Phenobarbital response elements of cytochrome P450 genes and nuclear receptors

Annu Rev Pharmacol Toxicol. 2001;41:123-43. doi: 10.1146/annurev.pharmtox.41.1.123.


Phenobarbital (PB) response elements are composed of various nuclear receptor (NR)-binding sites. A 51-bp distal element PB-responsive enhancer module (PBREM) conserved in the PB-inducible CYP2B genes contains two NR-binding direct repeat (DR)-4 motifs. Responding to PB exposure in liver, the NR constitutive active receptor (CAR) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates PBREM via binding to DR-4 motifs. For CYP3A genes, a common NR site [DR-3 or everted repeat (ER)-6] is present in proximal promoter regions. In addition, the distal element called the xenobiotic responsive module (XREM) is found in human CYP3A4 genes, which contain both DR-3 and ER-6 motifs. Pregnane X receptor (PXR) could bind to all of these sites and, upon PB induction, a PXR:RXR heterodimer could transactivate XREM. These response elements and NRs are functionally versatile, and capable of responding to distinct but overlapping groups of xenochemicals.

Publication types

  • Review

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / genetics*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Hypnotics and Sedatives / pharmacology*
  • Phenobarbital / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Response Elements / drug effects*


  • Hypnotics and Sedatives
  • Receptors, Cytoplasmic and Nuclear
  • Cytochrome P-450 Enzyme System
  • Phenobarbital