Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent

Xianai Wu, Izabela Kania-Korwel, Hao Chen, Marianna Stamou, Karigowda J. Dammanahalli, Michael Duffel, Pamela J Lein, Hans Joachim Lehmler

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)933-947
Number of pages15
JournalXenobiotica
Volume43
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Polychlorinated Biphenyls
Phenobarbital
Metabolism
Dexamethasone
Rats
Tissue
Liver
Cytochrome P-450 Enzyme System
Ryanodine Receptor Calcium Release Channel
2,3,6,2',3',6'-hexachlorobiphenyl
Metabolites
Enzyme Induction
Sprague Dawley Rats

Keywords

  • Atropisomeric enrichment
  • Cytochrome P450 enzymes
  • Sex differences

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis

Cite this

Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent. / Wu, Xianai; Kania-Korwel, Izabela; Chen, Hao; Stamou, Marianna; Dammanahalli, Karigowda J.; Duffel, Michael; Lein, Pamela J; Lehmler, Hans Joachim.

In: Xenobiotica, Vol. 43, No. 11, 11.2013, p. 933-947.

Research output: Contribution to journalArticle

Wu, Xianai ; Kania-Korwel, Izabela ; Chen, Hao ; Stamou, Marianna ; Dammanahalli, Karigowda J. ; Duffel, Michael ; Lein, Pamela J ; Lehmler, Hans Joachim. / Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent. In: Xenobiotica. 2013 ; Vol. 43, No. 11. pp. 933-947.
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AU - Kania-Korwel, Izabela

AU - Chen, Hao

AU - Stamou, Marianna

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AB - 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.

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