PT  - JOURNAL ARTICLE
AU  - Jeff Staudinger
AU  - Yaping Liu
AU  - Ajay Madan
AU  - Sultan Habeebu
AU  - Curtis D. Klaassen
TI  - Coordinate Regulation of Xenobiotic and Bile Acid Homeostasis by Pregnane X Receptor
DP  - 2001 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1467--1472
VI  - 29
IP  - 11
4099  - http://dmd.aspetjournals.org/content/29/11/1467.short
4100  - http://dmd.aspetjournals.org/content/29/11/1467.full
SO  - Drug Metab Dispos2001 Nov 01; 29
AB  - Identification and characterization of the pregnane X receptor (PXR) as a key regulator of cytochrome P450 3A (CYP3A) gene expression has led to an increased 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 CYP3A, organic anion transporting polypeptide-2 (Oatp2), andCyp7a1 (cholesterol 7α-hydroxylase) gene products in vivo. Pregnenolone-16α-carbonitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PXR-KO mice. PCN increased both the number of proliferating cell nuclear antigen 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 CYP3A activity, 6β-hydroxylation of testosterone and the duration of the loss of righting reflex following administration of the muscle-relaxant zoxazolamine were measured. PCN increased the level of testosterone 6β-hydroxylation and decreased the duration of the loss of righting-reflex time following zoxazolamine administration in wild-type mice, but did not effect either of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [3H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO 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 role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo. The American Society for Pharmacology and Experimental Therapeutics