Regulation of gene expression by CAR: an update

Arch Toxicol. 2015 Jul;89(7):1045-55. doi: 10.1007/s00204-015-1522-9. Epub 2015 May 16.


The constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, is a well-known xenosensor that regulates hepatic drug metabolism and detoxification. CAR activation can be elicited by a large variety of xenobiotics, including phenobarbital (PB) which is not a directly binding CAR ligand. The mechanism of CAR activation is complex and involves translocation from the cytoplasm into the nucleus, followed by further activation steps in the nucleus. Recently, epidermal growth factor receptor (EGFR) has been identified as a PB-responsive receptor, and PB activates CAR by inhibiting the EGFR signaling. In addition to regulation of drug metabolism, activation of CAR has multiple biological end points such as modulation of xenobiotic-elicited liver injury, and the role of CAR in endobiotic functions such as glucose metabolism and cholesterol homeostasis is increasingly recognized. Thus, investigations on the molecular mechanism of CAR activation are critical for the real understanding of CAR-mediated processes. Here, we summarize the current understanding of mechanisms by which CAR activators regulate gene expression through cellular signaling pathways and the roles of CAR on xenobiotic-elicited hepatocellular carcinoma, liver injury, glucose metabolism and cholesterol homeostasis.

Publication types

  • Review

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Biotransformation
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cholesterol / metabolism
  • Constitutive Androstane Receptor
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism
  • Gene Expression Regulation / drug effects*
  • Glucose / metabolism
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Phenobarbital / toxicity
  • Receptor Cross-Talk
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects
  • Xenobiotics / toxicity*


  • Constitutive Androstane Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Xenobiotics
  • Cholesterol
  • ErbB Receptors
  • Glucose
  • Phenobarbital