Doxorubicin-dependent lipid peroxidation at low partial pressures of O 2

Abstract

Doxorubicin semiquinone, produced by reduction of doxorubicin with xanthine oxidase or ferredoxin reductase, reacted with H 2O 2 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 H 2O 2 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 pO 2 of approximately 1.5 mm Hg, when the inhibitory effect of O 2 on initiation is balanced by its stimulatory effects on propagation. The results imply that H 2O 2 and the doxorubicin semiquinone at low iron and O 2 concentrations are very effective at initiating lipid peroxidation.