Sulfasalazine reduces bile acid induced apoptosis in human hepatoma cells and perfused rat livers.

Rust, Christian; Bauchmüller, Kris Benjamin; Berndt, C.; Vennegerts, Timo; Fickert, P.; Fuchsbichler, A. and Beuers, Ulrich (2005): Sulfasalazine reduces bile acid induced apoptosis in human hepatoma cells and perfused rat livers. In: Gut, Vol. 55, No. 5: pp. 719-727

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.

• Item Type: Journal article
• Form of publication: Publisher's Version
• Keywords: Bile secretion, cholestasis, cell signaling, death receptor, liver disease.
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• Alliance/National Licence: This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
• Language: English