ANTHRACYCLINE ANTIBIOTIC-STIMULATED SUPEROXIDE, HYDROGEN-PEROXIDE, AND HYDROXYL RADICAL PRODUCTION BY NADH DEHYDROGENASE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4543-4551
Abstract
The effect of the anthracycline antibiotics on oxygen radical metabolism by cardiac mitochondrial NADH dehydrogenase was investigated. Superoxide formation by NADH dehydrogenase after anthracycline treatment appeared to follow saturation kinetics with an apparent Km of 167.3, 73.3, 64.0 or 47.6 .mu.M 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 H2O2. 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, H2O2 and trace amounts of Fe or a chelate of Fe and EDTA 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. 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 cardiac toxicity of these drugs.