Acute and Chronic Effects of Adriamycin on Fatty Acid Oxidation in Isolated Cardiac Myocytes

Abstract This study was designed to determine if acute ( in vitro ) or chronic ( in 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- 14 C]palmitate, [1- 14 C] octanoate, [1- 14 C]butyrate, [U- 14 C]glucose, and [2- 14 C]pyruvate in isolated cardiac myocytes. Acute exposure to adriamycin caused a concentration- and time-dependent inhibition of carnitine palmitoyl transferase I (CPT I) dependent long-chain fatty acid, palmitate, oxidation. Chronic exposure to (18 mg/kg) adriamycin inhibited palmitate oxidation 40% to a similar extent seen in vitro with 0.5 m m adriamycin. Acute or chronic administration of l -carnitine completely abolished the adriamycin-induced inhibition of palmitate oxidation. Interestingly, medium- and short-chain fatty acid oxidation, which are independent of CPT I, were also inhibited acutely by adriamycin and could be reversed by l -carnitine. In isolated rat heart mitochondria, adriamycin 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 concentrations greater than 1 m m . 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 substrate, l -carnitine, in cardiac tissue. However, these findings also suggest that l -carnitine plays an additional role in fatty acid oxidation independent of CPT I or fatty acid chain length.