Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR

Wen Xie, Joyce L. Barwick, Cynthia M. Simon, Alexis M. Pierce, Stephen Safe, Bruce Blumberg, Philip S. Guzelian, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

446 Scopus citations

Abstract

The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR/PXR (steroid and xenobiotic receptor/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A genes, while similar studies have established constitutive androstane receptor (CAR) as a CYP2B regulator. The response elements in these genes are also distinct, furthering the concept of independent regulation. Unexpectedly, we found that SXR can regulate CYP2B, both in cultured cells and in transgenic mice via adaptive recognition of the phenobarbital response element (PBRE). In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elements. These observations not only provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics, but also reveal the existence of a metabolic safety net that confers a second layer of protection to the harmful effects of toxic compounds and at the same time increases the propensity for drug-drug interactions.

Original languageEnglish (US)
Pages (from-to)3014-3023
Number of pages10
JournalGenes and Development
Volume14
Issue number23
DOIs
StatePublished - 2000

Keywords

  • CAR, metabolic safety
  • CYP gene
  • Nuclear receptor
  • SXR/PXR

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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