ANTIOXIDANT INTERACTIONS OF SELENIUM AND VITAMINS

该项目的目标是确定硒在预防 氧化损伤，在体外和体内。 硒，未知 机制，长期以来一直被认为是"备用"维生素E从氧化损失 在动物饮食研究中。 维生素E，或α-生育酚，是 脂蛋白和细胞膜中的初级断链抗氧化剂 必须从其氧化形式中回收。 回收阿尔法- 生育酚被认为至少部分地由维生素C介导， 或抗坏血酸。 该项目将测试假设， 硒酶硫氧还蛋白还原酶和其他硒蛋白是至关重要的 在回收抗坏血酸、保存α-生育酚和 防止细胞和动物中的脂质过氧化损伤。 加速的脂质过氧化作用与几种人类 疾病，包括动脉粥样硬化、炎性病症，以及 老年痴呆症 有三个具体目标。 第一个目标的研究将审查 硫氧还蛋白还原酶再生抗坏血酸的机制 从它的氧化形式，并将建立在何种程度上， 在培养的人肝癌细胞（HepG2）中发生再循环。 新角色 低分子量硒蛋白，以提高能力， 硫氧还蛋白还原酶再循环抗坏血酸将被检查， 有计划纯化和表征一种或多种这些蛋白质， 鼠肝第二个目标的研究将检验以下假设： 硫氧还蛋白还原酶既节省α-生育酚， 通过减少脂质双层中的脂质过氧化氢来进行过氧化。 的 硫氧还蛋白还原酶和谷胱甘肽的相对贡献 过氧化物酶对这种保护作用的影响将使用差异 这些酶对HepG2细胞中硒缺乏的敏感性。 在 第三个目标，几内亚复合营养素缺乏的膳食模型 将建立猪来检查硒能在多大程度上 防止抗坏血酸和α-生育酚的氧化损失。 像 人类和豚鼠不能合成抗坏血酸。 因此，使用 抗坏血酸缺乏的动物将提供体内测试的手段 硒是否能保存抗坏血酸，以及这是否有助于 α-生育酚的硒依赖性节约和预防 脂质过氧化

The goal of this project is to define a role for selenium in preventing oxidant damage, both in vitro and in vivo. Selenium, by as yet unknown mechanisms, has long been known to "spare" vitamin E from oxidative loss in animal dietary studies. Vitamin E, or alpha-tocopherol, is the primary chain-breaking antioxidant in lipoproteins and cell membranes that must be recycled from its oxidized form. Recycling of alpha- tocopherol is thought to be mediated, at least in part, by vitamin C, or ascorbic acid. This project will test hypotheses that the selenoenzyme thioredoxin reductase and other selenoproteins are crucial in recycling ascorbic acid, in preserving alpha-tocopherol and in preventing lipid peroxidative damage in cells and in animals. Accelerated lipid peroxidation has been associated with several human diseases, including atherosclerosis, inflammatory conditions, and Alzheimer's disease. There are three specific aims. Studies in the first aim will examine the mechanisms by which thioredoxin reductase regenerates ascorbic acid from its oxidized forms, and will establish the extent to which such recycling occurs in cultured human hepatoma cells (HepG2). A novel role for low molecular weight selenoproteins to enhance the ability of thioredoxin reductase to recycle ascorbate will be examined, and there are plans to purify and characterize one or more of these proteins from rat liver. Studies in the second aim will test the hypothesis that thioredoxin reductase both spares alpha-tocopherol and prevents lipid peroxidation by reducing lipid hydroperoxides in lipid bilayers. The relative contributions of thioredoxin reductase and the glutathione peroxidases to such protection will be assessed using the differential sensitivity of these enzymes to selenium deficiency in HepG2 cells. In the third aim, a dietary model of combined nutrient deficiency in guinea pigs will be established to examine the extent to which selenium can prevent oxidative loss of both ascorbate and alpha-tocopherol. Like humans, guinea pigs cannot synthesize ascorbic acid. Thus, use of ascorbate-deficient animals will provide the means to test in vivo whether selenium preserves ascorbate, and whether this contributes to selenium-dependent sparing of alpha-tocopherol and to prevention of lipid peroxidation.