[h=1]Effect of tauroursodeoxycholicacid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes[/h]
- Christine Benz
,
- Sabine Angermüller[SUP]a[/SUP],
- Ulrich Töx,
- Petra Klöters-Plachky,
- Hans-Dieter Riedel,
- Peter Sauer,
- Wolfgang Stremmel,
- Adolf Stiehl
- Department of Medicine, University of Heidelberg, Germany
- [SUP]a[/SUP] Department of Anatomy and Cell Biology, University of Heidelberg, Germany
- Received 22 April 1997. Revised 1 August 1997. Accepted 6 August 1997. Available online 16 November 2001
[h=2]Abstract[/h]
Background/Aims: In cholestatic liver disease, bile acids may initiate or aggravate hepatocellular damage. Cellular necrosis and cell death may be due to detergent effects of bile acids, but apoptosis may also play a role. In cholestasis, the conditions determining either apoptotic or cytolytic cell death are still unclear. Primary rat hepatocytes in culture represent a suitable model to study bile-acid-induced liver damage.
Methods: Glycochenodeoxycholic acid, a hydrophobic bile acid, was used to induce cell damage. Tauroursodeoxycholicacid, a hydrophilic bile acid, served as substrate to study possible protective effects of such compounds. To study the time and concentration dependency of bile-acid-induced cytolysis and apoptosis, morphologic alterations, hepatocellular enzyme release and nucleosomal DNA fragmentation were evaluated.
Results: Bile-acid-induced cytolysis, as indicated by hepatocellular enzyme release and by morphologic signs of membrane destruction, increased with concentration and time. Addition of tauroursodeoxycholicacid to the incubation medium reduced cytolysis significantly, indicating a direct hepatoprotective effect of this bile acid against the detergent action of hydrophobilic bile acids. In contrast to cytolysis, apoptosis with DNA fragmentation was induced by low concentrations of glycochenodeoxycholic acid a few hours after incubation. Coincubation with tauro-ursodeoxycholic acid in equimolar concentrations significantly reduced apoptosis, indicating another direct hepatoprotective effect of tauroursodeoxycholicacid.
Conclusions: It seems likely that in severe cholestasis, bile-acid-induced injury of hepatocytes is due mainly to cytolysis, whereas in moderately severe cholestasis apoptosis represents the predominant mechanism of bile acid toxicity. Tauroursodeoxycholicacid may reduce both bile-acid-induced apoptosis and cytolysis.
