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Molecular Pharmacology

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Research ArticleArticle

Activators of the Rat Pregnane X Receptor Differentially Modulate Hepatic and Intestinal Gene Expression

Dylan P. Hartley, Xudong Dai, Yudong D. He, Edward J. Carlini, Bonnie Wang, Su-er W. Huskey, Roger G. Ulrich, Thomas H. Rushmore, Raymond Evers and David C. Evans
Molecular Pharmacology May 2004, 65 (5) 1159-1171; DOI: https://doi.org/10.1124/mol.65.5.1159
Dylan P. Hartley
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Xudong Dai
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Yudong D. He
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Edward J. Carlini
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Bonnie Wang
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Su-er W. Huskey
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Roger G. Ulrich
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Thomas H. Rushmore
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Raymond Evers
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Abstract

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.

  • Received December 10, 2003.
  • Accepted February 18, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (5)
Molecular Pharmacology
Vol. 65, Issue 5
1 May 2004
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Research ArticleArticle

Activators of the Rat Pregnane X Receptor Differentially Modulate Hepatic and Intestinal Gene Expression

Dylan P. Hartley, Xudong Dai, Yudong D. He, Edward J. Carlini, Bonnie Wang, Su-er W. Huskey, Roger G. Ulrich, Thomas H. Rushmore, Raymond Evers and David C. Evans
Molecular Pharmacology May 1, 2004, 65 (5) 1159-1171; DOI: https://doi.org/10.1124/mol.65.5.1159

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Research ArticleArticle

Activators of the Rat Pregnane X Receptor Differentially Modulate Hepatic and Intestinal Gene Expression

Dylan P. Hartley, Xudong Dai, Yudong D. He, Edward J. Carlini, Bonnie Wang, Su-er W. Huskey, Roger G. Ulrich, Thomas H. Rushmore, Raymond Evers and David C. Evans
Molecular Pharmacology May 1, 2004, 65 (5) 1159-1171; DOI: https://doi.org/10.1124/mol.65.5.1159
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