Use of comprehensive screening methods to detect selective human CAR activators

Biochem Pharmacol. 2011 Dec 15;82(12):1994-2007. doi: 10.1016/j.bcp.2011.08.027. Epub 2011 Sep 8.


The so-called human xenosensors, constitutive androstane receptor (hCAR), pregnane X receptor (hPXR) and aryl hydrocarbon receptor (hAhR), participate in drug metabolism and transport as well as in several endogenous processes by regulating the expression of their target genes. While the ligand specificities for hPXR and hAhR are relatively well described, this property of hCAR still remains fairly unclear. Identifying hCAR agonists for drug development and for studying hCAR biology are hindered mainly by the unique properties of the receptor, such as the high constitutive activity and complex signaling network but also by the lack of robust and reliable assays and cellular models. Here, validated reporter assays for these three xenosensors are presented and thereafter used to screen a large set of chemicals in order to find novel selective hCAR ligands. We introduce a novel selective hCAR agonist, FL81, which can be used as a stable positive control in hCAR activity assays. Our established receptor-selective ligand identification methods consisting of supporting biological assays and molecular modeling techniques are then used to study FL81 as well as other discovered ligands, such as diethylstilbestrol, o,p'-DDT, methoxychlor and permethrin, for their ability to specifically activate hCAR and to regulate the CYP enzyme expression and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / agonists*
  • Cell Line, Tumor
  • Constitutive Androstane Receptor
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Enzymologic
  • Hepatocytes / metabolism*
  • Humans
  • Molecular Structure
  • Pregnane X Receptor
  • Protein Binding
  • Receptors, Aryl Hydrocarbon / agonists*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Steroid / agonists*
  • Reproducibility of Results
  • Small Molecule Libraries


  • AHR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Constitutive Androstane Receptor
  • Pregnane X Receptor
  • Receptors, Aryl Hydrocarbon
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Small Molecule Libraries
  • Cytochrome P-450 Enzyme System