EFFECT OF TAUROURSODEOXYCHOLIC ACID ON BILE-ACID-INDUCED APOPTOSIS AND CYTOLYSIS IN RAT HEPATOCYTES

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 apoptot ic 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, Tauroursodeoxycholic acid, a hydrophi lic bile acid, served as substrate to study possible protective effect s of such compounds, To study the time and concentration dependency of bile-acid-induced cytolysis and apoptosis, morphologic alterations, h epatocellular enzyme release and nucleosomal DNA fragmentation were ev aluated, Results: Bile-acid-induced cytolysis, as indicated by hepatoc ellular enzyme release and by morphologic signs of membrane destructio n, increased with concentration and time, Addition of tauroursodeoxych olic acid to the incubation medium reduced cytolysis significantly, in dicating a direct hepatoprotective effect of this bile acid against th e detergent action of hydrophobic bile acids, In contrast to cytolysis , apoptosis with DNA fragmentation was induced by low concentrations o f glycochenodeoxycholic acid a few hours after incubation, Coincubatio n with tauroursodeoxycholic acid in equimolar concentrations significa ntly reduced apoptosis, indicating another direct hepatoprotective eff ect of tauroursodeoxycholic acid. Conclusions: It seems likely that in severe cholestasis, bile-acid-induced injury of hepatocytes is due ma inly to cytolysis, whereas in moderately severe cholestasis apoptosis represents the predominant mechanism of bile acid toxicity, Tauroursod eoxycholic acid may reduce both bile-acid-induced apoptosis and cytoly sis.