RT Journal Article
SR Electronic
T1 The Human Organic Cation Transporter-1 Gene Is Transactivated by Hepatocyte Nuclear Factor-4α
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 778
OP 785
DO 10.1124/jpet.105.099929
VO 317
IS 2
A1 Michael Saborowski
A1 Gerd A. Kullak-Ublick
A1 Jyrki J. Eloranta
YR 2006
UL http://jpet.aspetjournals.org/content/317/2/778.abstract
AB 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. Because 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 hepatocyte nuclear factor-4α (HNF-4α) in the hOCT1 promoter. Each element is of the direct repeat (DR)-2 format, containing directly repeated hexamers separated by two bases. In electrophoretic mobility shift assays, both elements directly interacted with HNF-4α. A luciferase reporter construct containing the hOCT1 promoter was strongly activated by HNF-4α in transiently transfected Huh7 cells. Site-directed mutagenesis of either DR-2 element alone or in combination severely decreased the HNF-4α-mediated activation of the hOCT1 promoter, indicating that both elements are functionally important. Because HNF-4α is a known target for bile acid-mediated suppression of transcription, we studied whether chenodeoxycholic acid (CDCA) suppresses hOCT1 gene expression by inhibiting HNF-4α-mediated transactivation. Treatment of cells with CDCA could indeed suppress the activation of the endogenous hOCT1 gene by HNF-4α. In addition, 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-4α. In conclusion, the hOCT1 gene, encoding an important drug transporter in the human liver, is activated by HNF-4α and suppressed by bile acids via SHP. The American Society for Pharmacology and Experimental Therapeutics