SELENIUM METABOLISM AND CHEMOPREVENTION

硒代谢和化学预防

• 批准号: 2087631
• 负责人: CLEMENT C IP
• 金额: $ 18.67万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2087631
• 关键词: arsenic; benzanthracenes; blood tests; breast neoplasms; cancer prevention; cancer risk; carcinogenesis inhibitor; cellular oncology; chemical carcinogenesis; chemoprevention; corticosteroid receptors; diet therapy; dietary lipid; dietary supplements; dietary trace element; disease /disorder model; fluorimetry; gel electrophoresis; glutathione peroxidase; hormone binding protein; laboratory rat; ligands; membrane proteins; metal metabolism; methionine; nutrition related tag; peroxidation; protein biosynthesis; selenium; selenomethionine; stainings; tissue /cell preparation

Metabolism alters the chemical form of selenium (Se) and plays a key role in determining its biological activity. Our current approach is directed towards providing information of how Se metabolism could play a role in cancer prevention. There are 5 specific aims in this proposal. Aim 1 is designed to study the in vivo metabolism of Se under conditions in which selenite and selenomethionine are found to have anticarcinogenic activities. Experiments will be carried out to quantitate 4 classes of Se metabolites: hydrogen selenide, methylselenol, dimethylselenide and trimethylselenonium. The objective is to characterize the profile of Se metabolites with respect to dose, forms of Se administered, length of exposure and other modifying factors in an attempt to determine whether the excretion of certain metabolite(s) can be correlated with the anticarcinogenic efficacy of selenite or selenomethionine treatment. The work proposed in Aim 2 is an extension of Aim 1, but advances the concept to a direct individual Se metabolism and cancer risk correlation study. Rats with different sensitivities to Se-mediated inhibition of DMBA-induced mammary carcinogenesis will be used. Animals that develop multiple tumors with a short latent period will be compared in their ability to metabolize Se with those that are tumor-free at the same time point subsequent to Se supplementation. Aim 3 is designed to investigate the modulation of Se chemoprevention and Se metabolism by arsenic. Preliminary study from our laboratory has shown that arsenite reduced the anticarcinogenic response to selenite. A dose titration study with arsenite will be carried out in order to validate the specificity of the arsenite effect. Results of this experiment will be integrated with that from Aim 1 with the objective of cementing the hypothesis regarding the essentiality of the generation of critical Se intermediates in cancer prevention. The in vivo Se metabolism studies only measure the overall capacity of the host to handle a given load of a Se compound, but provides no information on the type and level of Se metabolites in tissues, or the extent of Se binding to cellular proteins. Aim 4 is therefore targeted towards determination of the last two parameters in liver, kidney, muscle and the mammary gland. The results from this study will answer the question of whether tissues retain inorganic and methylated Se metabolites, and if so, how much. Aim 5 is focused on studying the interference by Se on the activity of specific regulatory proteins. The glucocorticoid receptor is chosen here as the prototype protein model because the cysteine residues in the hormone binding domain are very sensitive to sulfhydryl modification of functional activity. Consequently the binding of Se to the -SH groups may alter ligand binding capacity or affinity. Experiments are designed to investigate the physical association of Se with the glucocorticoid receptor, the chemical form of Se involved, and the nature of the inhibition of hormone binding to the receptor. Information obtained from this project will be used to study the effect of Se on other cytoplasmic and cell membrane regulatory proteins.

代谢改变硒的化学形式并起关键作用 在确定其生物学活性时。 我们当前的方法是指导的 为了提供有关SE代谢如何在中发挥作用的信息 预防癌症。 该提案中有5个具体目标。 目标1是 旨在研究SE的体内代谢 发现硒石和硒甲氨酸具有抗癌作用 活动。 将进行实验以量化4类SE 代谢物：硒化氢，甲基塞烯醇，二甲基塞雷尼德和 三甲基塞林尼群。 目的是表征SE的轮廓 代谢物相对于剂量，施用的SE形式，长度的长度 暴露和其他修改因素试图确定是否是否 某些代谢产物的排泄可以与 亚硒酸盐或硒甲米氨酸治疗的抗癌疗法。 这 AIM 2中提出的工作是AIM 1的扩展，但提出了概念 进行直接的个人SE代谢和癌症风险相关研究。 对DMBA诱导的SE介导的抑制作用的敏感性不同的大鼠 将使用乳腺癌发生。 发展多个肿瘤的动物 在短时间内将比较其代谢的能力 SE与SE之后的同一时间点无肿瘤的SE 补充。 AIM 3旨在研究SE的调制 砷的化学预防和SE代谢。 我们的初步研究 实验室表明，砷减少了对 亚硒酸盐。 将在砷中进行剂量滴定研究 为了验证砷效应的特异性。 结果 实验将与AIM 1集成为目标 巩固有关产生的本质的假设 癌症预防中的关键SE中间体。 体内新陈代谢 研究仅衡量宿主处理给定的总体能力 SE化合物的负载，但没有提供有关类型和水平的信息 组织中的SE代谢物或SE与细胞结合的程度 蛋白质。 因此，目标4是针对确定最后的目标 肝脏，肾脏，肌肉和乳腺的两个参数。 结果 从这项研究中将回答组织是否保留的问题 无机和甲基化的SE代谢产物，如果是，多少。 目标5是 专注于研究SE对特定活性的干扰 调节蛋白。 在此选择糖皮质激素受体 原型蛋白质模型，因为激素中的半胱氨酸残基 结合结构域对功能的硫瑞尔尔的修饰非常敏感 活动。 因此，SE与-SH组的结合可能会改变 配体结合能力或亲和力。 实验被设计为 研究SE与糖皮质激素的物理关联 受体，涉及的化学形式，以及 抑制激素与受体的结合。 从中获得的信息 该项目将用于研究SE对其他细胞质的影响 和细胞膜调节蛋白。