A study was made of the conditions of the killing of cultured hepatocytes by the reactive disulfide cystamine. Six to 12 mM cystamine killed up to 60% of the hepatocytes within 3 hours. The cytosolic calcium ion concentration rose prior to the loss of viability. Treatment with EGTA in a Ca2+-free medium lowered the initial Ca2+ concentration and prevented the rise in response to cystamine. However, there was no change in the number of dead cells. Furthermore, the sensitivity of cultured hepatocytes to cystamine was unaffected by the concentration of calcium in the culture medium. Addition to the culture medium of 3 protease inhibitors, leupeptin, antipain, or chymostatin, did not reduce the extent of cell killing by cystamine despite an inhibition of protein degradation. These data do not support the hypothesis that the toxicity of cystamine is necessarily mediated by proteases activated by a rise in the cytosolic calcium ion concentration.
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