A Nuclear Receptor-Mediated Xenobiotic Response and Its Implication in Drug Metabolism and Host Protection

J.      Sonoda; J.   M.   Rosenfeld; L.      Xu; R.   M.   Evans; W.      Xie

doi:10.2174/1389200033336739

Abstract

Regulation of the Phase I CYP enzymes and Phase II conjugating enzymes is implicated in both drug metabolism and drug-drug interactions. Moreover, the elimination of numerous xenobiotic and endobiotic toxic chemicals also requires a concerted function of Phase I and II enzymes, as well as the membrane spanning drug transporters. The genes that encode these enzymes and transporters are inducible by numerous xenobiotics, yet the inducibility shows clear species specificity. In the last 3-4 years, orphan nuclear receptors (NRs) such as PXR, CAR, and FXR have been established as species-specific xeno-sensors that regulate the expression of Phase I and II enzymes, as well as selected drug transporters. This transcriptional regulation is achieved by binding of these xenobiotic receptors to the NR response elements found within the promoter regions of target genes. The identification of NRs as xenosensors represents a major step forward in understanding the genetic mechanisms controlling the expression of drug metabolizing enzymes. The establishment of NR-mediated and mechanism-guided xenobiotic screening systems by using cultured cells or genetically engineered mouse models has not only advanced our understanding of the molecular complexity of this drug-induced xenobiotic response, but has also provided in vitro and in vivo platforms to facilitate the development of safer drugs.

Keywords: xenobiotic response, drug metabolism, nuclear receptors, nrs, pxr, car, fxr, phase I cyp enzymes