RT Journal Article SR Electronic T1 Activators of the Rat Pregnane X Receptor Differentially Modulate Hepatic and Intestinal Gene Expression JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1159 OP 1171 DO 10.1124/mol.65.5.1159 VO 65 IS 5 A1 Dylan P. Hartley A1 Xudong Dai A1 Yudong D. He A1 Edward J. Carlini A1 Bonnie Wang A1 Su-er W. Huskey A1 Roger G. Ulrich A1 Thomas H. Rushmore A1 Raymond Evers A1 David C. Evans YR 2004 UL http://molpharm.aspetjournals.org/content/65/5/1159.abstract AB Ligand-mediated activation of the pregnane X receptor (PXR, NR1I2) is postulated to affect both hepatic and intestinal gene expression, because of the presence of this nuclear receptor in these important drug metabolizing organs; as such, activation of this receptor may elicit the coordinated regulation of PXR target genes in both tissues. Induction of hepatic and intestinal drug metabolism can contribute to the increased metabolism of drugs, and can result in adverse or undesirable drug-drug interactions. 2(S)-((3,5-bis(Trifluoromethyl)benzyl)-oxy)-3(S)phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (L-742694) is a potent activator of the rat PXR and was characterized for its effects on hepatic and intestinal gene expression in female Sprague-Dawley rats by DNA microarray analysis. Transcriptional profiling in liver and small intestine revealed that L-742694 and dexamethasone (DEX) induced the prototypical battery of PXR target genes in liver, including CYP3A, Oatp2, and UGT1A1. In addition, both DEX and L-742694 induced common gene expression profiles that were specific to liver or small intestine, but there was a distinct lack of coordinated gene expression of genes common to both tissues. This pattern of gene regulation occurred in liver and small intestine independent of PXR, constitutive androstane receptor, or hepatic nuclear factor-4α expression, suggesting that other factors are involved in controlling the extent of coordinated gene expression in response to a PXR agonist. Overall, these results suggest that ligand-mediated activation of PXR and induction of hepatic, rather than small intestinal, drug metabolism genes would contribute to the increased metabolism of orally administered pharmaceuticals.