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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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Activation of xenobiotic receptors: driving into the nucleus

Haishan Li1, Hongbing Wang

  • 1University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, 20 Penn Street, Baltimore, MD 21201, USA.

Expert Opinion on Drug Metabolism & Toxicology
|February 2, 2010
PubMed
Abstract

Insights

Nuclear import is crucial for activating xenobiotic receptors (XRs). Research on constitutive androstane receptor (CAR) and other XRs reveals mechanisms of cellular localization and activation, essential for detoxification processes.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cell Biology

Background:

  • Xenobiotic receptors (XRs) regulate detoxification genes.
  • XRs shuttle between cytoplasm and nucleus.
  • Activation is linked to xenobiotic-induced nuclear import.

Purpose of the Study:

  • Review nuclear translocation and activation of XRs.
  • Focus on constitutive androstane receptor (CAR), pregnane X receptor, and aryl hydrocarbon receptor.
  • Incorporate novel laboratory data.

Main Methods:

  • Literature review of XR nuclear translocation and activation.
  • Analysis of unpublished laboratory data.
  • Utilized primary hepatocyte cultures to study CAR localization.

Main Results:

  • Identified molecular chaperones involved in XR cellular localization.
  • Demonstrated primary hepatocyte cultures retain inactive CAR in the cytoplasm.
  • Observed altered localization and activation in human CAR splicing variants.

Conclusions:

  • Nuclear accumulation is a key step for XR activation.
  • Mechanisms of XR intracellular localization and trafficking are complex.
  • Both direct ligand-binding and indirect pathways are involved.

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