Stereoselective formation of mono- and dihydroxylated polychlorinated biphenyls by rat cytochrome P450 2B1.
Changes in atropisomer composition of chiral polychlorinated biphenyls (PCBs) and their mono- and dihydroxylated metabolites (OH- and diOH-PCBs) via rat cytochrome P450 2B1 (CYP2B1) mediated biotransformation were investigated in vitro. Rat CYP2B1 could stereoselectively biotransform chiral PCBs to generate meta-OH-PCBs as the major metabolites after 60 min incubations. Nonracemic enantiomer fractions (EFs: concentration ratios of the (+)-atropisomer or the first-eluting atropisomer over the total concentrations of two atropisomers) of 5-OH-PCBs, were 0.17, 0.20, 0.85, 0.77, and 0.41 for incubations with PCBs 91, 95, 132, 136, and 149, respectively. CYP-mediated stereoselective formation of diOH-PCBs from OH-PCBs was observed for the first time. After 60 min stereoselective biotransformation, the EFs of both 4-OH-PCB 95 and 5-OH-PCB 95 changed from racemic (i.e., 0.50) to 0.62 and 0.46, respectively. These transformations generated statistically nonracemic 4,5-diOH-PCB 95, with EFs of 0.53 and 0.58 for 4-OH-PCB 95 and 5-OH-PCB 95 incubations, respectively. Biotransformation of PCBs 91 and 136 also generated 4,5-diOH-PCB 91 and 4,5-diOH-PCB 136, respectively. These in vitro results were consistent with that observed for stereoselective PCB biotransformation by rat liver microsomes and in vivo. Biotransformation interference between two atropisomers of PCB 136 was investigated for the first time in this study. The biotransformation process of (-)-PCB 136 was significantly disrupted by the presence of (+)-PCB 136 but not the other way around. Thus, stereoselective metabolism of chiral PCBs and OH-PCBs by CYPs is a major mechanism for atropisomer composition change of PCBs and their metabolites in the environment, with the degree of composition change dependent, at least in part, on stereoselective interference of atropisomers with each other at the enzyme level.
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
Zhe
Z
Lu
Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242,United States.
Izabela
I
Kania-Korwel
Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242,United States.
Hans-Joachim
HJ
Lehmler
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.|Department of Environmental Studies and Sciences and Department of Chemistry, Richardson College for the Environment, University of Winnipeg, Winnipeg, MB, R3B 2E9, Canada.
Charles S
CS
Wong
D000818:Animals; D001711:Biotransformation; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D004777:Environment; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism
D011078:Polychlorinated Biphenyls; D019362:Cytochrome P-450 CYP2B1