Abstract
Phenobarbital (PB) was the first therapeutic drug to be characterized for its induction of hepatic drug metabolism (Remmer and Merker, 1963). Essentially at the same time, cytochrome P450 (CYP), an enzyme that metabolizes drugs, was discovered (Omura and Sato, 1962). After nearly 50 years of investigations, the molecular target of PB induction has now been delineated to phosphorylation at threonine 38 of nuclear receptor, constituitive androstane receptor (CAR) (NR1I3) (Mutoh et al., 2009), 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 our works and accomplishment of my laboratory at National Institute of Environmental Health Sciences, NIH, and the future research directions of where our study of CAR might take us.
- The American Society for Pharmacology and Experimental Therapeutics