SXR, a novel steroid and xenobioticsensing nuclear receptor

  1. Bruce Blumberg1,4,5,
  2. Walid Sabbagh, Jr.1,4,
  3. Henry Juguilon1,2,
  4. Jack Bolado, Jr.1,2,3,
  5. Casey M. van Meter1,
  6. Estelita S. Ong1,2, and
  7. Ronald M. Evans1,2
  1. 1Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037; 2Howard Hughes Medical Institute (The Salk Institute)

Abstract

An important requirement for physiologic homeostasis is the detoxification and removal of endogenous hormones and xenobiotic compounds with biological activity. Much of the detoxification is performed by cytochrome P-450 enzymes, many of which have broad substrate specificity and are inducible by hundreds of different compounds, including steroids. The ingestion of dietary steroids and lipids induces the same enzymes; therefore, they would appear to be integrated into a coordinated metabolic pathway. Instead of possessing hundreds of receptors, one for each inducing compound, we propose the existence of a few broad specificity, low-affinity sensing receptors that would monitor aggregate levels of inducers to trigger production of metabolizing enzymes. In support of this model, we have isolated a novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), which activates transcription in response to a diversity of natural and synthetic compounds. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P-450 genes and is expressed in tissues in which these catabolic enzymes are expressed. These results strongly support the steroid sensor hypothesis and suggest that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.

Keywords

Footnotes

  • Present addresses: 3Aurora Biosciences, San Diego, California 92037 USA; 4Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300 USA.

  • 5 Corresponding author.

  • E-MAIL blumberg{at}salk.edu; FAX (619) 455-1349.

    • Received July 24, 1998.
    • Accepted August 26, 1998.
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