Protection by acidotic pH and fructose against lethal injury to rat hepatocytes from mitochondrial inhibitors, ionophores and oxidant chemicals.

The importance of mitochondrial ATP formation and extracellular acidosis was evaluated in hepatocyte suspensions after different toxic treatments. Acidotic pH was protective against cell killing from all toxic treatments examined except for pronase, a toxic protease. Fructose, a substrate for glycolytic ATP formation, provided good protection against toxicity from cyanide, oligomycin, t-butyl hydroperoxide, menadione and cystamine. Protection by fructose against CCCP, gramicidin and Br-A23187 required oligomycin. This indicated that these ionophores were causing cytotoxicity by uncoupling oxidative phosphorylation. Fructose provided little protection against pronase and HgCl2, the latter compound being a potent inhibitor of glycolysis. In conclusion, disruption of mitochondrial ATP formation was a common event contributing to the toxicity of chemical oxidants and ionophores. Acidotic pH was generally protective under these conditions of impaired ATP generation.