TY - JOUR T1 - Regulation of Drug Transporter Gene Expression by Nuclear Receptors JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 523 LP - 527 DO - 10.1124/dmd.31.5.523 VL - 31 IS - 5 AU - Jeff L. Staudinger AU - Ajay Madan AU - Kathleen M. Carol AU - Andrew Parkinson Y1 - 2003/05/01 UR - http://dmd.aspetjournals.org/content/31/5/523.abstract N2 - Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are key regulators of xenobiotic-inducible cytochrome P450 gene expression. Whereas much is known about their role in regulating drug metabolism, little is known regarding their role in regulating drug transport in vivo. Wild-type mice and mice lacking PXR (PXR-KO) were used to examine the inducible expression of two drug transporter genes, Oatp2 (Slc21a5) andMrp3 (Abcc3), in liver following treatment with selective PXR and CAR activators. Selective activation of PXR or CAR induced Oatp2 and Mrp3expression in wild-type mice but not in PXR-KO mice. Basal expression levels of Oatp2 and Mrp3 gene were significantly higher in PXR-KO mice when compared with wild-type mice. Additionally, phenobarbital (PB)-inducible Oatp2 andMrp3 gene expression was significantly increased in the PXR-KO mice when compared with wild-type PB-treated mice. We also examined the effect of PXR ablation on PB-inducible hepatic CYP3A activity in vivo. Microsomes isolated from PB-treated PXR-KO mice exhibited a significantly elevated rate of testosterone 6β-hydroxylation when compared with microsomes isolated from wild-type PB-treated mice. PB treatment produced significantly increased levels of hepatomegaly in PXR-KO mice when compared with wild-type PB-treated mice. Taken together, these results suggest that nonliganded PXR plays a net negative role in coregulating shared PXR/CAR-target gene expression in vivo and extend the hypothesis that PXR and CAR coregulate not only drug metabolism but also drug transport. The American Society for Pharmacology and Experimental Therapeutics ER -