CAR: Discovery and development by the pharmacogenetics laboratory at NIEHS, NIH.

Our studies on the molecular mechanisms of phenobarbital induction of hepatic drug metabolism began in 1995 at the Pharmacogenetics Laboratory, National Institute of Environmental Health Sciences, NIH. Almost all pharmacology textbooks at the time described the phenomenon, but the mechanisms remained unknown. Within a few years, we revealed that the nuclear receptor CAR, constitutive active/androstane receptor, is the key molecule in these mechanisms. Since then, CAR research has branched into various directions. CAR is involved in controlling energy metabolism and has been shown to be an essential factor in promoting hepatocellular carcinoma by phenobarbital. It also functionally and physically interacts with other nuclear receptors and factors in cell signaling pathways, controlling many genes and biological responses. Research into CAR phosphorylation has led to new insights into other nuclear receptors such as PXR, RXRα, RORα, ERα, and AR. In this review, we summarize the evolution of CAR research within our group, describing background information and key findings for us to move to new directions. Furthermore, we will illustrate currently unanswered questions, hoping our discussions will inspire scientists with fresh ideas.