Addition of more than 10 pM of adriamycin to cultured rat hepatocytes loaded with a-linolenic acid (linolenic acid-loaded hepatocytes) caused marked lipid peroxidation as measured by an accumulation of malondialdehyde during a 9 hr incubation. After addition of 50 pM of adriamycin to linolenic acid-loaded hepatocytes, malondialdehyde accumulation significantly increased at 3 hr, followed by cellular reduced glutathione decrease and lactate dehydrogenase leakage after 6 hr. Inhibition of adriamycin-induced lipid peroxidation by addition of N,N'-diphenyl-p-phenylenediamine or atocopherol, both lipid radical scavengers, or deferoxamine, which is a Fe ion chelator, prevented both glutathione decrease and lactate dehydrogenase leakage, indicating that lipid peroxidation caused cellular damage to linolenic acid-loaded hepatocytes exposed to adriamycin. The effect of SKF 525-A, which is a cytochrome P450 inhibitor, on adriamycininduced lipid peroxidation and on 7-ethoxycoumarin 0-deethylase activity was determined by 6 hr incubation of linolenic acid-loaded cells. Addition of SKF 525-A suppressed adriamycin-induced lipid peroxidation comparably with its 7-ethoxycoumarin 0-deethylase inhibitory activity. These results suggest that cytochrome P450 contributes to the one-electron bioreduction of adriamycin into its semiquinone radical in rat hepatocytes.
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