Reduction of oxygen by NADH/NADH dehydrogenase in the presence of adriamycin.
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.
Thornalley
P J
PJ
Department of Pharmaceutical Sciences, Aston University, Birmingham, England.
Bannister
W H
WH
Bannister
J V
JV
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D003579:Cytochrome Reductases / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006861:Hydrogen Peroxide; D006878:Hydroxides; D066298:In Vitro Techniques; D007700:Kinetics; D009206:Myocardium / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D013481:Superoxides; D013552:Swine
D002614:Chelating Agents; D005609:Free Radicals; D006878:Hydroxides; D013481:Superoxides; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D003579:Cytochrome Reductases; D009245:NADH Dehydrogenase; D010100:Oxygen