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: 3179578
• 负责人: Jean-Pierre H Perchellet
• 金额: $ 8.08万
• 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/3179578
• 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-tetradecanoylphorbol-13-acetate（TPA）的最早反应之一 可能是活性氧物质的产生。 因此，抗氧化剂 它们终止自由基链式反应的能力 有望改变肿瘤促进过程。 我们最近的研究 实验室表明TPA迅速降低细胞内 表皮细胞还原型谷胱甘肽（GSH）/氧化型谷胱甘肽（GSSG） 停职 此外，用半胱氨酸（Cys）、GSH和 α-生育酚显著抑制表皮鸟氨酸的诱导 脱羧酶（ODC）活性的TPA，其中一个重要组成部分， 小鼠皮肤肿瘤的促进作用，以及皮肤肿瘤的发病率 启动-促进协议。 我们的研究结果表明，半胱氨酸和谷胱甘肽可能 抑制TPA诱导的ODC活性和促进皮肤乳头状瘤 通过增加细胞内GSH/GSSG的比例。 以来 Cys对GSH/GSSG比值的降低和 TPA对ODC活性的诱导作用被抑制剂大大降低 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是很重要的 GSH是一种天然抗氧化剂，可抑制化学致癌作用， 在皮肤肿瘤促进过程中。 首先，我们将研究各种因素的影响。 肿瘤促进剂对GSH水平、γ-GT和GSH过氧化物酶活性的影响，以及 离体表皮细胞中的O2产生。 第二，因为功能 含硫氨基酸、硒、维生素 E和GSH过氧化物酶已经假定，我们将确定是否治疗 包括GSH水平提高剂、硒氨基酸和α-生育酚 可能会增加抗氧化剂谷胱甘肽过氧化物酶保护系统的 细胞和抑制与皮肤肿瘤促进有关的氧化挑战。 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物， 多阶段皮肤肿瘤促进的抑制剂。 这些研究应该有助于 我们要确定新的抑制剂的皮肤致癌作用，一般应 更好地了解肿瘤促进的生物化学， 其规定。