Inhibitory effects of anthracenedione antineoplastic agents on hepatic and cardiac lipid peroxidation.

The effects of mitoxantrone, ametantrone and a monohydroxylated anthracenedione on hepatic microsomal, cardiac sarcosomal and cardiac mitochondrial lipid peroxidation were examined and compared with those of doxorubicin and daunorubicin. Rabbit microsomal NADPH-dependent lipid peroxidation was inhibited by the anthracenediones in a concentration-dependent manner, whereas doxorubicin caused a concentration-dependent enhancement of peroxidation. Mitoxantrone and ametantrone (200 microM) completely inhibited microsomal malondialdehyde production while an identical concentration of doxorubicin caused a 2.5-fold stimulation. Rabbit cardiac sarcosomal NADPH-dependent malondialdehyde production was also abolished by 100 microM anthracenedione. Mitochondria isolated from rabbit hearts were found to support NADH-dependent lipid peroxidation. Doxorubicin produced a maximal 3-fold enhancement of mitochondrial malondialdehyde production at 25 microM. The anthracenediones however, completely inhibited mitochondrial lipid peroxidation Drug-stimulated lipid peroxidation was also effectively diminished by mitoxantrone and ametantrone in a concentration-dependent manner. Half-maximal inhibition of doxorubicin-stimulated rabbit microsomal malondialdehyde production was achieved by 4 anal 6 microM mitoxantrone and ametantrone, respectively. Furthermore this effect was not limited to anthracycline-induced lipid peroxidation. Mitoxantrone and ametantrone also protected against rat microsomal lipid peroxidation produced by nitrofurantoin, paraquat and doxorubicin, decreasing these rates by 80, 90, and 50%, respectively, at 10 microM anthracenedione. The relative inability of the anthracenediones to stimulate lipid peroxidation is consistent with the diminished cardiotoxicity of ametantrone and mitoxantrone relative to doxorubicin and daunorubicin.

Duke Scholars

Author Evan Kharasch Anesthesiology, General, Vascular, High Risk Transplant & Cr ...