PMID- 16436500
OWN - NLM
STAT- MEDLINE
DCOM- 20060609
LR  - 20081121
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 317
IP  - 2
DP  - 2006 May
TI  - The human organic cation transporter-1 gene is transactivated by hepatocyte 
      nuclear factor-4alpha.
PG  - 778-85
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-4alpha 
      (HNF-4alpha) 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-4alpha. A luciferase reporter construct containing the hOCT1 promoter was 
      strongly activated by HNF-4alpha in transiently transfected Huh7 cells. 
      Site-directed mutagenesis of either DR-2 element alone or in combination severely 
      decreased the HNF-4alpha-mediated activation of the hOCT1 promoter, indicating 
      that both elements are functionally important. Because HNF-4alpha is a known 
      target for bile acid-mediated suppression of transcription, we studied whether 
      chenodeoxycholic acid (CDCA) suppresses hOCT1 gene expression by inhibiting 
      HNF-4alpha-mediated transactivation. Treatment of cells with CDCA could indeed 
      suppress the activation of the endogenous hOCT1 gene by HNF-4alpha. 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-4alpha. In conclusion, the hOCT1 gene, encoding an important 
      drug transporter in the human liver, is activated by HNF-4alpha and suppressed by 
      bile acids via SHP.
FAU - Saborowski, Michael
AU  - Saborowski M
AD  - Division of Gastroenterology and Hepatology, University Hospital Zurich, 
      Ramistrasse 100, CH-8091 Zurich, Switzerland. jyrki.eloranta@usz.ch.
FAU - Kullak-Ublick, Gerd A
AU  - Kullak-Ublick GA
FAU - Eloranta, Jyrki J
AU  - Eloranta JJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060125
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Bile Acids and Salts)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Organic Cation Transporter 1)
SB  - IM
MH  - Base Sequence
MH  - Bile Acids and Salts/physiology
MH  - Cell Line, Tumor
MH  - Hepatocyte Nuclear Factor 4/*physiology
MH  - Hepatocytes/*metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - Organic Cation Transporter 1/*genetics
MH  - Promoter Regions, Genetic
MH  - Response Elements
MH  - Transcriptional Activation/*physiology
EDAT- 2006/01/27 09:00
MHDA- 2006/06/10 09:00
CRDT- 2006/01/27 09:00
PHST- 2006/01/27 09:00 [pubmed]
PHST- 2006/06/10 09:00 [medline]
PHST- 2006/01/27 09:00 [entrez]
AID - jpet.105.099929 [pii]
AID - 10.1124/jpet.105.099929 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2006 May;317(2):778-85. doi: 10.1124/jpet.105.099929. Epub 
      2006 Jan 25.