Synergism of cyclosporin A and phospholipase inhibitors in protection against lethal injury to rat hepatocytes from oxidant chemicals

Cyclosporin A and phospholipase inhibitors block the oxidant-induced mitochondrial permeability transition. Here, protection by these agents against cytotoxicity of oxidant chemicals was evaluated in rat hepatocytes. The combination of cyclosporin A and a phospholipase inhibitor (trifluoperazine, mepacrine, or dibucaine), but neither alone, substantially protected against lethal injury from 0.5 mM iodoacetate but had little effect against iodoacetate plus 2.5 mM KCN. Against 100 μM t-butylhydroperoxide, cyclosporin A and trifluoperazine protected only if fructose was present. Cyclosporin A plus phospholipase inhibition protected slightly against 2.5 mM cystamine, but actually increased lethal injury after 100 μM menadione. These effects are consistent with an oxidant-induced mitochondrial permeability transition that accelerates cell killing after iodoacetate and t-butylhydroperoxide.