Gene induction by Phenobarbital: an update on an old question that receives key novel answers.
Phenobarbital has long been used as a sedative and antiepileptic drug. The drug is the representative of a myriad of lipophilic molecules able to evoke a pleiotropic response in the liver and also in prokaryotes and flies. A great deal of novel information has been obtained in recent years regarding the mechanism of cytochrome P450 (CYP) gene induction by phenobarbital. Most importantly, a nuclear orphan receptor, the constitutive androstane receptor has been identified as a primary determinant of the transcriptional activation of CYP genes in response to phenobarbital-like inducers in mammals. Another nuclear receptor, the pregnane X receptor can also mediate some of the phenobarbital response, but the functional overlap of the two inductive pathways is only partial. The response of mammalian CYP2B genes to phenobarbital was abolished in the liver of mice carrying a null allele of the constitutive androstane receptor gene, whereas that of CYP3A genes was lost in pregnane X receptor knock-out mice.
Corcos
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Inserm U517, Faculty of Medicine, 7, Bd. Jeanne d'Arc, F-21033 Dijon Cedex, France. laurent.corcos@u-borgogne.fr
Lagadic-Gossmann
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D000731:Androstanes / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004247:DNA; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010634:Phenobarbital / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015533:Transcriptional Activation
D000731:Androstanes; D006993:Hypnotics and Sedatives; D018160:Receptors, Cytoplasmic and Nuclear; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D011494:Protein Kinases; D010634:Phenobarbital