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Received for publication December 14, 2005.
Revised January 18, 2006.
Accepted for publication January 23, 2006.
The organic cation transporter 1 (OCT1) mediates the hepatocellular uptake of cationic drugs and endobiotics from sinusoidal blood. The uptake rates of these compounds may depend on OCT1 expression level. As little is known about the regulation of the human OCT1 (hOCT1) gene, we characterized the hOCT1 promoter with respect to DNA response elements and their binding factors. By computer analysis we identified two adjacent putative DNA response elements for the liver-enriched homodimeric nuclear receptor HNF-4
in the hOCT1 promoter. Each element is of the DR-2 format, containing directly repeated hexamers separated by two bases. In electrophoretic mobility shift assays both elements directly interacted with HNF-4. A luciferase reporter construct containing the hOCT1 promoter was strongly activated by HNF-4 in transiently transfected Huh7 cells. Site-directed mutagenesis of either DR-2 element alone, or in combination, severely decreased the HNF-4-mediated activation of the hOCT1 promoter, indicating that both elements are functionally important. As HNF-4 is a known target for bile acid-mediated suppression of transcription, we studied whether chenodeoxycholic acid (CDCA) suppresses hOCT1 gene expression by inhibiting HNF-4-mediated transactivation. Treatment of cells with CDCA could indeed suppress the activation of the endogenous hOCT1 gene by HNF-4. Additionally, bile acid-inducible transcriptional repressor, small heterodimer partner (SHP), inhibited activation of the reporter-linked hOCT1 promoter and of the endogenous hOCT1 gene by HNF-4. In conclusion, the hOCT1 gene, encoding an important drug transporter in the human liver, is activated by HNF-4 and suppressed by bile acids via SHP.
Key words:
bile acids, drug transporters, hepatocyte nuclear factors, nuclear receptors, organic cation transporters, transcriptional regulation
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