ANTIOXIDANT INTERACTIONS OF SELENIUM AND VITAMINS

该项目的目标是确定硒在预防疾病中的作用 体外和体内的氧化损伤。硒，目前还不为人所知 长期以来，人们一直知道这种机制可以使维生素E免受氧化损失 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主要断链抗氧化剂 必须从其氧化形式中回收利用。回收利用阿尔法- 生育酚被认为至少部分是由维生素C介导的， 或者是抗坏血酸。这个项目将检验假设 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-生育酚和在 防止细胞和动物体内的脂质过氧化损伤。 加速的脂质过氧化与几种人类 疾病，包括动脉粥样硬化、炎症状况和 阿尔茨海默氏症。 有三个具体目标。第一个目标中的研究将检查 硫氧还蛋白还原酶再生抗坏血酸的机制 从其氧化形式，并将确定在多大程度上这种 在培养的人肝癌细胞(HepG2)中发生循环。新奇的角色 对于低分子量硒蛋白来说，可以增强其识别能力 将检测硫氧还蛋白还原酶以回收抗坏血酸，并在 是否计划从这些蛋白质中提纯并鉴定其中的一种或多种 老鼠肝。第二个目标的研究将检验这一假设 硫氧还蛋白还原酶既可节省α-生育酚，又可防止脂质 通过减少脂质双层中的脂质氢过氧化而产生的过氧化作用。这个 硫氧还蛋白还原酶与谷胱甘肽的相对贡献 过氧化物酶对这种保护作用的评估将使用差异 这些酶在HepG2细胞中对缺硒的敏感性。在……里面 第三个目标，建立豚鼠复合性营养缺乏的膳食模型 将建立猪来检查硒可以在多大程度上 防止维生素C和α-生育酚的氧化损失。喜欢 人类、豚鼠不能合成抗坏血酸。因此，使用 缺乏抗坏血酸的动物将提供体内测试的手段 硒是否保存抗坏血酸，以及这是否有助于 α-生育酚的硒依赖节余及其预防 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.