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Free radicals formation and membrane damages induced by adriamycin in mitochondria: A study in vivo and in vitro

par Goormaghtigh, Erik ;Pollakis, Georges ;Praet, Michel;Delmelle, Michel;Lion, Yves;Ruysschaert, Jean Marie
Référence Archives of physiology and biochemistry, 92, 2, page (BP12-BP13)
Publication Publié, 1984

Article révisé par les pairs

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Résumé :

Adriamicin (ADM) is one of the most effective anthracycline glycoside antibiotic in the treatment of several types of cancer. Its clinical use is however limited by a specific cardiotoxicity. Deviation of electrons from NADPH supplemented cytochrome P-450 to the anthracycline results in the formation of a semiquinone radical which react with O2 to form toxic oxygen species (O2-, OH). These reactions were suggested to be involved in the cardiac toxicity process of ADM till the recent finding that cardiac microsomes do not participate to such reactions (Nohl & Jordan, 1983). Using the spin trapper DMPO combined with a flow technique, we were able to demonstrate that beef heart mitochondria, submitochondrial particles and complex I containing proteoliposomes catalyse the formation of O2- and OH species when incubated in presence of ADM and NADH. The semiquinone radical was also observed by ESR with a characteristic g value of 2.0024 and a line width of 0.4 mT. Interestingly, the 5-iminodaunorubicin analog did not induce the formation of oxygen radical species in good correlation with its weak cardiac toxicity. Membrane damages were further studied on heart mitochondria extracted from ADM-treated mice. A strong rigidifi-cation of the mitochondrial membrane was observed using fluorescence depolarization of a probe (DPH) embedded in the membrane. The rigidification can be considered as resulting from polymerization of peroxidized lipids in presence of O2- and OH species. No rigidification was observed on mitochondrial memmembrane extracted from 5-iminodaunorubicin-tretead mice in good agreement with our ESR results. © 1984 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.