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 ofl-carnitine in reversing or preventing this effect was examined. We determined the effects of adriamycin in the presence or absence ofl-carnitine on the oxidation of the metabolic substrates [1-14C]palmitate, [1-14C] octanoate, [1-14C]butyrate, [U-14C]glucose, and [2-14C]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 seenin vitrowith 0.5 mmadriamycin. Acute or chronic administration ofl-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 byl-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 mm. These data suggest that afterin vitroorin vivoadministration, 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 thatl-carnitine plays an additional role in fatty acid oxidation independent of CPT I or fatty acid chain length.