Induction of Drug Metabolism: Role for Nuclear Receptors

Xenobiotics regulate the transcription of many genes in the liver, intestine, kidney and other organs to alter their own metabolism and excretion. The barbiturate phenobarbital (PB)isoneofthebest studied examples of a drug that potently induces cytochrome P450s (CYPs) and other genes in the liver. The mechanisms that control the induction of detoxifying genes and the receptors recognizing those have remained elusive for many years. This changed in 1998 when the pregnane X receptor [PXR, alternatively called pregnane activated receptor (PAR) or steroid and xenobiotic receptor (SXR); NR1I2] and the constitutive androstane receptor (CAR, alternatively called constitutive active receptor; NR1I3) were discovered to play a role in xenobiotic mediated induction of CYPs. It turned out that PXR and CAR could accommodate all the conundrums associated with induction of CYPs by xenobiotics. First, due to an unusually flexible ligand-binding domain (LBD), PXR and CAR are promiscuous towards many structurally diverse compounds. Second, as heterodimers with the retinoid X receptor (RXR; NR2B1, 2 and 3), PXR and CAR are able to bind to different DNA-binding elements and thus directly activate many genes involved in drug detoxification and excretion. Third, the LBDs of PXR and CAR orthologs are unusually divergent between species, and therefore are activated by different chemicals in a very species-specific manner. A number of review articles provide an up-to-date description of the basic functions of PXR and CAR. This chapter is focused on the recent advances in the characterization of PXR and CAR. In particular, it highlights the novel findings about endogenous functions and their clinical implications