MECHANISMS OF PROTECTION AGAINST CANCER BY INDUCTION OF PHASE 2 ENZYMES

通过诱导 2 相酶预防癌症的机制

• 批准号: 6102351
• 负责人: PAUL TALALAY
• 金额: $ 22.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102351
• 关键词: Cruciferae; NAD(P)H dehydrogenase; affinity chromatography; aflatoxins; antioxidants; benzanthracenes; carcinogen testing; carcinogenesis inhibitor; chemical carcinogenesis; cytochrome P450; enzyme induction /repression; enzyme inhibitors; gel mobility shift assay; genetic enhancer element; isothiocyanates; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; nutrition related tag; plant extracts; recombinant proteins; transcription factor

The overall goals of this project are to lower the risk of cancer by reducing susceptibility to the toxic and neoplastic effects of carcinogens. This project exploits the well-established observation that many chemicals (some present in edible plants) protect against cancer an also induce Phase 2 detoxication enzymes such as glutathione transferases (GST) and NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase; OR), and elevate tissue glutathione levels. This cellular response boosts the capacity to dispose of carcinogens. Chemoprotective enzyme inducers are of many structural types, an are either monofunctional (elevate Phase 2 enzymes selectively), or bifunctional (elevate both Phase 1 enzymes [cytochromes P- 450] and Phase 2 enzymes [e.g., QR,GST] in animal cells and tissues. Nearly all monofunctional inducers are electrophilic. In Aim 1.1 inducer- rich edible plants will be produced in the laboratory under highly standardized conditions, and the chemistry of their inducers will be characterized. Since the isothiocyanate sulforaphane [1-isothiocyanato-4- (methylsulfinyl)butane] is the principal monofunctional inducer of some varieties of crucifers (broccoli), and blocks mammary tumor formation in rats, a major new direction is the study of the mechanism of the anticarcinogenic actions of isothiocyanates (Aim 1.2). What is the relative importance of Phase 2 enzyme induction and Phase 1 enzyme inhibition in blocking carcinogenesis, and what is the role of GSTs in isothiocyanate metabolism. Aim 1.3 is designed to evaluate, in the DMBA rat mammary tumor model, the anticarcinogenic properties of sulforaphane and synthetic analogs, of high inducer plants, and of other Phase 2 enzyme inducers that will be isolated or synthesized. Aim 1.4 is to identify the primary cellular signaling protein(s) that react with the inducers, and to elucidate the molecular mechanisms of the regulation of Phase 2 enzymes by inducers. The proposed molecular, cellular, plant and animal studies will identify new chemoprotectors, throw light on their mechanisms, and assess their efficacy in animals. They will also provide preparations of edible plants rich in inducers and suitable for human studies proposed in Project No. 2.

该项目的总体目标是通过 减少对致癌物的毒性和肿瘤作用的敏感性。 该项目利用了许多化学物质的公认观察 （有些存在于食用植物中）预防癌症也会诱导阶段 2种解毒酶，例如谷胱甘肽转移酶（GST）和NAD（P）H： （奎因酮受体）氧化还原酶（喹酮还原酶; OR），并升高 组织谷胱甘肽水平。 这种细胞反应可以提高 处置致癌物。 化学保护酶诱导剂是许多 结构类型，A是单功能的（抬高2期酶 有选择地）或双功能（升高两个相1酶[细胞色素p- 450]和第2阶段的酶[例如，QR，GST]在动物细胞和组织中。 几乎所有单官能诱导剂都是亲电的。 在AIM 1.1诱导器中 丰富的可食用植物将在实验室生产高度 标准化条件，其诱导者的化学反应将是 特征。 由于异硫氰酸硫酸硫烷[1-异硫氰酸盐-4-- （甲基硫芬）丁烷]是某些的主要单官能诱导剂 十字花序（西兰花）的品种，并阻塞乳腺肿瘤形成 大鼠，一个主要的新方向是研究 异硫氰酸酯的抗癌作用（AIM 1.2）。 什么是 阶段2酶诱导和1阶段酶的相对重要性 抑制癌变中的抑制作用，GST在 异硫氰酸酯代谢。 AIM 1.3旨在评估DMBA 大鼠乳腺肿瘤模型，磺胺的抗癌特性 和合成类似物，高诱导剂植物和其他2阶段酶 将被隔离或合成的诱导者。 目标1.4是确定 与诱导剂反应的一级细胞信号传导蛋白，并 阐明2期酶调节的分子机制 诱导者。 提出的分子，细胞，动植物研究将 识别新的化学保护器，阐明其机制并评估 它们在动物中的功效。 他们还将提供可食用的准备 富含诱导剂的植物，适合项目中提出的人类研究 第2号。