Abstract
Background: Bile acid-induced apoptosis in hepatocytes can be antagonized by NF-κBdependent survival pathways. Sulfasalazine modulates NF-κB in different cell types. We aimed to determine the effects of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid (5-ASA) on bile acid-induced apoptosis in hepatocytes. Methods: Apoptosis was determined by caspase assays and immunoblotting, NF-κB activation by EMSA and reporter gene assays, generation of reactive oxygen species (ROS) fluorometrically, bile secretion gravimetrically and bile acid uptake radiochemically and by gaschromatography in HepG2-Ntcp cells and isolated perfused rat livers. Results: Glycochenodeoxycholic acid (GCDCA, 75μmol/L)-induced apoptosis was reduced by sulfasalazine dose-dependently (1-1000 μmol/L) in HepG2-Ntcp cells, whereas its metabolites 5- ASA and sulfapyridine had no effect. Sulfasalazine significantly reduced GCDCA-induced activation of caspases 9 and 3. In addition, sulfasalazine activated NF-κB, and decreased GCDCA-induced generation of ROS. Bile acid uptake was competetively inhibited by sulfasalazine. In perfused rat livers, GCDCA (25 μmol/L)-induced liver injury and extensive hepatocyte apoptosis were significantly reduced by simultaneous administration of 100 μmol/L sulfasalazine: LDH and GPT activities were reduced by 82% and 87%, respectively, and apoptotic hepatocytes were observed only occasionally. GCDCA uptake was reduced by 45±5% when sulfasalazine was coadministered. However, when 50% of GCDCA (12.5 μmol/L) were administered alone, marked hepatocyte apoptosis and liver injury were again observed questioning the impact of reduced GCDCA uptake for the antiapoptotic effect of sulfasalazine. Conclusion: Sulfasalazine is a potent inhibitor of GCDCA-induced hepatocyte apoptosis in vitro and in the intact liver.
Dokumententyp: | Zeitschriftenartikel |
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Publikationsform: | Publisher's Version |
Keywords: | Bile secretion, cholestasis, cell signaling, death receptor, liver disease. |
Fakultät: | Medizin |
Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
URN: | urn:nbn:de:bvb:19-epub-15872-2 |
Allianz-/Nationallizenz: | Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich. |
Sprache: | Englisch |
Dokumenten ID: | 15872 |
Datum der Veröffentlichung auf Open Access LMU: | 10. Jul. 2013, 13:52 |
Letzte Änderungen: | 04. Nov. 2020, 12:57 |