Reduction of Oxygen by NADH/NADH Dehydrogenase in the Presence of adriamycin

Abstract

Cardiac mitochondrial NADH dehydrogenase (Cytochrome c reductase, EC1.6.99.3) catalyses the reduction of ferricytochrome c to ferrocytochrome c by NADH. In the presence of the anthracycline anti-tumour drug, adriamycin, electron transfer from NADH is subverted to dioxygen. Using the electron spin resonance technique of spin trapping with the spin trapping agent 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) adriamycin was found to stimulate the formation of superoxide and hydroxyl radicals in the NADH/NADH dehydrogenase reaction. Hydroxyl radical formation is dependent on the availability of trace amounts of redox active metal ions - particularly ferric ions. Trace amounts of ferric ions catalyse the formation of hydroxyl radicals by both superoxide-dependent and adriamycin-dependent one electron reduction of hydrogen peroxide. The metabolism of adriamycin by cardiac mitochondrial NADH dehydrogenase may be an important etiological factor in adriamycin-induced cardiotoxicity. It may be therapeutically beneficial to keep nonessential ferric/ferrous ions in the myocardium at minimum levels with siderophoric iron chelators - providing the anti-tumour activity of adriamycin is not impaired.