Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor

Identification and characterization of the pregnane X receptor (PXR) as a k ey regulator of cytochrome P450 3A (CYP3A) gene expression has led to an in creased understanding of the molecular basis of many drug-drug interactions . Mice lacking PXR (PXR-KO) were used in the present study to delineate the role of PXR in regulating hepatomegaly and regulating the activity of CYP3 A, organic anion transporting polypeptide-2 (Oatp2), and Cyp7a1 (cholestero l 7 alpha -hydroxylase) gene products in vivo. Pregnenolone-16 alpha -carbo nitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PX R-KO mice. PCN increased both the number of proliferating cell nuclear anti gen immuno-positive nuclei and apparent cell size in the wild-type mice but not in the PXR-KO mice. To determine the role PXR plays in regulating CYP3 A activity, 6 beta -hydroxylation of testosterone and the duration of the l oss of righting reflex following administration of the muscle-relaxant zoxa zolamine were measured. PCN increased the level of testosterone 6 beta -hyd roxylation and decreased the duration of the loss of righting-reflex time f ollowing zoxazolamine administration in wildtype mice, but did not effect e ither of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [H-3]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-K O mice. Similarly, PCN decreased bile acid excretion in wild-type mice but not in the PXR-KO mice. Taken together, these data demonstrate a pivotal ro le for PXR in the regulation of drug-induced hepatomegaly and in the metabo lism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xe nobiotics and bile acids in vivo.