Reduction of O2 by iron-adriamycin

Electron paramagnetic resonance studies of the Fe2+- and Fe3+-adriamycin complexes are reported which demonstrate iron-mediated reduction of O2 by adriamycin. Under anaerobic conditions, Fe2+ binds to adriamycin, giving rise to an EPR-silent Fe2+-adriamycin complex. On addition of O2, the Fe2+ is oxidized to Fe3+ and a spectrum of Fe3+-adriamycin is seen. Under anaerobic conditions, the signal of Fe3+-adriamycin decreases as a function of time as the Fe3+ bound to adriamycin is reduced to Fe2+, and a transient spectrum of iron bound to oxidized adriamycin is observed. On addition of O2, the EPR signal of Fe3+-adriamycin returns as Fe2+ is oxidized back to Fe3+ with electron transfer to O2. This cycle of iron-catalyzed O2 reduction may be the mechanism of adriamycin's antitumor potency and some of its toxic side effects.