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Related Experiment Videos

Functional evolution of the pregnane X receptor.

Manisha Iyer1, Erica J Reschly, Matthew D Krasowski

  • 1Department of Pathology, University of Pittsburgh, Scaife Hall S-730, 3550 Terrace Street, Pittsburgh, PA 15261, USA.

Expert Opinion on Drug Metabolism & Toxicology
|July 26, 2006
PubMed
Summary

The pregnane X receptor (PXR) is a nuclear hormone receptor regulating drug metabolism. Its broad ligand specificity and evolutionary diversity present challenges for predicting human drug responses using animal models.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Evolutionary Biology

Background:

  • The pregnane X receptor (PXR; NR1I2) is a nuclear hormone receptor controlling genes for drug metabolism and transport.
  • PXR activation enhances the metabolism and elimination of xenobiotics and endogenous compounds.
  • PXR exhibits broad ligand specificity due to a large, flexible ligand-binding cavity.

Purpose of the Study:

  • To explore the evolutionary history and functional significance of PXR.
  • To understand the structural basis for PXR's broad ligand specificity.
  • To highlight the challenges in using animal models for human PXR pharmacology.

Main Methods:

  • Comparative sequence analysis of PXR across vertebrate species.
  • Structural analysis of the PXR ligand-binding domain.

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  • Review of existing literature on PXR function and pharmacology.

    • Main Results:

    • PXR displays extensive sequence diversity, particularly in the ligand-binding domain, across species.
    • Significant pharmacological differences exist between human, rodent, and non-mammalian PXRs.
    • The unique properties of PXR complicate predictions of human drug metabolism from animal studies.

    Conclusions:

    • The evolutionary trajectory of PXR has resulted in unique pharmacological properties in humans.
    • Understanding PXR's evolutionary past is crucial for accurate prediction of drug responses.
    • Further research is needed to bridge the gap between animal models and human PXR function.