EFFECT OF ANTHRACYCLINE ANTIBIOTICS ON OXYGEN RADICAL FORMATION IN RAT-HEART

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (2) , 460-472
Abstract
The effect was studied of the anthracycline antitumor agents on reactive oxygen metabolism in rat heart. Oxygen radical production by doxorubicin, daunorubicin and various anthracycline analogs [rubidazone, 5-iminodaunorubicin, aclacinomycin A, antinomycin D] [antitumor agents] was determined in heart homogenate, sarcoplasmic reticulum, mitochondria and cytosol, the major sites of cardiac damage by the anthracycline drugs. Superoxide production in heart sarcosomes was significantly increased by anthracycline treatment; for doxorubicin, the reaction appeared to follow saturation kinetics, required NADPH as cofactor, was accompanied by the accumulation of hydrogen peroxide, and probably resulted from the transfer of electrons to molecular oxygen by the doxorubicin semiquinone after reduction of the drug by sarcosomal NADPH:cytochrome P-450 reductase (EC 1.6.2.4). Superoxide formation was also significantly enhanced by the anthracycline antibiotics in the mitochondrial fraction. Doxorubicin stimulated mitochondrial superoxide formation in a dose-dependent manner that also appeared to follow saturation kinetics; however, drug-related superoxide production by mitochondria required NADH rather than NADPH and was significantly increased in the presence of rotenone, which suggested that the proximal portion of the mitochondrial NADH dehydrogenase complex (EC 1.6.99.3) was responsible for the reduction of doxorubicin at this site. In heart cytosol, anthracycline-induced superoxide formation and oxygen consumption required NADH and were significantly reduced by allopurinol. Reactive oxygen production was detected in all studies. Free radical formation by the anthracycline antitumor agents, which occurs in the same myocardial compartments that are subject to drug-induced tissue injury, may damage the heart by exceeding the oxygen radical detoxifying capacity of cardiac mitochondria and sarcoplasmic reticulum.