Down‐regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

• Published in: Hepatology (Baltimore, Md.) Vol. 39; no. 5; pp. 1382 - 1389
• Main Authors: Denk, Gerald U., Soroka, Carol J., Mennone, Albert, Koepsell, Hermann, Beuers, Ulrich, Boyer, James L.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2004; Wiley
• Subjects: Animals; Bile Ducts; Biological and medical sciences; Blotting, Western; Carbon Radioisotopes; Cholestasis, Extrahepatic - metabolism; Down-Regulation; Fluorescent Antibody Technique; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Ligation; Liver - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Organic Anion Transport Protein 1 - genetics; Organic Anion Transport Protein 1 - metabolism; Other diseases. Semiology; Potassium Channel Blockers - pharmacokinetics; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Tetraethylammonium - pharmacokinetics; Organic cation; Rat; Liver; Rodentia; Biliary tract disease; Vertebrata; Regulation(control); Mammalia; Animal; Cholostasis; Gastroenterology; Digestive diseases; Regulation
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.20176

The liver plays a major role in biotransformation and elimination of various therapeutic agents and xenobiotics, many of which are organic cations and substrates of the organic cation transporter 1 (Oct1, Slc22a1). Oct1 is expressed at the basolateral membranes of hepatocytes and proximal renal tubules. Although Oct1 is the major uptake mechanism in hepatocytes for many pharmaceutical compounds, little is known about the effects of liver injury on this process. Our aim was to investigate the effects of obstructive cholestasis on Oct1 expression and function in liver and kidney. The effects of bile duct ligation (BDL) on Oct1 protein, messenger RNA (mRNA) expression, and tissue localization were determined in rat liver and kidney with Western analysis, real‐time reverse transcriptase‐mediated polymerase chain reaction (RT‐PCR), and immunofluorescence. To assess Oct1 function, the model substrate tetraethylammonium ([14C]TEA) was administered intravenously to BDL and control rats and distribution of radioactivity was determined. Oct1 protein significantly decreased in cholestatic livers to 42.1 ± 17.7% (P < .001), 15.5 ± 4.7% (P < .05), and 8.6 ± 2.7% (P < .05) of controls after 3, 7, and 14 days, respectively, but not in kidneys. Hepatic Oct1 mRNA decreased to 77.2 ± 12.7%, 40.7 ± 8.1% (P < .05), and 50.3 ± 7.5% (P < .05) 3, 7, and 14 days after BDL, respectively. Tissue immunofluorescence corroborated these data. Hepatic accumulation of [14C]TEA in 14‐day BDL rats was reduced to 29.6 ± 10.9% of controls (P < .0005). In conclusion, obstructive cholestasis down‐regulates Oct1 and impairs Oct1‐mediated uptake in rat liver, suggesting that hepatic uptake of small cationic drugs may be impaired in cholestatic liver injury. (HEPATOLOGY 2004;39:1382–1389.)