Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.
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.
Sueyoshi
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Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Negishi
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D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D020218:Response Elements / Q000187:drug effects*
D006993:Hypnotics and Sedatives; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital