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

  1. Wen Xie1,
  2. Joyce L. Barwick3,
  3. Cynthia M. Simon1,
  4. Alexis M. Pierce1,
  5. Stephen Safe4,
  6. Bruce Blumberg5,
  7. Philip S. Guzelian3, and
  8. Ronald M. Evans1,2,6,7
  1. 1Gene Expression Laboratory, 2Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA; 3Medical Toxicology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA; 4Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA; 5Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA

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.

Keywords

Footnotes

  • Present address: 6Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

  • 7 Corresponding author.

  • Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.846800.

    • Received August 30, 2000.
    • Accepted October 18, 2000.
| Table of Contents

Life Science Alliance