THE ROLE OF LIPID-PEROXIDATION IN MENADIONE-MEDIATED TOXICITY IN CARDIOMYOCYTES

The role of lipid peroxidation in menadione-mediated toxicity was stud ied in neonatal rat cardiomyocytes. Incubation of cardiomyocytes with menadione resulted in depleted cellular glutathione levels, increased intracellular Ca2+ and increased lipid peroxidation which all occurred prior to cell degeneration, Pre-treatment of cells with cysteine supp ressed the menadione-induced cell degeneration and prevented changes i n glutathione levels, intracellular Ca2+, and lipid peroxidation, Pre- treatment of cells with fura-2 acetoxymethyl ester, a Ca2+ chelator, r educed menadione-induced cell degeneration and lipid peroxidation but it did not block cellular glutathione depletion. Pre-treatment of cell s with deferoxamine mesylate, an iron chelator, also reduced both mena dione-induced cell degeneration and lipid peroxidation; however, it di d not prevent the menadione-induced increase in intracellular Ca2+, no r the depletion of glutathione. Thus, the inhibition of menadione-indu ced lipid peroxidation by deferoxamine mesylate prevented cell degener ation even though intracellular Ca2+ remained elevated and glutathione remained depleted, The protective effects of deferoxamine mesylate an d fura-2 AM on menadione's toxicity were inhibited by addition of FeCl 3 to cells, Ferric ions did not inhibit the protective effect of cyste ine. These data suggest that menadione-induced cardiomyocyte degenerat ion is directly linked to iron-dependent lipid peroxidation and less t ightly coupled to elevation in intracellular Ca2+ or depletion of glut athione. (C) 1995 Academic Press Limited