Journal article
2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) atropisomers interact enantioselectively with hepatic microsomal cytochrome P450 enzymes
Chemical research in toxicology, Vol.21(6), pp.1295-1303
06/2008
DOI: 10.1021/tx800059j
PMCID: PMC2574739
PMID: 18494506
Abstract
2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is a chiral and highly neurotoxic PCB congener of environmental relevance. (+)-PCB 136 was previously shown to be enriched in tissues from mice treated with racemic PCB 136. We investigated the spectral interactions of (+)-, (-)-, and (+/-)-PCB 136 with mouse and rat hepatic microsomal cytochrome P450 (P450) enzymes to test the hypothesis that enantioselective binding to specific P450 enzymes causes the enrichment of (+)-PCB 136 in vivo. Hepatic microsomes prepared from C57BL/6 mice or Long Evans rats treated with beta-naphthoflavone or 3-methylcholanthrene, phenobarbital, and dexamethasone (prototypical inducers of CYP1A, CYP2B, and CYP3A, respectively) were used to determine first, whether the (+)-PCB 136 atropisomer binds to hepatic microsomal P450 enzymes to a greater extent than does the (-)-PCB 136 atropisomer and second, whether P450 enzymes of one subfamily bind the two PCB 136 atropisomers more efficiently than do P450 enzymes of other subfamilies. Increasing concentrations of (+)-, (-)-, or (+/-)-PCB 136 were added to hepatic microsomes, and the difference spectrum and maximal absorbance change, a measure of PCB binding to P450 enzymes, were measured. A significantly larger absorbance change was observed with (+)-PCB 136 than with (-)-PCB 136 with all four hepatic microsomal preparations in mice and rats, indicating that (+)-PCB 136 interacted with microsomal P450 enzymes to a greater degree than did (-)-PCB 136. In addition, binding of the PCB 136 atropisomers was greatest in microsomes from PB-treated mice and rats and was inhibited by CYP2B antibodies, indicating the involvement of CYP2B enzymes. Together, these results suggest preferential binding of (+)-PCB 136 to P450 enzymes (such as CYP2B and CYP3A) in hepatic microsomes, an observation that may explain the enantioselective enrichment of the (+)-PCB 136 atropisomer in tissues of mice.
Details
- Title: Subtitle
- 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) atropisomers interact enantioselectively with hepatic microsomal cytochrome P450 enzymes
- Creators
- Izabela Kania-Korwel - Department of Occupational and Environmental Health, University of Iowa, 100 Oakdale Campus #124 IREH, Iowa City, Iowa 52242, USAEugene G HrycayStelvio M BandieraHans-Joachim Lehmler
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.21(6), pp.1295-1303
- DOI
- 10.1021/tx800059j
- PMID
- 18494506
- PMCID
- PMC2574739
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS P30 ES005605-17 / NIEHS NIH HHS P42 ES013661 / NIEHS NIH HHS P42 ES013661-02 / NIEHS NIH HHS ES012475 / NIEHS NIH HHS K25 ES012475-01A1 / NIEHS NIH HHS K25 ES012475-03 / NIEHS NIH HHS K25 ES012475 / NIEHS NIH HHS ES013661 / NIEHS NIH HHS P42 ES013661-03 / NIEHS NIH HHS K25 ES012475-04 / NIEHS NIH HHS P30 ES005605-18 / NIEHS NIH HHS ES05605 / NIEHS NIH HHS K25 ES012475-02 / NIEHS NIH HHS
- Language
- English
- Date published
- 06/2008
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984000933302771
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