Effects of doxorubicin on cardiomyocytes with reduced level of superoxide dismutase.

Our previous studies have shown that isolated adult rat cardiomyocytes with normal and reduced Cu/Zn SOD activities are equally susceptible to extracellularly generated oxidants (hydrogen peroxide, glucose oxidase/glucose and xanthine oxidase/xanthine systems). In the present study we exposed myocytes with reduced SOD activity to doxorubicin (adriamycin). Cardiotoxicity of doxorubicin has been attributed to the production of superoxide anion inside the cell. Cardiomyocytes with reduced SOD activity, but normal ATP content and viability, were obtained by the treatment of isolated cells with diethyldithiocarbamate (DDC). DDC-treated myocytes were significantly less resistant to doxorubicin than controls. Doxorubicin-stimulated superoxide anion formation, measured by the rate of SOD-inhibitable acetylated cytochrome C reduction, was significantly higher in the cytosolic fraction of DDC-treated cells compared to controls. These results indicate that for isolated cardiac myocytes an essential part of cytotoxicity of doxorubicin can be explained by the formation of superoxide anion and that the level of intracellular SOD activity should be considered as a significant factor for cell protection.