inhibition of bilesaltinduced hepatocyte apoptosis by the antioxidant lazaroid u83836e intracellular retention of toxic bile salts contributes to hepatocellular injury during cholestasis we have recently demonstrated that toxic bile salts directly induce apoptosis in hepatocytes as oxidative stress has been implicated in many models of apoptosis our aim was to determine if oxidative injury is a critical event during bilesaltinduced hepatocyte apoptosis cultured rat hepatocytes incubated with 50 microm glycochenodeoxycholate gcdc exhibited the characteristic morphological features of apoptosis such as nuclear fragmentation and cellular fragmentation into organellecontaining membranebound apoptotic bodies after a 3hr incubation apoptosis was observed in 60 8 of cells compared to 1 in controls gcdcinduced apoptosis was associated with lipid peroxidation as demonstrated by an increase in 8isoprostane release the antioxidant lazaroid u83836e inhibited 8isoprostane generation during gcdcinduced hepatocye apoptosis in addition u83836e also reduced gcdcmediated apoptosis by 70 as assessed using both stringent morpholgic nuclear fragmentation and biochemical determination of dna strand breaks criteria in summary during treatment of hepatocytes with gcdc 1 apoptosis is associated with lipid peroxidation and 2 the antioxidant lazaroid u83836e inhibits both lipid peroxidation and apoptosis in conclusion these data suggest that oxidative stress contributes to bilesaltinduced apoptosis we speculate that antioxidants may be useful in ameliorating liver injury during chronic cholestasis