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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response

P Wei1, J Zhang, D H Dowhan

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

The Pharmacogenomics Journal
|June 7, 2002
PubMed

Insights

Constitutive Androstane Receptor (CAR) mediates the induction of detoxification genes, including CYP2B10 and CYP3A11, in response to xenobiotics. CAR knockout mice reveal its crucial role in both liver and small intestine xenobiotic metabolism.

Area of Science:

  • Pharmacology
  • Toxicology
  • Molecular Biology

Background:

  • Cytochrome P450 (CYP) enzymes are vital for detoxifying foreign compounds.
  • Nuclear receptors like Constitutive Androstane Receptor (CAR) regulate CYP gene expression.
  • CAR's role in xenobiotic response beyond known pathways requires further investigation.

Purpose of the Study:

  • To investigate the broader functions of CAR in xenobiotic metabolism using a CAR knockout mouse model.
  • To determine CAR's role in the induction of specific CYP genes (CYP2B10, CYP3A11, CYP2A4) in response to various inducers.
  • To compare CAR-mediated responses with those of the Pregnane X Receptor (PXR).

Main Methods:

  • Utilized CAR knockout mice and wild-type littermates.
  • Administered known CAR activators (phenobarbital, TCPOBOP) and other xenobiotics (chlorpromazine, clotrimazole, dieldrin, dexamethasone).
  • Measured gene expression of CYP2B10, CYP3A11, and CYP2A4 in liver and small intestine tissues.
  • Investigated the effect of a CAR inverse agonist (androstenol) on gene expression.

Main Results:

  • CAR is expressed in the liver and small intestine, mediating CYP2B10 induction in both tissues.
  • CAR is essential for PB and TCPOBOP induction of CYP3A11 in the liver and CYP2A4 in male livers.
  • CAR mediates responses to several xenobiotics, with some responses overlapping with PXR, such as chlorpromazine induction of CYP3A11.

Conclusions:

  • CAR plays a broad role in xenobiotic detoxification, acting in both the liver and small intestine.
  • CAR-specific functions and overlapping roles with PXR in regulating drug-metabolizing enzymes like CYP3A have been identified.
  • CAR is a key regulator of the response to a wide range of environmental contaminants and foreign chemicals.

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