DOXORUBICIN-INDUCED AND DAUNORUBICIN-INDUCED ENERGY DEPRIVATION AND NUCLEOTIDE DEGRADATION IN ISOLATED CARDIOMYOCYTES

Cytotoxic mechanisms of the antitumor agents daunorubicin and doxorubi cin were elucidated in isolated cardiomyocytes from adult rats. Incuba tion with daunorubicin resulted in a concentration-dependent loss of c ell viability and changes of the cell structure. Only the highest conc entration of doxorubicin (1 mM) caused similar effects. Doxorubicin wa s found to stimulate oxygen consumption by cardiomyocytes (about 20%), while the opposite effect was observed after daunorubicin treatment. A rapid decrease of the mitochondrial ATP content (more than 40%) and elevation of the cytosolic ADP level (doxorubicin 2-fold and daunorubi cin 6-fold) was followed by increased release of adenosine and inosine to the surrounding medium. When myocytes were exposed to an anthracyc line concentration lower than plasma levels measured clinically (0.15 mu M), doxorubicin and daunorubicin significantly decreased the intrac ellular ADP and NAD levels. Isolated cardiomyocytes were found to be a ble to form daunorubicinol from daunorubicin. In contrast, no conversi on of doxorubicin was detected in our experiments. In conclusion, our data demonstrate that decreased ATP production and increased nucleosid e formation are major events in the toxicity induced by daunorubicin a nd doxorubicin in isolated cardiomyocytes. The results also suggest th at the toxic effects may be caused by separate mechanisms.