Journal article
Human CYP2A6, CYP2B6, AND CYP2E1 Atropselectively Metabolize Polychlorinated Biphenyls to Hydroxylated Metabolites
Environmental science & technology, Vol.53(4), pp.2114-2123
02/19/2019
DOI: 10.1021/acs.est.8b05250
PMCID: PMC6380921
PMID: 30576102
Abstract
Exposure to chiral polychlorinated biphenyls (PCBs) has been associated with neurodevelopmental disorders. Their hydroxylated metabolites (OH-PCBs) are also potentially toxic to the developing human brain; however, the formation of OH-PCBs by human cytochrome P450 (P450) isoforms is poorly investigated. To address this knowledge gap, we investigated the atropselective biotransformation of 2,2',3,4',6-pentachlorobiphenyl (PCB 91), 2,2',3,5',6-pentachlorobiphenyl (PCB 95), 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132), and 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) by different human P450 isoforms. In silico predictions with ADMET Predictor and MetaDrug software suggested a role of CYP1A2, CYP2A6, CYP2B6, CYP2E1, and CYP3A4 in the metabolism of chiral PCBs. Metabolism studies with recombinant human enzymes demonstrated that CYP2A6 and CYP2B6 oxidized PCB 91 and PCB 132 in the meta position and that CYP2A6 oxidized PCB 95 and PCB 136 in the para position. CYP2B6 played only a minor role in the metabolism of PCB 95 and PCB 136 and formed meta-hydroxylated metabolites. Traces of para-hydroxylated PCB metabolites were detected in incubations with CYP2E1. No hydroxylated metabolites were present in incubations with CYP1A2 or CYP3A4. Atropselective analysis revealed P450 isoform-dependent and congener-specific atropselective enrichment of OH-PCB metabolites. These findings suggest that CYP2A6 and CYP2B6 play an important role in the oxidation of neurotoxic PCBs to chiral OH-PCBs in humans.
Details
- Title: Subtitle
- Human CYP2A6, CYP2B6, AND CYP2E1 Atropselectively Metabolize Polychlorinated Biphenyls to Hydroxylated Metabolites
- Creators
- Eric Uwimana - Interdisciplinary Graduate Program in Human Toxicology and Department of Occupational and Environmental Health , University of Iowa , Iowa City , Iowa 52242 , United StatesPatricia Ruiz - Division of Toxicology and Human Health Sciences, Computational Toxicology and Methods Development Lab , Agency for Toxic Substances and Disease Registry , Atlanta , Georgia 30333 , United StatesXueshu Li - Interdisciplinary Graduate Program in Human Toxicology and Department of Occupational and Environmental Health , University of Iowa , Iowa City , Iowa 52242 , United StatesHans-Joachim Lehmler - Interdisciplinary Graduate Program in Human Toxicology and Department of Occupational and Environmental Health , University of Iowa , Iowa City , Iowa 52242 , United States
- Resource Type
- Journal article
- Publication Details
- Environmental science & technology, Vol.53(4), pp.2114-2123
- DOI
- 10.1021/acs.est.8b05250
- PMID
- 30576102
- PMCID
- PMC6380921
- NLM abbreviation
- Environ Sci Technol
- ISSN
- 0013-936X
- eISSN
- 1520-5851
- Publisher
- United States
- Grant note
- P42 ES013661 / NIEHS NIH HHS P30 ES005605 / NIEHS NIH HHS R21 ES027169 / NIEHS NIH HHS
- Language
- English
- Date published
- 02/19/2019
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984065385602771
Metrics
36 Record Views