Biphasic actions of chlorpromazine and mepacrine on modulation of hepatic cell injury in the perfused cat liver.

The effect of chlorpromazine (CPZ) and mepacrine on hypoxic liver cell damage was studied using an isolated perfused cat liver preparation. High concentrations of CPZ (10(-4) M) significantly augmented the hypoxic leakage of the lysosomal enzyme, cathepsin D, and the cytoplasmic enzyme, lactate dehydrogenase (LDH) into the perfusate. The per cent free cathepsin D activity of hepatic tissue was significantly higher in the 10(-4) M CPZ treated groups (87%) than in the vehicle group (65%). CPZ at a concentration of 10(-6) M also possessed a detrimental effect on hypoxic liver integrity but to a lesser extent compared to 10(-4) M. In contrast, low concentrations of CPZ (10(-7) M) showed a protective effect during hypoxia (i.e., significantly lower perfusate cathepsin D activity and per cent free cathepsin D activity) compared to livers receiving only the vehicle. Mepacrine, another phospholipase A2 inhibitor, showed no significant effect on hypoxic liver damage at concentration of 10(-6) and 5 x 10(-5) M. CPZ has a biphasic action on liver integrity during hypoxia, low concentrations being protective and high concentrations are deleterious. Mepacrine had no significant effect in the hypoxic liver.