Importance of Fe2+-ADP and the relative unimportance of OH in the mechanism of mitomycin C-induced lipid peroxidation.
The mechanism of mitomycin C-induced lipid peroxidation has been studied at pH 7.5, using systems containing phospholipid membranes (liposomes) and an Fe3+-ADP complex with purified NADPH-cytochrome P-450 reductase. Both O2- and H2O2 are generated during the aerobic enzyme-catalyzed reaction in the presence of mitomycin C. Hydroxyl radical is formed in the reaction by the reduction of H2O2. This is catalyzed by the Fe2+-ADP complex in a phosphate buffer or to a lesser extent when in a Tris-HCl buffer. The reduction of Fe3+-ADP to Fe2+-ADP is mainly achieved by O2-. The resulting Fe2+-ADP in the presence of O2 forms a perferryl ion complex which is a powerful stimulator of lipid peroxidation. However, the formation of such an iron-oxygen complex is strongly inhibited by phosphate ions, which do not interfere with the generation of OH radicals. These findings suggest that, since lipid peroxidation occurs in a Tris-HCl buffer (but not in a phosphate buffer), the OH radical is unlikely to be involved in the observed lipid peroxidation process.
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006878:Hydroxides / Q000378:metabolism*; D017665:Hydroxyl Radical; D007425:Intracellular Membranes / Q000378:metabolism; D007501:Iron / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007700:Kinetics; D008054:Lipid Peroxides / Q000378:metabolism*; D008081:Liposomes; D008563:Membrane Lipids / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats
D000903:Antibiotics, Antineoplastic; D005296:Ferrous Compounds; D006878:Hydroxides; D007502:Iron Chelating Agents; D008054:Lipid Peroxides; D008081:Liposomes; D008563:Membrane Lipids; D008937:Mitomycins; D010743:Phospholipids; C029936:adenosine diphosphate-ferric chelate; D017665:Hydroxyl Radical; D016685:Mitomycin; D000244:Adenosine Diphosphate; D007501:Iron; D009251:NADPH-Ferrihemoprotein Reductase