title: Hepatic metabolism affects the atropselective disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice.
abstract: To understand the role of hepatic vs extrahepatic metabolism in the disposition of chiral PCBs, we studied the disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) and its hydroxylated metabolites (HO-PCBs) in mice with defective hepatic metabolism due to the liver-specific deletion of cytochrome P450 oxidoreductase (KO mice). Female KO and congenic wild type (WT) mice were treated with racemic PCB 136, and levels and chiral signatures of PCB 136 and HO-PCBs were determined in tissues and excreta 3 days after PCB administration. PCB 136 tissue levels were higher in KO compared to WT mice. Feces was a major route of PCB metabolite excretion, with 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol being the major metabolite recovered from feces. (+)-PCB 136, the second eluting PCB 136 atropisomers, was enriched in all tissues and excreta. The second eluting atropisomers of the HO-PCBs metabolites were enriched in blood and liver; 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol in blood was an exception and displayed an enrichment of the first eluting atropisomers. Fecal HO-PCB levels and chiral signatures changed with time and differed between KO and WT mice, with larger HO-PCB enantiomeric fractions in WT compared to KO mice. Our results demonstrate that hepatic and, possibly, extrahepatic cytochrome P450 (P450) enzymes play a role in the disposition of PCBs.
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Xianai
authors.initials: X
authors.lastname: Wu
authors.forename: Christopher
authors.initials: C
authors.lastname: Barnhart
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
mesh_terms: D000818:Animals; D005591:Chemical Fractionation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004777:Environment; D005243:Feces / Q000737:chemistry; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism*; D018345:Mice, Knockout; D009928:Organ Specificity; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism* / Q000652:urine; D013237:Stereoisomerism; D013429:Sulfatases / Q000378:metabolism
chemical_list: D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D013429:Sulfatases; D005966:Glucuronidase; C010498:2,3,6,2',3',6'-hexachlorobiphenyl