ACUTE AND CHRONIC EFFECTS OF ADRIAMYCIN ON FATTY-ACID OXIDATION IN ISOLATED CARDIAC MYOCYTES

This study was designed to determine if acute (in vitro) or chronic (i n vivo) adriamycin inhibits cardiac fatty acid oxidation and if so at what sites in the fatty acid oxidation pathway. In addition, the role of L-carnitine in reversing or preventing this effect was examined. We determined the effects of adriamycin in the presence or absence of L- carnitine on the oxidation of the metabolic substrates [1-C-14]palmita te, [1-C-14] octanoate, [1-C-14]butyrate, [U-C-14]glucose, and [2-C-14 ]pyruvate in isolated cardiac myocytes. Acute exposure to adriamycin c aused a concentration- and time-dependent inhibition of carnitine palm itoyl transferase I (CPT I) dependent long-chain fatty acid, palmitate , oxidation. Chronic exposure to (18 mg/kg) adriamycin inhibited palmi tate oxidation 40% to a similar extent seen in vitro with 0.5 mM adria mycin. Acute or chronic administration of L-carnitine completely aboli shed the adriamycin-induced inhibition of palmitate oxidation. Interes tingly, medium- and short-chain fatty acid oxidation, which are indepe ndent of CPT I, were also inhibited acutely by adriamycin and could be reversed by L-carnitine. In isolated rat heart mitochondria, adriamyc in significantly decreased oxidation of the CPT I dependent substrate palmitoyl-CoA by 50%. However, the oxidation of a non-CPT I dependent substrate palmitoylcarnitine was unaffected by adriamycin except at co ncentrations greater than 1 mM. These data suggest that after in vitro or in vivo administration, adriamycin, inhibits fatty acid oxidation in part secondary to inhibition of CPT I and/or depletion of its subst rate, L-camitine, in cardiac tissue. However, these findings also sugg est that L-carnitine plays an additional role in fatty acid oxidation independent of CPT I or fatty acid chain length. (C) 1997 Academic Pre ss Limited.