The influence of the hydrophobic-hydrophilic properties of bile salts (BS) on acute ethanol hepatotoxicity was investigated. Bile flow, biliary BS secretion and enzyme (LDH,AST) release in the perfusate were measured before and after exposure to low (0.1%) or high (1%) doses of ethanol in in vitro isolated livers perfused with 1 microM/min taurocholate (TCA), tauroursodeoxycholate (TUDCA) or taurodeoxycholate (TDCA). Ethanol promotes a rapid decrease of basal bile flow and BS secretion in TCA-perfused livers [-28% of basal values with 0.1% (N = 6), and -35% with 1% ethanol (N = 6)]. Bile flow and BS secretion were minimally decreased by ethanol in livers perfused with a hydrophilic BS (TUDCA) [-8% decrease of basal values with 0.1% ethanol (N = 6), and -10% with 1% ethanol (N = 9); p < 0.02 vs TCA-perfused livers]. In contrast, when livers were perfused with a hydrophobic BS (TDCA), ethanol showed a higher cholestatic effect than either TCA- or TUDCA-perfused livers. Enzyme release in the perfusate was not modified by 0.1% ethanol, while 1% ethanol promoted a 4-5 fold increase in LDH and AST release in the perfusate of TCA-perfused livers with respect to a mere 2-fold increase in TUDCA-perfused livers and a 6-7 fold increase in TDCA perfused livers (p < 0.03). In conclusion, we showed that TUDCA almost completely counteracts the cholestatic and cytolitic effects promoted by ethanol in the isolated perfused rat liver.