PMID: 11901222Mar 20, 2002Paper

Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16alpha-carbonitrile is via interaction with pregnane X receptor

Molecular Pharmacology
Grace L GuoCurtis D Klaassen

Abstract

The rat organic anion transporting polypeptide 2 (oatp2; Slc21a5) is a liver transporter that mediates the uptake of a variety of structurally diverse compounds, and has a high affinity for cardiac glycosides. Treatment of rats with pregnenolone-16alpha-carbonitrile (PCN), a ligand for the rodent pregnane X receptor (PXR), significantly enhances the rat oatp2 gene expression. To understand the molecular mechanism of oatp2 induction by PCN, rat oatp2 gene was cloned. The rat oatp2 gene consists of 16 exons; alternative splicing of the second noncoding exon gives rise to the two published rat oatp2 cDNAs. Approximately 8700 base pairs (bp) of the 5'-flanking region of the rat oatp2 gene were linked to the luciferase reporter gene and used in transient transfection assays in H4IIE cells. Treatment of PCN induced the expression of the reporter gene in a dose-dependent manner. Four potential PXR response elements (PXREs) were identified in the 5'-flanking region of the rat oatp2 gene. One element (DR3-1) is located approximately -5000 bp with three more (DR3-2, DR3-3, and DR3-4) clustered at about -8000 bp. Results from electrophoretic mobility shift assays showed that the PXR-retinoid X receptor alpha heterodimer binds to the DR3-2...Continue Reading

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