Molecular mechanisms of drug transporter regulation.

Interindividual differences in drug transporter expression can result in variability in drug response. This variation in gene expression is determined, in part, by the actions of nuclear hormone receptors that act as xenobiotic- and endobiotic-sensing transcription factors. Among the ligand-activated nuclear receptors, signaling through the pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and vitamin D receptor (VDR) constitute major pathways regulating drug transporter expression in tissues. Hence, these endobiotic- and xenobiotic-sensing nuclear receptors are intrinsically involved in environmental influences of drug response. Moreover, because nuclear receptor genes are polymorphic, these transcription factors are also thought to contribute to heritability of variable drug action. In this chapter, the molecular aspects of drug transporter gene regulation by ligand-activated nuclear receptors will be reviewed including their clinical relevance.