CHEMICAL TOXICITY AND GLUTATHIONE REGULATION

研究的目标是确定细胞的作用和地位 在细胞防御系统中对反应性起作用的成分 从有毒化学品中提取的中间体。被调查的特工 谷胱甘肽(GSH)、维生素E(α-生育酚)和维生素C (L-抗坏血酸)。这些研究是在老鼠身上进行的 肝细胞模型在其细胞防御中受到损害 抗化学诱导的细胞损伤和死亡的机制。模特们 包括具有以下任一项细胞：1)不可逆灭活的谷胱甘肽 还原酶，2)由于分离到低水平的谷胱甘肽过氧化物酶 来自缺硒饮食的大鼠，3)维生素E缺乏症 从缺乏维生素E饮食的大鼠中分离出来，4)受到 从培养液中省略钙，并通过以下方式耗尽GSH GSH耗尽剂，并放置在不含硫氨基的介质中 酸。这些肝细胞模型正被用来研究 一种假说，即细胞可能具有导致损伤和死亡的共同途径 暴露在许多有毒化学物质中，细胞防御系统的丧失 允许内源性氧化应激对显著的 细胞活力丧失的程度。提出了内生性的机制 氧化应激和化学诱导的氧化应激是这种变化 某些蛋白质的巯基的动态平衡会导致 细胞生存所需的硫醇/二硫化物氧化还原平衡。一项重大努力 将致力于阐明硫基混合蛋白 在急性细胞损伤过程中形成的二硫化物。此外, 实验旨在确定谷胱甘肽、维生素E和维生素C 接触有毒物质期间肝细胞中的水平 环境保护剂是这些细胞保护剂的结果 具有电子抗氧化性，因此有可能“节约” 效果。正在努力确定细胞内的氧化还原是否 谷胱甘肽、维生素C和维生素E之间存在关系，涉及 电子和氢转移的不同速率可能有一个关键 在急性化学治疗期间和之后维持细胞活性的作用 诱导细胞损伤。具有特定磷脂的体外模型正在进行中 用来为解释来自 折衷肝细胞模型实验。正在使用的模型化学品 包括甲烷磺酸乙酯、溴苯、对乙酰氨基酚、A23187 阿霉素、过氧化叔丁基氢、过氧化甲乙酮和 1，3-双-(20氯乙基)-1-亚硝脲(BCNU)。

The research objective is to define the role and status of cellular constituents that function in cellular defense systems against reactive intermediates derived from toxic chemicals. The agents to be investigated are glutathione (GSH), vitamin E (alpha-tocopherol) and vitamin C (L-ascorbic acid). The studies are being conducted with rat hepatocytemodels that have been compromised in their cellular defense mechanisms against chemically induced cell injury and death. The models include cells that have either; 1) irreversibly inactivated glutathione reductase, 2) low levels of glutathione peroxidase due to being isolated from rats on a selenium deficient diet, 3) vitamin E deficiency due to being isolated from rats on a vitamin E deficient diet, 4) compromised by omission of calcium from the medium and 5) undergone depletion of GSH by GSH-depleting agents and placed in a medium that is free of sulfur amino acids. These hepatocyte models are being utilized to investigate the hypothesis that cells may have as a common pathway to injury and death from exposure to many toxic chemicals the loss of cellular defense systems which allows for endogenous oxidative stress to contribute to a significant degree to loss of cell viability. The mechanism proposed for endogenous oxidative stress and chemically induced oxidative stress is the alteration of the homeostasis of certain protein sulfhydryls leading to a loss of the thiol/disulfide redox balance needed for cell survival. A major effort will be devoted to the elucidation of the protein sulfhydryl mixed disulfides that are formed during acute cell injury. In addition, experiments are designed to determine if the GSH, vitamin E and vitamin C levels in hepatocytes during exposure to toxic agents including environmental agents are the result of these cellular protective agents having on electron antioxidant properties and thus possible "sparing" effects. Efforts are being made to determine if an intracellular redox relationship exists between GSH, vitamins C and E that involves differential rates of electron and hydrogen transfers that may have a key role in the maintenance of cell viability during and after acute chemically induced cell injury. In vitro models with specific phospholipids are being utilized to provide the basis for the interpretation of results from the compromised hepatocyte model experiments. Model chemicals being used include ethyl methanesulfonate, bromobenzene, acetaminophen, A23187, Adriamycin, t-butyl hydroperoxide, methyl ethylketone peroxide and 1,3-bis-(20chlorethyl)-1-nitrosourea (BCNU).