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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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Genomic and non-genomic interactions of PPARalpha with xenobiotic-metabolizing enzymes

Olivier Barbier1, Coralie Fontaine, Jean-Charles Fruchart

  • 1UR 545 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université Lille II, Lille, 59019 France.

Trends in Endocrinology and Metabolism: TEM
|September 8, 2004
PubMed

Insights

Fibrates activate peroxisome proliferator-activated receptor alpha (PPARalpha), influencing drug metabolism. PPARalpha activators affect xenobiotic-metabolizing enzymes (XMEs) through genomic and non-genomic mechanisms, impacting drug interactions.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • Fibrates are known for their lipid-lowering effects.
  • Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor activated by fibrates.
  • Emerging evidence suggests PPARalpha regulates endobiotic and xenobiotic metabolism.

Purpose of the Study:

  • To investigate the role of PPARalpha activators in regulating xenobiotic-metabolizing enzymes (XMEs).
  • To understand the genomic and non-genomic mechanisms by which PPARalpha affects XMEs.
  • To highlight the physiological and pharmaceutical implications of PPARalpha's influence on metabolism.

Main Methods:

  • Analysis of gene expression changes (e.g., cytochrome P450, phase II conjugating genes) in response to PPARalpha activators.
  • Assessment of species-specific responses to PPARalpha activation.
  • Evaluation of non-genomic effects, including competitive inhibition and drug-drug interactions.

Main Results:

  • PPARalpha activators alter the expression of numerous cytochrome P450 (CYP) and phase II conjugating genes in a species-distinct manner.
  • PPARalpha activation impacts the homeostasis of natural ligands and other compounds like bile acids.
  • Non-genomic mechanisms involve competitive inhibition, potentially leading to drug-drug interactions.

Conclusions:

  • PPARalpha plays a significant role in regulating both endobiotic and xenobiotic metabolism.
  • The effects of PPARalpha activators on XMEs are complex, involving both genomic and non-genomic pathways.
  • Thorough investigation of novel PPARalpha agonists' effects on XMEs is crucial due to their physiological and pharmaceutical importance.

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