Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta

Nature. 1998 Oct 8;395(6702):612-5. doi: 10.1038/26996.


The orphan receptor CAR-beta binds DNA as a heterodimer with the retinoid-X receptor and activates gene transcription in a constitutive manner. Here we show that, in contrast to the classical nuclear receptors, the constitutive activity of CAR-beta results from a ligand-independent recruitment of transcriptional co-activators. While searching for potential ligands of CAR-beta, we found that the steroids androstanol and androstenol inhibit the constitutive activity of CAR-beta. This effect is stereospecific: only 3alpha-hydroxy, 5alpha-reduced androstanes are active. These androstanes do not interfere with heterodimerization or DNA binding of CAR-beta; instead, they promote co-activator release from the ligand-binding domain. These androstane ligands are examples of naturally occurring inverse agonists that reverse transcriptional activation by nuclear receptors. CAR-beta (constitutive androstane receptor-beta), therefore, defines an unanticipated steroidal signalling pathway that functions in a manner opposite to that of the conventional nuclear receptor pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstanes / metabolism*
  • Androstanols / metabolism*
  • Animals
  • Binding Sites
  • COS Cells
  • Constitutive Androstane Receptor
  • Ligands
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Saccharomyces cerevisiae
  • Stereoisomerism
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors*
  • Transfection


  • Androstanes
  • Androstanols
  • Constitutive Androstane Receptor
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • androstan-3-ol
  • androstane