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A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection

J Sonoda1, J M Rosenfeld, L Xu

  • 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15213, USA.

Current Drug Metabolism
|February 7, 2003
PubMed

Insights

Orphan nuclear receptors (NRs) act as species-specific sensors for xenobiotics, regulating drug-metabolizing enzymes and transporters. This discovery advances understanding of drug metabolism and aids in developing safer pharmaceuticals.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Toxicology

Background:

  • Drug metabolism and xenobiotic elimination involve Phase I CYP and Phase II conjugating enzymes, alongside drug transporters.
  • The expression of genes encoding these enzymes and transporters is inducible by xenobiotics, exhibiting species-specific patterns.
  • Orphan nuclear receptors (NRs) like PXR, CAR, and FXR are emerging as key regulators in this process.

Purpose of the Study:

  • To elucidate the role of orphan nuclear receptors (NRs) as species-specific xenosensors.
  • To understand the transcriptional regulation of drug-metabolizing enzymes and transporters by NRs.
  • To establish novel screening systems for safer drug development.

Main Methods:

  • Investigated the transcriptional regulation mediated by NR binding to response elements in target gene promoters.
  • Utilized cultured cells and genetically engineered mouse models for NR-mediated screening.
  • Employed mechanism-guided xenobiotic screening systems.

Main Results:

  • Established orphan nuclear receptors (PXR, CAR, FXR) as species-specific xenosensors.
  • Demonstrated NR-mediated transcriptional regulation of Phase I and II enzymes and drug transporters.
  • Developed in vitro and in vivo platforms for xenobiotic screening.

Conclusions:

  • NRs are crucial genetic determinants of species-specific xenobiotic responses.
  • NR-mediated regulation provides a framework for understanding drug metabolism and interactions.
  • NR-based screening systems facilitate the development of safer drugs.

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