The impairment of essential fatty acid metabolism as a key factor in doxorubicin-induced damage in cultured rat cardiomyocytes

The clinical use of the antitumoral doxorubicin (DOX) is limited by its car diotoxicity, which is mediated through different mechanisms. The membrane l ipid peroxidation induced by DOX may cause disruption of the unsaturated fa tty acyl chains; in the endoplasmic reticulum, containing the system cataly zing the desaturation/elongation of fatty acids, DOX could interfere with t he metabolism of linoleic and alpha-linolenic acids. Using primary cultures of neonatal rat cardiomyocytes we demonstrated that the exposure to differ ent concentrations of DOX (10(-5) and 10(-7) M) for 24 h caused an increase in the production of conjugated dienes, an impairment in the desaturation/ elongation of essential fatty acids, and a reduction in the cellular conten t of highly unsaturated fatty acids. Conversely, 1 h exposure to 10(-5) M D OX was sufficient to induce alterations in the desaturation/elongation of l inoleic and alpha-linolenic acids, but did not cause either formation of co njugated dienes or modification of the fatty acyl pattern. Therefore, DOX h as a dual negative effect, depending on its concentration and on the time o f exposure, one directed against the membrane highly unsaturated fatty acid s, the other against the system which is required for the synthesis of thes e fatty acids themselves. These two effects synergically act in causing hea rt cell damage. (C) 1999 Elsevier Science B.V. All rights reserved.