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Constitutive androstane receptor-vitamin D receptor crosstalk: consequence on CYP24 gene expression

Amélie Moreau1, Patrick Maurel, Marie-José Vilarem

  • 1Inserm, Université Montpellier1, UMR-632, Montpellier F-34293, France.

Biochemical and Biophysical Research Communications
|June 26, 2007
PubMed

Insights

Constitutive Androstane Receptor (CAR) activates the CYP24 gene by binding to the same DNA regions as the Vitamin D Receptor (VDR). This interaction influences vitamin D metabolism and drug-metabolizing enzymes.

Area of Science:

  • Molecular Endocrinology
  • Pharmacology
  • Gene Regulation

Background:

  • Pregnane X receptor (PXR) and Vitamin D Receptor (VDR) share target genes like CYP24.
  • Constitutive Androstane Receptor (CAR) and PXR often share regulatory elements in target genes.

Purpose of the Study:

  • To investigate whether CAR, similar to PXR, interferes with CYP24 expression.
  • To elucidate the mechanism of CAR interaction with the CYP24 promoter.

Main Methods:

  • Electrophoretic mobility shift assays (EMSAs) to assess CAR-RXR heterodimer binding.
  • Reporter gene assays to evaluate transactivation of the CYP24 promoter and its response elements (VDREs).
  • Site-directed mutagenesis of VDREs in the CYP24 promoter.
  • Analysis of gene expression in primary human hepatocytes treated with a CAR agonist (CITCO).

Main Results:

  • CAR-RXR heterodimers bind to and transactivate the proximal CYP24 promoter, including VDRE-1 and VDRE-2.
  • Androstanol, an inverse agonist of CAR, inhibits CAR-mediated transactivation of VDREs.
  • Mutations in VDRE-1 or VDRE-2 half sites abolish CAR-mediated transactivation.
  • CITCO induces CYP24, CYP2B6, and CYP3A4 mRNA in primary human hepatocytes.

Conclusions:

  • CAR binds to and transactivates the same response elements in the CYP24 promoter as VDR.
  • CAR and VDR coordinately regulate CYP24 expression through shared response elements.
  • CAR activation leads to the induction of CYP24 and key drug-metabolizing enzymes (CYP2B6, CYP3A4).

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