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 evok e 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. Mo st importantly, a nuclear orphan receptor, the constitutive androstane rece ptor has been identified as a primary determinant of the transcriptional ac tivation of CYP genes in response to phenobarbital-like inducers in mammals . Another nuclear receptor, the pregnane X receptor can also mediate some o f the phenobarbital response, but the functional overlap of the two inducti ve pathways is only partial. The response of mammalian CYP2B genes to pheno barbital was abolished in the liver of mice carrying a null allele of the c onstitutive androstane receptor gene, whereas that of CYP3A genes was lost in pregnane X receptor knock-out mice.