrome P450 Family 2 - metabolism

Female

Hydroxylation

Male

Mice

Mice, Knockout

Mice, Transgenic

Microsomes, Liver - metabolism

Polychlorinated Biphenyls - metabolism

UIOWA OA Agreement

Details

Title: Subtitle: Probing the Role of CYP2 Enzymes in the Atropselective Metabolism of Polychlorinated Biphenyls Using Liver Microsomes from Transgenic Mouse Models
Creators: Hans-Joachim Lehmler - University of Iowa
Eric Uwimana - University of Iowa
Laura E Dean - University of Iowa
Nataliia Kovalchuk - University of Arizona
Qing-Yu Zhang - University of Arizona
Xinxin Ding - University of Arizona
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.35(12), pp.2310-2323
DOI: 10.1021/acs.chemrestox.2c00276
PMID: 36473170
PMCID: PMC9957597
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Publisher: American Chemical Society
Grant note: P30 ES005605 / NIEHS NIH HHS
Language: English
Date published: 12/06/2022
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9984345164102771

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