The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis
| Autor: | Carol J. Soroka, James L. Boyer, Meenakshisundaram Ananthanarayanan, Marco Arrese, Frederick J. Suchy, Dietrich Keppler, Thomas A. Koeppel, Stephan F. Schlosser, Michael Trauner |
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| Rok vydání: | 1997 |
| Předmět: |
Lipopolysaccharides
Male medicine.medical_specialty Blotting Western Down-Regulation Cholestasis Intrahepatic Biology Ethinyl Estradiol Excretion Rats Sprague-Dawley Cholestasis Internal medicine medicine Animals Northern blot RNA Messenger Fluorescent Antibody Technique Indirect Common Bile Duct Messenger RNA Hepatology Multidrug resistance-associated protein 2 Bile Canaliculi Gastroenterology medicine.disease Blotting Northern Drug Resistance Multiple Rats Blot Endocrinology Gene Expression Regulation Biliary tract Triphosphatase ATP-Binding Cassette Transporters Multidrug Resistance-Associated Proteins |
| Zdroj: | Gastroenterology. 113(1) |
| ISSN: | 0016-5085 |
| Popis: | BACKGROUND & AIMS: The excretion of various organic anions into bile is mediated by an adenosine triphosphate-dependent conjugate export pump, which has been identified as the canalicular isoform of the multidrug resistance protein (Mrp2). Mrp2 function is impaired in various experimental models of intrahepatic and obstructive cholestasis, but the underlying molecular mechanisms are unclear. The aim of this study was to investigate these molecular mechanisms. METHODS: The effects of endotoxin, ethinylestradiol, and common bile duct ligation (CBDL) on Mrp2 protein, messenger RNA (mRNA) expression, and Mrp2 tissue localization were determined in rat livers by Northern blotting, Western analysis, and tissue immunofluorescence. To assess whether changes were specific for Mrp2, we also examined the expression of canalicular ecto-adenosine triphosphatase (ecto-ATPase) and mdr P- glycoproteins (P-gp). RESULTS: All three cholestatic models resulted in a marked decrease in Mrp2 protein (P < 0.01) and its tissue localization at the canalicular membrane. Mrp2 mRNA levels diminished profoundly after endotoxin (P < 0.0005) and CBDL (P < 0.05), but did not change after ethinylestradiol. In contrast to Mrp2, protein expression of ecto-ATPase and P-gp remained unchanged in endotoxin- and ethinylestradiol-treated animals, whereas P-gp levels increased after CBDL (P < 0.05). CONCLUSIONS: Down-regulation of Mrp2 expression may explain impaired biliary excretion of amphiphilic anionic conjugates in these models of cholestasis. (Gastroenterology 1997 Jul;113(1):255-64) |
| Databáze: | OpenAIRE |
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