Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Trauner, M; Arrese, M; Soroka, CJ; Ananthanarayanan, M; Koeppel, TA; Schlosser, SF; Suchy, FJ; Keppler, D; Boyer, JL.
The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis.
Gastroenterology. 1997; 113(1):255-264
Doi: 10.1016/S0016-5085(97)70103-3
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- Führende Autor*innen der Med Uni Graz
- Trauner Michael
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- Abstract:
- 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 multi-drug resistance protein (Mrp2). Mrp2 function is impaired in various experimental models of intrahepatic and obstructive cholestasis, but the underlying molecular mechanisms ave 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.
- Find related publications in this database (using NLM MeSH Indexing)
- ATP-Binding Cassette Transporters - drug effects ATP-Binding Cassette Transporters - metabolism
- Animals -
- Bile Canaliculi - metabolism
- Blotting, Northern -
- Blotting, Western -
- Cholestasis - etiology Cholestasis - metabolism
- Cholestasis, Intrahepatic - etiology Cholestasis, Intrahepatic - metabolism
- Common Bile Duct - surgery
- Down-Regulation - drug effects
- Drug Resistance, Multiple -
- Ethinyl Estradiol -
- Fluorescent Antibody Technique, Indirect -
- Gene Expression Regulation -
- Lipopolysaccharides -
- Male -
- Multidrug Resistance-Associated Proteins -
- RNA, Messenger - genetics
- Rats -
- Rats, Sprague-Dawley -