Self-reduction of the iron(III)-doxorubicin complex

The Fe3(+)-doxorubicin complex undergoes reactions that suggest that the complex self-reduces to a ferrous oxidized-doxorubicin free radical species. The Fe3(+)-doxorubicin system is observed to reduce ferricytochrome c, consume O2 and react with 2,2'-bipyridine. Bipyridine acts as a "ferrous ion scavenger" as it reacts with the ferrous ion produced by Fe3(+)-doxorubicin self-reduction. In the absence of O2, a ferrous doxorubicin complex accumulates. In the presence of oxygen, Fe2+ recycles back to Fe3+. The rates of these reactions were measured and the Fe3(+)-doxorubicin self-reduction was determined to be the rate-determining step. The Fe3(+)-doxorubicin induced inactivation of cytochrome c oxidase and NADH cytochrome c reductase on beef heart submitochondrial particles occurs at a rate similar to Fe3(+)-doxorubicin self-reduction. Thus the rate at which damage to these mitochondrial enzymes occurs may be controlled by a nonenzymatic Fe3(+)-doxorubicin self-reduction.