title: Phenobarbital Meets Phosphorylation of Nuclear Receptors.
abstract: Phenobarbital was the first therapeutic drug to be characterized for its induction of hepatic drug metabolism. Essentially at the same time, cytochrome P450, an enzyme that metabolizes drugs, was discovered. After nearly 50 years of investigation, the molecular target of phenobarbital induction has now been delineated to phosphorylation at threonine 38 of the constitutive androstane receptor (NR1I3), a member of the nuclear receptor superfamily. Determining this mechanism has provided us with the molecular basis to understand drug induction of drug metabolism and disposition. Threonine 38 is conserved as a phosphorylation motif in the majority of both mouse and human nuclear receptors, providing us with an opportunity to integrate diverse functions of nuclear receptors. Here, I review the works and accomplishments of my laboratory at the National Institutes of Health National Institute of Environmental Health Sciences and the future research directions of where our study of the constitutive androstane receptor might take us.
authors.affiliation: Pharmacogenetics, Reproductive and Developmental Biology, National Institutes of Health National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina negishi@niehs.nih.gov.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D010634:Phenobarbital / Q000494:pharmacology*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism
chemical_list: D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D013912:Threonine; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital