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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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The alternatively spliced murine pregnane X receptor isoform, mPXR(delta171-211) exhibits a repressive action

Marko Matic1, Anthony P Corradin, Maria Tsoli

  • 1Cancer Pharmacology Unit, ANZAC Research Institute, Hospital Road, Concord RG Hospital, NSW 2139, Australia. mmatic@med.usyd.edu.au

The International Journal of Biochemistry & Cell Biology
|January 12, 2010
PubMed

Insights

A variant mouse pregnane X receptor (PXR) isoform, mPXR(Δ171-211), represses drug-metabolizing enzymes and transporters. This isoform functions differently from the major mPXR(431), impacting drug clearance pathways.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • The pregnane X receptor (PXR) is a nuclear receptor regulating xenobiotic and endobiotic metabolism.
  • Multiple PXR isoforms exist, but their functions are largely unknown.
  • Understanding PXR isoform function is crucial for drug metabolism and toxicity.

Purpose of the Study:

  • To investigate functional differences between major mouse PXR isoforms: mPXR(431) and mPXR(Δ171-211).
  • To elucidate the mechanism underlying the repressive function of mPXR(Δ171-211).

Main Methods:

  • Transient transfection assays to assess gene transcription.
  • DNA-binding domain swap experiments.
  • Histone deacetylase inhibitor treatment.
  • Protein-protein interaction assays.

Main Results:

  • mPXR(Δ171-211) reduced basal transcription of CYP3A4 and P-glycoprotein.
  • mPXR(Δ171-211) repressed mPXR(431) activity independently of PXR response elements.
  • Repressive function of mPXR(Δ171-211) is independent of histone acetylation.
  • Differential binding to retinoid X receptor and heterodimerization observed between isoforms.

Conclusions:

  • The mPXR(Δ171-211) isoform exhibits a distinct repressive function compared to mPXR(431).
  • This variant PXR isoform influences the regulation of key drug-metabolizing enzymes and transporters.
  • Findings highlight the importance of PXR isoform diversity in drug response.

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