Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond

Expert Opin Drug Metab Toxicol. 2013 Mar;9(3):253-66. doi: 10.1517/17425255.2013.754010. Epub 2013 Jan 17.

Abstract

Introduction: 'Orphan' nuclear receptors belong to the nuclear receptor (NR) superfamily of transcriptional factors. Binding of ligands to these receptors results in the recruitment of the co-activators, thereby regulating the expression of cognate target genes.

Areas covered: This review discusses the transcriptional regulation of P450 genes by two major xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Additional PXR and CAR target genes include those encoded for UDP-glucuronosyltransferases, glutathione S-transferases, sulfotransferases and drug transporters. The authors discuss the involvement of PXR and CAR in endobiotic metabolism. They also review the polymorphisms of PXR and CAR.

Expert opinion: PXR and CAR are both xenobiotic and endobiotic receptors. A remarkably diverse set of chemicals can activate PXR and CAR. There is significant cross-talk among xenobiotic receptors. Future studies are needed to focus on the polymorphisms of the nuclear receptors and the complex regulatory networks among nuclear receptors. Considerations should be given while designing PXR- or CAR-targeting pharmaceutics to avoid adverse drug effects. In the meantime, due to the diverse functions of PXR and CAR, agonists or antagonists for these receptors may have therapeutic potentials in managing certain diseases and enhancing therapeutic indexes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism
  • Biological Transport
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Inactivation, Metabolic
  • Lipid Metabolism / drug effects
  • Pharmacogenetics*
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Steroid / metabolism*
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Xenobiotics / metabolism

Substances

  • Bile Acids and Salts
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • Xenobiotics
  • constitutive androstane receptor
  • Cytochrome P-450 Enzyme System
  • Glucuronosyltransferase
  • Glutathione Transferase
  • Sulfotransferases
  • Glucose