We seek to elucidate the major mechanisms of tocopherol regeneration from its metastable oxidation product, the tocopheroxyl radical, by enzymatic as well as non-enzymatic means. We postulate that tocopheroxyl radicals can be reduced back to tocopherol by """"""""free radical reductase"""""""" and components of the mitochondrial electron transport chain. If so, this would imply, that free radical reductase (and mitochondria) play a central role in prevention of membrane lipid peroxidation, which is the cause of various pathologic conditions. In addition we will test the hypothesis, that the enzyme, thioredoxin-reductase, which is known to reduce stable free radical species like nitroxides, works also as a free radical reductase for tocopheroxyl radicals. This will give novel insights into the understanding of prevention of lipid peroxidation by this membrane-associated and widely distributed cellular enzyme. We will compare the effectiveness of various water and lipid soluble antioxidants with the reducing potential of thioredoxin-reductase and the mitochondrial electron transport complexes and will achieve a better understanding of the interactions between different antioxidant systems for the prevention of lipid peroxidation. We will test the hypothesis that formation of tocopherolquinone, and end product of tocopherol oxidation, can have adverse (pro- oxidant) effects via formation of oxyl radicals in its semireduced state.
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