GLUTATHIONE METABOLISM DURING SKIN TUMOR PROMOTION

对12-0-十四酰佛波醇-13-乙酸酯(TPA)最早的反应之一 可能是产生了活性氧物种。因此，抗氧化剂 它们终止自由基链反应的能力将是 预计将修改肿瘤促进过程。我们最近的研究 实验室研究表明，TPA能迅速降低细胞内比例。 表皮细胞中还原型谷胱甘肽(GSH)/氧化型谷胱甘肽(GSSG) 停职。此外，半胱氨酸(Cys)、谷胱甘肽(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，其中一个重要成分 小鼠皮肤肿瘤的促进作用以及皮肤肿瘤的发生率 启动-促进协议。我们的发现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。自.以来 半胱氨酸对小鼠GSH/GSSG比值降低和GSH/GSSG比值降低的抑制作用 抑制剂可显著降低TPA对ODC活性的诱导作用 γ-谷氨酰转肽酶和γ-谷氨酰半胱氨酸 合成酶，我们认为严格研究新陈代谢是很重要的 GSH是一种天然抗氧化剂，可以抑制化学致癌作用， 在皮肤肿瘤推广期间。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 在分离的表皮细胞中产生氧气。第二，因为功能性 含硫氨基酸与硒、维生素的相互关系 E，和GSH过氧化物酶已经被推测，我们将确定是否治疗 包括谷胱甘肽提高剂、硒氨基酸和α-生育酚 可能会增加抗氧化的GSH过氧化物酶保护系统 并抑制与促进皮肤肿瘤有关的氧化挑战。 最后，我们将确定联合治疗的有效性 谷胱甘肽提高剂、含硒化合物和 α-生育酚作为TPA对GSH代谢影响的修饰剂 依赖GSH的抗氧化保护系统的刺激物和 多阶段皮肤肿瘤促进剂的抑制剂。这些研究应该会有所帮助 美国寻找新的皮肤癌抑制剂，总体上应该 更好地了解促进肿瘤的生物化学和 它的规定。

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.