title: Metabolism of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent.
abstract: 1. Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized. 2. The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups. 3. In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected. 4. Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs.
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa , Iowa City, IA , USA .
authors.forename: Xianai
authors.initials: X
authors.lastname: Wu
authors.forename: Izabela
authors.initials: I
authors.lastname: Kania-Korwel
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Marianna
authors.initials: M
authors.lastname: Stamou
authors.forename: Karigowda J
authors.initials: KJ
authors.lastname: Dammanahalli
authors.forename: Michael
authors.initials: M
authors.lastname: Duffel
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006900:Hydroxylation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013237:Stereoisomerism; D014022:Tissue Survival
chemical_list: D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C010498:2,3,6,2',3',6'-hexachlorobiphenyl; D010634:Phenobarbital