Oxyradical production results from the Fe3+–doxorubicin complex undergoing self-reduction by its α-ketol group

Abstract

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 α-ketol acetol to Fe³⁺–daunorubicin resulted in greately increased rates of (i) ferricytochrome c reduction, (ii) Fe²⁺ production, and (iii) hydroxyl radical production. These results support the hypothesis that the α-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.Key words: doxorubicin, adriamycin, iron, self-reduction, oxyradical.