Oxyradical production results from the Fe3(+)-doxorubicin complex undergoing self-reduction by its alpha-ketol group.
A variety of different measures have been used to compare the self-reduction of the Fe3+ complexes of doxorubicin and daunorubicin. The Fe3(+)-doxorubicin complex exhibited a much faster rate of (i) O2 consumption, (ii) self-reduction under Ar to the Fe2+ complex, (iii) aerobic reduction of ferricytochrome c, (iv) scavenging of Fe2+ by bipyridine, (v) hydroxyl radical production measured by electron paramagnetic resonance spin-trapping experiments, and (vi) inactivation of the cytochrome c oxidase activity of beef heart submitochondrial particles, than did the corresponding Fe3(+)-daunorubicin complex. In contrast to Fe3(+)-doxorubicin, the Fe3(+)-daunorubicin complex displayed only a fast phase of inhibition of the cytochrome c oxidase activity, indicating that the initial binding of these two Fe3(+)-drug complexes is very similar. All of these results indicate that Fe3(+)-doxorubicin undergoes a much faster self-reduction to the Fe2+ complex and hence a much greater rate of production of damaging oxyradicals when the Fe2+ is reoxidized by O2 or H2O2. The addition of the alpha-ketol acetol to Fe3(+)-daunorubicin resulted in greatly increased rates of (i) ferricytochrome c reduction, (ii) Fe2+ production, and (iii) hydroxyl radical production. These results support the hypothesis that the alpha-ketol functional group of doxorubicin (which is not present on daunorubicin and is the only structural difference between these two compounds) reduces the Fe3+ while undergoing oxidation itself.
Hasinoff
B B
BB
Department of Chemistry, Memorial University of Newfoundland, St. John's, Canada.
D003574:Cytochrome c Group / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D013329:Structure-Activity Relationship
D003574:Cytochrome c Group; D005609:Free Radicals; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D007501:Iron; D003576:Electron Transport Complex IV; D010100:Oxygen; D003630:Daunorubicin