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.

最早对12-0-四烷酰基-13-乙酸盐（TPA）的反应之一 可能是活性氧的产生。 因此，抗氧化剂 终止自由基链反应的能力将是 预计会改变肿瘤促进过程。 我们最近的研究 实验室表明TPA迅速降低了细胞内比率 表皮细胞中还原的谷胱甘肽（GSH）/氧化的谷胱甘肽（GSSG） 悬架。 此外，用半胱氨酸（CYS），GSH和 α-生育酚显着抑制表皮鸟氨酸 TPA的脱羧酶（ODC）活性是TPA的活性，这是一个必不可少的组成部分之一 小鼠皮肤肿瘤促进以及皮肤肿瘤的发生率 启动促进协议。 我们的发现表明CYS和GSH可能 抑制TPA诱导的ODC活性和促进皮肤乳头状瘤 通过增加GSH/GSSG的细胞内比率。 自从 CYS对GSH/GSSG和GSSG比率下降的抑制作用和 抑制剂大大降低了TPA的ODC活性的诱导 γ-谷氨酰胺转肽酶（伽马 - GM）和γ-谷氨酰半胱氨酸的含量 合成酶，我们认为严格研究新陈代谢很重要 GSH是一种抑制化学癌变的天然抗氧化剂 在促进皮肤肿瘤期间。 首先，我们将研究各种的影响 GSH水平，γ-GT和GSH过氧化物酶活性的肿瘤启动子，以及 孤立表皮细胞中的O2产生。 第二，因为功能 含硫氨基酸，硒，维生素之间的相互关系 E和GSH过氧化物酶已经假设，我们将确定是否治疗 包括GSH升级剂，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有关的氧化挑战。 最后，我们将确定合并治疗与 GSH升级剂，含硒的化合物和 α-生育酚作为TPA对GSH代谢的影响的修饰符， 依赖GSH的抗氧化剂保护系统的刺激剂 多抗皮肤肿瘤促进的抑制剂。 这些研究应该有助于 我们确定皮肤致癌的新抑制剂，通常应该 更好地了解肿瘤促进的生物化学和 它的监管。