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 nonezymatic Fe³⁺-doxorubicin self-reduction.