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Identification of human CYP2C8 as a retinoid-related orphan nuclear receptor target gene

Yuping Chen1, Sherry Coulter, Anton M Jetten

  • 1Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

The Journal of Pharmacology and Experimental Therapeutics
|January 24, 2009
PubMed

Insights

Retinoid-related orphan receptors (RORs) alpha and gamma regulate the CYP2C8 gene in the liver. This finding is crucial for understanding drug metabolism and the function of RORs in various tissues.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Endocrinology

Background:

  • Retinoid-related orphan receptors (RORs) alpha and gamma are nuclear receptors involved in circadian rhythm and immune function.
  • Cytochrome P450 2C enzymes, highly expressed in the liver, metabolize numerous drugs and endogenous compounds.
  • The transcriptional regulation of CYP2C8, a key drug-metabolizing enzyme, by RORs is not well understood.

Purpose of the Study:

  • To investigate the role of RORs alpha and gamma in regulating the transcription of the human CYP2C8 gene.
  • To identify the specific regulatory elements within the CYP2C8 promoter involved in ROR-mediated transactivation.

Main Methods:

  • Reporter gene assays using HepG2 cells to assess CYP2C8 promoter activity.
  • Bioinformatic analyses, promoter deletion studies, gel shift assays, and mutational analysis to pinpoint ROR-responsive elements.
  • Adenoviral overexpression and RNA interference (RNAi) to manipulate ROR and CYP2C8 expression in HepG2 cells and primary hepatocytes.

Main Results:

  • RORs alpha and gamma significantly enhanced the CYP2C8 promoter activity, but not CYP2C9 or CYP2C19.
  • A specific ROR-responsive element was identified at -2045 base pairs in the CYP2C8 promoter.
  • Overexpression of RORs induced endogenous CYP2C8 transcripts, while ROR knockdown decreased CYP2C8 mRNA levels by approximately 50%.

Conclusions:

  • RORs alpha and gamma transcriptionally up-regulate CYP2C8 expression in human liver cells.
  • RORs may play a significant role in modulating the metabolism of drugs and endogenous compounds via CYP2C8.
  • These findings highlight RORs as potential regulators of drug metabolism in both hepatic and extrahepatic tissues.

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