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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047597-02
Application #
3191325
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Podda, M; Weber, C; Traber, M G et al. (1999) Sensitive high-performance liquid chromatography techniques for simultaneous determination of tocopherols, tocotrienols, ubiquinols, and ubiquinones in biological samples. Methods Enzymol 299:330-41
Kilic, F; Handelman, G J; Traber, K et al. (1998) Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione concentrations in lens in model diabetic cataractogenesis. Biochem Mol Biol Int 46:585-95
Weber, C; Podda, M; Rallis, M et al. (1997) Efficacy of topically applied tocopherols and tocotrienols in protection of murine skin from oxidative damage induced by UV-irradiation. Free Radic Biol Med 22:761-9
Sen, C K; Roy, S; Han, D et al. (1997) Regulation of cellular thiols in human lymphocytes by alpha-lipoic acid: a flow cytometric analysis. Free Radic Biol Med 22:1241-57
Haramaki, N; Han, D; Handelman, G J et al. (1997) Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Free Radic Biol Med 22:535-42
Han, D; Handelman, G; Marcocci, L et al. (1997) Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 6:321-38
Sen, C K; Packer, L (1996) Antioxidant and redox regulation of gene transcription. FASEB J 10:709-20
Sen, C K; Roy, S; Packer, L (1996) Involvement of intracellular Ca2+ in oxidant-induced NF-kappa B activation. FEBS Lett 385:58-62
Konishi, T; Handelman, G; Matsugo, S et al. (1996) Amplified determination of lipoyl groups by lipoamide dehydrogenase in the presence of oxidized glutathione. Biochem Mol Biol Int 38:1155-61
Podda, M; Weber, C; Traber, M G et al. (1996) Simultaneous determination of tissue tocopherols, tocotrienols, ubiquinols, and ubiquinones. J Lipid Res 37:893-901

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