ADRIAMYCIN DEPRESSES IN-VIVO AND IN-VITRO PHOSPHATIDYLETHANOLAMINE N-METHYLATION IN RAT-HEART SARCOLEMMA

Adriamycin, an effective anticancer chemotherapeutic agent, causes an insidious and delayed cardiotoxicity. Different subcellular abnormalit ies including calcium transport changes in the sarcolemma (SL) as well as downregulation of the adrenergic system have been shown to be asso ciated with the development of this cardiomyopathy. Since both of thes e activities are influenced by phospholipid methylation, effects of ad riamycin on the three catalytic sites of SL phosphatidylethanolamine N -methyltransferase were examined. Rats were administered with a cumula tive dose of adriamycin (15 mg/kg) over 2 weeks and examined after 3 w eeks. Vehicle injected animals served as controls. Dyspnea, high morta lity rate, ascites and decrease in aortic and left ventricular systoli c pressure, as well as increase in left ventricular end diastolic pres sure were seen in the adriamycin group. Myocardial cell damage typical of adriamycin cardiomyopathy, i.e. sarcotubular swelling, vacuolizati on and myofibrillar drop-out, was also apparent. Total methyl group in corporation into SL phosphatidylethanolamine using radiolabeled S-aden osyl-L-methionine as the donor was significantly depressed in the 3 we ek group at catalytic sites II and III. Decreased production of methyl ated intermediates, phosphatidyl-N-monomethylethanolamine and phosphat idyl-N,N-dimethyiethanolamine as well as phosphatidylcholine (PC) was seen. Depression of phosphatidylethanolamine N-methylation was also no ticed when SL, isolated from untreated hearts, was exposed in vitro to different concentrations (10, 100 and 1000 mu M) of adriamycin. Inhib ition of phosphatidylethanolamine N-methylation appears to be mediated by adriamycin-induced increase in the oxidative stress and may contri bute in the pathogenesis of subcellular changes associated with this c ardiomyopathy.