Biological function and mode of action of nuclear xenobiotic receptors

Two related nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), act as xenobiotic sensors that protect the body from a multitude of foreign chemicals (xenobiotics) and play a central role in the metabolism and clearance of steroids and toxic endogenous lipids (endobiotics). A structurally diverse array of chemicals including pharmaceutical drugs, steroids, herbal extracts, and pesticides activate PXR or CAR. This activation results in induction of overlapping, but yet distinct drug clearance pathways consisting of cytochrome P450 enzymes, conjugating enzymes, drug transporters, and other related proteins. Similar pathways are also utilized to protect the body from toxic compounds of endogenous origin. Thus, the xenobiotic regulatory circuit contributes both to drug-drug and food-drug interactions as well as endocrine disruption. Consistent with the notion that xenobiotic receptors regulate drug clearance, single nucleotide polymorphisms (SNPs) in either the receptors themselves or receptor-binding sites in the regulatory region of genes encoding metabolic enzymes appear to contribute to the polymorphic expression of components of drug clearance pathways. Together, the xenobiotic receptors PXR and CAR confer metabolic immunity via the ability to control an integrated array of target genes.