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.