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The transcriptional regulation of the human CYP2C genes

Yuping Chen1, Joyce A Goldstein

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

Current Drug Metabolism
|August 26, 2009
PubMed

Insights

The CYP2C enzyme family significantly impacts drug metabolism and response. Understanding their transcriptional regulation is key to preventing drug interactions and therapeutic failures, especially in the liver.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Genetics

Background:

  • The CYP2C subfamily (CYP2C8, CYP2C9, CYP2C18, CYP2C19) is crucial for metabolizing over 20% of therapeutic drugs and endogenous compounds.
  • These enzymes constitute about 20% of hepatic cytochrome P450, playing a dominant role in liver metabolism.
  • Induction of CYP2C genes by xenobiotics can lead to drug interactions, tolerance, and treatment failure.

Purpose of the Study:

  • To elucidate the transcriptional regulatory mechanisms governing CYP2C gene expression in humans.
  • To identify the key nuclear receptors and transcription factors involved in both constitutive and induced expression of CYP2C genes.
  • To explore the regulation of CYP2C genes in extrahepatic tissues and potential alterations in pathological conditions.

Main Methods:

  • Analysis of transcriptional induction of CYP2C genes in primary human hepatocytes.
  • Identification of drug-responsive elements (DREs) in the 5' flanking promoter regions of CYP2C genes.
  • Investigation of the roles of various nuclear receptors (CAR, PXR, VDR, GR) and hepatic factors (HNF4α, HNF3γ, C/EBPα, RORs) in CYP2C gene regulation.

Main Results:

  • Xenobiotics like phenobarbital, rifampicin, and hyperforin induce CYP2C gene expression and substrate metabolism.
  • Drug-activated nuclear receptors (CAR, PXR, VDR, GR) mediate xenobiotic-induced upregulation via DREs.
  • Constitutive expression is regulated by hepatic factors including HNF4α, HNF3γ, C/EBPα, and RORs.
  • Optimal induction involves cross-talk between xenobiotic receptors, hepatic factors, and coactivators.

Conclusions:

  • Transcriptional regulation of CYP2C genes is complex, involving multiple nuclear receptors and hepatic factors.
  • Coordinated interactions are essential for achieving maximal CYP2C gene induction.
  • Extrahepatic CYP2C gene regulation is less understood but may be influenced by pathological states like ischemia.

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