The role of hepatocyte RXRα in xenobiotic-sensing nuclear receptor-mediated pathways

Yan Cai, Tamiko Konishi, Guang Han, Khozema H. Campwala, Samuel W. French, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) cross talk and serve as xenobiotic sensors to form a safety net against the toxic effects of harmful substances. Retinoid x receptor α (RXRα) dimerizes with CAR and PXR. In order to analyze the role of RXRα in these xeno-sensor-mediated pathways, hepatocyte RXRα-deficient mice were challenged by CAR and PXR ligands including androstanol, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), and pregnenolone 16α-carbonitrile (PCN). We demonstrate that hepatocyte RXRα deficiency prevents TCPOBOP-induced hepatomegaly and morphological changes. We also show that in vivo the cytochrome P450 (CYP) genes including CYP2A5, CYP2B10, CYP3A1, but not CYP2E1 and CYP2D6, are the RXRα target genes. Androstanol, TCPOBOP, and PCN can differentially regulate the expression of these CYP450 genes. In addition, the most active peroxisome proliferator activated receptor (PPARα) ligand, Wy14,643, also regulates some of the xeno-sensor target genes such as CYP2A5 and CYP2B10 in vivo. Thus, the ligands of different nuclear receptors can regulate common CYP450 genes and hepatocyte RXRα is essential for xenobiotic metabolism in vivo.

Original languageEnglish (US)
Pages (from-to)89-96
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume15
Issue number1
DOIs
StatePublished - 2002

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Keywords

  • Constitutive androstane receptor
  • CYP450
  • Nulcear receptor
  • Peroxisome proliferator activated receptor
  • Pregnane X receptor
  • Retinoid x receptor
  • Xenobiotic

ASJC Scopus subject areas

  • Pharmaceutical Science

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