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Vol. 61, Issue 4, 832-839, April 2002
-carbonitrile Is via Interaction with Pregnane X
Receptor
Department of Pharmacology, Toxicology, and Therapeutics,
University of Kansas Medical Center, Kansas City, Kansas
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-16
-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
heterodimer binds to the DR3-2 with the highest affinity, to
the DR3-4 and DR3-1 with a lower affinity, and weakly or not at all to
the DR3-3. Furthermore, a series of partial deletions of the
5'-flanking region illustrated that both the proximal and distal
clusters of PXREs are required for maximal induction of rat oatp2 by
PCN. In conclusion, these data elucidate the molecular mechanism by
which PCN treatment induces rat oatp2 gene expression. In addition,
this study identifies rat oatp2 as a direct PXR-targeted gene and
further supports the hypothesis that activation of PXR affects a
network of genes that is involved in either metabolism or transport of
drugs, steroids, and bile acids.
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