The composition and properties of biological membranes confer upon these structures a particular susceptibility to oxidative free radical processes. Part of this susceptibility is due to their high content of polyunsaturated fatty acids and 8-fold greater solubility of oxygen in lipids (compared to water). Microsomes and mitochondria both perform oxido-reductase functions capable of generating reactive free radicals which, bomtined with the availability of oxygen, can trigger peroxidative chain reactions in these membranous organelles. The preliminary studies described in this report indicate that a membrane-bound, heat-labile factor found in microsomes and mitochondria facilitates the quenching of free radicals in the membranes of these organelles by cycling moderately stable tocopheroxyl radicals back to tocopherol as the latter scavenges reactive radicals generated by enzymic processes or by metal ion-catalyzed reactions. The membrane factor that appears to catalyze this cycling has a specific requirement for GSH, presumably to provide reducing equivalents for the reduction of tocopheroxyl radicals. The findings support the hypothesis that alpha-tocopherol is a cofactor for a """"""""free radical reductase"""""""" activity in biological membranes. This mechanism would explain how the small quantities of tocopherol present in membranes provide such effective protection against oxidative stress, i.e., by linking the cycling process to the abundant availability of GSH in most cells. The proposed investigations are designed to obtain more direct evidence for this function of tocopherol using EPR techniques. Experiments to prove that the GSH-dependent cycling of tocopherol occurs in biological membranes under oxidative stress would be done. It will also be determined if the function of tocopherol in this system can be substituted by other lipid-soluble antioxidant substances. Ascorbic acid also participates in sustaining tocopherol levels in membranes, but preliminary investigations in this laboratory have shown that ascorbate requires neither a heat-labile membrane component nor GSH for this action. These studies suggest that ascorbate may function by a different mechanism which spares tocopherol by direct quenching of reactive radicals in membranes, but appears to be less efficient than the GSH-depending tocopherolycycling system. The capacity of ascorbic acid to quench radical-mediated processes in membranes will also be investigated.

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Oklahoma Medical Research Foundation
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