In-vivo and in-vitro mitochondrial membrane damages induced in mice by adriamycin and derivatives

Abstract

A major limitation to a prolonged use of adriamycin (ADM) during a clinical treatment is its dose-dependent cardiotoxicity. This toxicity has been related to a general disturbance of the inner mitochondrial membrane structure and its essential biological functions, associated to the production of free radicals by the anthracyclines. 4′-Epiadriamycin (4′-epiADM), 4′-deoxyadriamycin (4′-deoxyADM), 4′-deoxy-4′-iodoadriamycin (4′-deoxy-4′-iodoADM) and 4′-demethoxydaunorubicin (4-demethoxyDNR) are ADM and daunorubicin (DNR) derivatives differing from their parent compounds by minor structural modifications. They are nevertheless documented as less cardiotoxic. Our purpose was to establish whether mitochondrial membrane damages induced in vivo in mice heart by those compounds are correlated with the free radical formation. Heart mitochondria of treated mice were isolated 48 h after a single drug injection in order to measure the acute mitochondrial toxicity. Enzymatic activities of complex I–III and complex IV of the mitochondrial respiratory chain, mitochondrial membrane fluidity and lipid peroxidation were measured. None of the ADM and DNR derivatives displayed a significant acute mitochondrial toxicity. A mitochondrial toxicity was however detected for 4-deoxyADM and 4-demethoxyDNR when drugs were given chronically, but it was strongly reduced as compared with ADM and DNR. Electron transfer between NADH and cytochrome c, formation of superoxide radicals and lipid peroxidation were measured in vitro for the various drugs. Comparison of the in-vivo and in-vitro results provides evidence that free radical production explains only partly the in-vivo toxicities.