Regulation of VDR expression in rat and human intestine and liver - Consequences for CYP3A expression

Ansar A. Khan*, Bieuwke S. Dragt, Robert J. Porte, Geny M. M. Groothuis

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)

Abstract

The vitamin D receptor (VDR) regulates the expression of drug metabolizing enzymes and transporters in intestine and liver, but the regulation of VDR expression in intestine and liver is incompletely understood. We studied the regulation of VDR mRNA expression by ligands for VDR, farnesoid X receptor (FXR), glucocorticoid receptor (GR) and protein kinase C alpha (PKC alpha) in rat and human ileum and liver using precision-cut slices. 1,25(OH)(2)D(3) induced VDR expression in rat ileum and liver, and human ileum but not in liver. Chenodeoxycholic acid (CDCA), but not lithocholic acid (LCA) and GW4064 induced VDR mRNA expression in rat ileum and liver. The PKCa activator, phorbol-12-myristate-13-acetate (PMA) induced the expression of VDR in the rat liver, and the induction of VDR by 1,25(OH)(2)D(3) and COCA was inhibited by the PKCa inhibitor, bisindolyl maleimide 1 (Bis 1). These results show that the expression of VDR is likely to be regulated by PKC but not by FXR or VDR activation at least in the rat liver. The VDR mediated induction of its target genes CYP3A1 and CYP3A2 by 1,25(OH)(2)D(3) or LCA in the rat ileum was strongly reduced in the presence of CDCA despite the higher VDR expression. Thus, CDCA might potentiate the toxicity of LCA by inhibiting its metabolism. (C) 2009 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)822-829
Number of pages8
JournalToxicology in Vitro
Volume24
Issue number3
DOIs
Publication statusPublished - Apr-2010

Keywords

  • Vitamin D receptor
  • Cytochrome P450
  • Induction
  • Intestinal slices
  • Liver slices
  • Lithocholic acid
  • VITAMIN-D-RECEPTOR
  • THYROID-HORMONE RECEPTOR
  • PRECISION-CUT SLICES
  • RETINOID-X-RECEPTOR
  • PROTEIN-KINASE-C
  • BILE-ACIDS
  • 1,25-DIHYDROXYVITAMIN-D3 RECEPTORS
  • DRUG-METABOLISM
  • NUCLEAR RECEPTOR
  • LITHOCHOLIC ACID

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