Superoxide anion production by adriamycinol from cardiac sarcosomes and by mitochondrial NADH dehydrogenase.
This study investigates the effects of both adriamycin and its 13-hydroxylated metabolite adriamycinol on superoxide anion production from cardiac sarcosomes and by mitochondrial NADH dehydrogenase. Superoxide anion production was determined by using the succinoylated cytochrome c reduction assay. Both adriamycin and adriamycinol stimulated superoxide formation in cardiac sarcosomes and by mitochondrial NADH dehydrogenase. In the first case only NADPH was required as a co-factor and in the second case only NADH. From sarcosomes as well as by NADH dehydrogenase, the superoxide production followed Michaelis-Menten kinetics. With both activating enzymatic systems, the Vmax of adriamycinol was found to be similar to that of adriamycin, but the Km for the former anthracycline was higher than for the latter. Adriamycinol also increased the rate of NADPH and NADH consumption, by sarcosomal fractions and by NADH dehydrogenase respectively. At equimolar consentrations, adriamycinol consumed less NADPH and NADH than adriamycin. These results suggest that adriamycinol could contribute to the chronic cardiac toxicity of adriamycin by forming superoxide anions in cardiac cells constituents.
D000818:Animals; D003579:Cytochrome Reductases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000096:biosynthesis*
D003574:Cytochrome c Group; D013481:Superoxides; D004317:Doxorubicin; D003579:Cytochrome Reductases; D009245:NADH Dehydrogenase; C010013:adriamycinol; C018979:5-iminodaunorubicin; D003630:Daunorubicin