Protective effects of glutathione on diethyldithiocarbamate (DDC) cytotoxicity: a possible mechanism

Rat cerebral astrocytes grown in culture were exposed to 35 micrograms diethyldithiocarbamate (DDC)/ml of medium for 1 hr and treated with 0 or 10 mM reduced glutathione (GSH) 1 hr post-DDC. DDC treatment resulted in a 90% reduction in cell adherence within 24 hr and complete inhibition of growth. The most pronounced ultrastructural lesion in DDC-treated cells was on mitochondria. Numerous lipofuscin-like deposits were seen in these cells. In addition, DDC treatment resulted in a greater than 400% increase in cellular copper. The activity of the selenoenzyme glutathione peroxidase was reduced by about 40% with no concomitant effect on cytosolic superoxide dismutase activity. The data suggest that DDC cytoxicity is peroxidative in nature, presumably due to the massive influx of copper into the astrocyte. GSH treatment 1 hr after exposure of the cells to DDC completely prevented the DDC-induced reduction in cell adherence and growth inhibition. Ultrastructurally, cells post-treated with GSH prevented much of the damage caused by DDC. This protection was associated with marked reduction in cellular copper and a return to control glutathione peroxidase activity.