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Anthracycline Antibiotic-stimulated Superoxide, Hydrogen Peroxide, and Hydroxyl Radical Production by NADH Dehydrogenase¹

Pharmacology Section, Department of Medical Oncology, City of Hope National Medical Center, Duarte, California 91010

This study investigated the effect of the anthracycline antibiotics on oxygen radical metabolism by cardiac mitochondrial reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase [NADH:(acceptor) oxidoreductase, EC 1.6.99.3]. Superoxide formation by NADH dehydrogenase after anthracycline treatment appeared to follow saturation kinetics with an apparent K_m of 167.3, 73.3, 64.0, or 47.6 µM for doxorubicin, daunorubicin, rubidazone, or aclacinomycin A, respectively. Superoxide formation by NADH dehydrogenase after doxorubicin treatment occurred with a pH optimum of 7.6 and was accompanied by the production of hydrogen peroxide. Furthermore, drug-related hydroxyl radical generation was detected in this enzyme system by the evolution of methane gas from dimethyl sulfoxide. Hydroxyl radical production proceeded only in the presence of superoxide anion, hydrogen peroxide, and trace amounts of iron or a chelate of iron and ethylenediaminetetraacetate and thus was probably the by-product of a transition metal-catalyzed Haber-Weiss reaction. The antitumor agents mitoxantrone and actinomycin D did not significantly enhance reactive oxygen metabolism by NADH dehydrogenase.

These results suggest that the specific activation of the anthracycline antibiotics to free radicals by NADH dehydrogenase leads to the formation of a variety of reactive oxygen species that may contribute to the mitochondrial toxicity of these drugs.

¹ This study was supported by USPHS Grant 31788-03 from the National Cancer Institute, Department of Health and Human Services.

² Recipient of a scholarship from the Leukemia Society of America. To whom requests for reprints should be addressed, at the Pharmacology Section, Department of Medical Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, Calif, 91010.

Received 7/26/82. Accepted 6/28/83.

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