Iron and free radical oxidations in cell membranes

Brain tissue being rich in polyunsaturated fatty acids, is very susceptible to lipid peroxidation. Iron is well known to be an important initiator of free radical oxidations. We propose that the principal route to iron-mediat ed lipid peroxidations is via iron-oxygen complexes rather than the reactio n of iron with hydrogen peroxide, the Fenton reaction. To test this hypothe sis, we enriched leukemia cells (K-562 and L1210 cells) with docosahexaenoi c acid (DHA) as a model for brain tissue, increasing the amount of DHA from approximately 3 mole % to 32 mole %. These cells were then subjected to fe rrous iron and dioxygen to initiate lipid peroxidation in the presence or a bsence of hydrogen peroxide. Lipid-derived radicals were detected using EPR spin trapping with alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN). As e xpected, lipid-derived radical formation increases with increasing cellular lipid unsaturation. Experiments with desferal demonstrate that iron is req uired for the formation of lipid radicals from these cells. Addition of iro n to DHA-enriched L1210 cells resulted in significant amounts of radical fo rmation; radical formation increased with increasing amount of iron. Howeve r, the exposure of cells to hydrogen peroxide before the addition of ferrou s iron did not increase cellular radical formation, but actually decreased spin adduct formation. These data suggest that iron-oxygen complexes are th e primary route to the initiation of biological free radical oxidations. Th is model proposes a mechanism to explain how catalytic iron in brain tissue can be so destructive.