GLUTATHIONE METABOLISM DURING SKIN TUMOR PROMOTION

皮肤肿瘤促进过程中的谷胱甘肽代谢

• 批准号: 3179575
• 负责人: Jean-Pierre H Perchellet
• 金额: $ 7.77万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3179575
• 关键词: aminoacid metabolism; antioxidants; carcinogenesis inhibitor; chemical carcinogen; chemical carcinogenesis; glutathione; phorbols; radiotracer; scintillation spectrometry; skin neoplasms; spectrometry; toxin metabolism; tumor promoters

One of the earliest responses to 12-0-tetradecanoylphorbol-13-acetate (TPA) may be the generation of reactive oxygen species. Therefore, antioxidants with their capacity to terminate free radical chain reactions would be expected to modify the tumor promotion process. Recent studies from our laboratory indicate that TPA decreases rapidly the intracellular ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) in epidermal cell suspensions. Moreover, treatments with cysteine (Cys), GSH and Alpha-tocopherol inhibit dramatically the induction of epidermal ornithine decarboxylase (ODC) activity by TPA, one of the essential components of mouse skin tumor promotion, as well as the incidence of skin tumors in the initiation-promotion protocol. Our findings suggest that Cys and GSH might inhibit TPA-induced ODC activity and the promotion of skin papillomas through an increase in the intracellular ratio of GSH/GSSG. Since the inhibitory effects of Cys on both the decrease in the ratio of GSH/GSSG and the induction of ODC activity by TPA are greatly reduced by the inhibitors of Gamma-glutamyl transpeptidase (Gamma-GT) and Gamma-glutamylcysteine synthetase, we believe it is important to rigorously study the metabolism of GSH, a natural antioxidant which inhibits chemical carcinogenesis, during skin tumor promotion. First, we will study the effects of various tumor promoters on GSH level, Gamma-GT and GSH peroxidase activities, and O2 production in isolated epidermal cells. Second, because functional interrelationships between sulfur-containing amino acids, selenium, vitamin E, and GSH peroxidase have been postulated, we will determine if treatments including GSH level-raising agents, selenoamino acids and Alpha-tocopherol might increase the antioxidant GSH peroxidase protective system of the cells and inhibit the oxidative challenge linked to skin tumor promotion. Finally, we will determine the effectiveness of combined treatments with GSH level-raising agents, selenium-containing compounds and Alpha-tocopherol as modifiers of the effects of TPA on GSH metabolism, stimulators of the GSH-dependent antioxidant protective system and inhibitors of multistage skin tumor promotion. These studies should help us to identify new inhibitors of skin carcinogenesis and in general should provide a better understanding of the biochemistry of tumor promotion and its regulation.

对 12-0-十四烷酰佛波醇-13-乙酸酯 (TPA) 最早的反应之一 可能是活性氧的产生。 因此，抗氧化剂 其终止自由基链式反应的能力是 有望改变肿瘤促进过程。 我们最近的研究 实验室表明 TPA 会迅速降低细胞内的比率 表皮细胞中的还原型谷胱甘肽 (GSH)/氧化型谷胱甘肽 (GSSG) 悬浮液。 此外，半胱氨酸（Cys）、谷胱甘肽（GSH）和 α-生育酚显着抑制表皮鸟氨酸的诱导 TPA 的脱羧酶 (ODC) 活性，TPA 的重要成分之一 小鼠皮肤肿瘤的促进以及皮肤肿瘤的发生率 启动-促进协议。 我们的研究结果表明 Cys 和 GSH 可能 抑制TPA诱导的ODC活性并促进皮肤乳头状瘤 通过增加细胞内 GSH/GSSG 的比率。 自从 Cys对GSH/GSSG比值下降的抑制作用 抑制剂大大降低了 TPA 对 ODC 活性的诱导作用 γ-谷氨酰转肽酶 (γ-GT) 和 γ-谷氨酰半胱氨酸 合成酶，我们认为严格研究代谢非常重要 GSH，一种抑制化学致癌作用的天然抗氧化剂， 在皮肤肿瘤促进期间。 首先我们要研究各种因素的影响 GSH 水平、Gamma-GT 和 GSH 过氧化物酶活性的肿瘤促进剂，以及 分离的表皮细胞中氧气的产生。 二、因为功能性 含硫氨基酸、硒、维生素之间的相互关系 E 和 GSH 过氧化物酶已被假设，我们将确定是否进行治疗 包括谷胱甘肽水平提升剂、硒氨基酸和α-生育酚 可能会增加抗氧化剂 GSH 过氧化物酶保护系统 细胞并抑制与皮肤肿瘤促进相关的氧化挑战。 最后，我们将确定联合治疗的有效性 GSH水平提高剂、含硒化合物和 α-生育酚作为 TPA 对 GSH 代谢影响的调节剂， GSH 依赖性抗氧化保护系统的刺激剂和 多阶段皮肤肿瘤促进的抑制剂。 这些研究应该有帮助 我们应该找出新的皮肤癌抑制剂 提供对肿瘤促进的生物化学的更好理解 其监管。