title: 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) atropisomers interact enantioselectively with hepatic microsomal cytochrome P450 enzymes.
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.
authors.affiliation: Department of Occupational and Environmental Health, University of Iowa, 100 Oakdale Campus #124 IREH, Iowa City, Iowa 52242, USA.
authors.forename: Izabela
authors.initials: I
authors.lastname: Kania-Korwel
authors.forename: Eugene G
authors.initials: EG
authors.lastname: Hrycay
authors.forename: Stelvio M
authors.initials: SM
authors.lastname: Bandiera
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000906:Antibodies; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C010498:2,3,6,2',3',6'-hexachlorobiphenyl