title: Biphasic actions of chlorpromazine and mepacrine on modulation of hepatic cell injury in the perfused cat liver.
abstract: 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.
mesh_terms: D000588:Amines / Q000378:metabolism; D000818:Animals; D002402:Cathepsin D; D002403:Cathepsins / Q000494:pharmacology; D002415:Cats; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology*; D002746:Chlorpromazine / Q000494:pharmacology*; D005260:Female; D000860:Hypoxia / Q000201:enzymology; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects; D008297:Male; D011796:Quinacrine / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000588:Amines; D007770:L-Lactate Dehydrogenase; D002403:Cathepsins; D002402:Cathepsin D; D011796:Quinacrine; D002746:Chlorpromazine