Doxorubicin-dependent lipid peroxidation at low partial pressures of O2

Doxorubicin semiquinone, produced by reduction of doxorubicin with xanthine oxidase or ferredoxin reductase, reacted with H₂O₂ to cause deoxyribose oxidation that was catalysed by sub-micromolar concentrations of complexed iron. Both the mechanism of deoxyribose oxidation and the yield of oxidation products depended on the chelator. With EDTA or diethylenetriamine penta-acetic acid (DTPA), the reactive species behaved like free ·OH. However, when ADP or no chelator was present, oxidation of deoxyribose was inhibited by mannitol but not benzoate or formate and was apparently not due to free ·OH. Doxorubicin semiquinone and H₂O₂ caused peroxidation of phospholipid lipsomes when ADP or no chelator was present, but not in the presence of EDTA or DTPA. Lipid peroxidation was iron dependent over a 0.1 to 1 μM range and was maximal with a pO₂ of approximately 1.5 mm Hg, when the inhibitory effect of O₂ on initiation is balanced by its stimulatory effects on propagation. The results imply that H₂O₂ and the doxorubicin semiquinone at low iron and O₂ concentrations are very effective at initiating lipid peroxidation.