MECHANISMS OF PROTECTION AGAINST CANCER BY INDUCTION OF PHASE 2 ENZYMES

该项目的总体目标是通过以下方式降低癌症风险： 降低对致癌物的毒性和肿瘤作用的敏感性。 该项目利用了一个公认的观察结果，即许多化学品 (some存在于可食用植物中）预防癌症，也诱导阶段 2种解毒酶，如谷胱甘肽转移酶（GST）和NAD（P）H： （醌受体）氧化还原酶（醌还原酶; OR），并提高 组织谷胱甘肽水平 这种细胞反应增强了 处理致癌物质。 化学保护酶诱导剂是许多 结构类型，或者是单功能（升高的2相酶 选择性地），或双功能的（提高两种1相酶[细胞色素P- 450]和2期酶[例如，QR，GST]在动物细胞和组织中。 几乎所有的单功能诱导剂都是亲电的。 In Aim 1.1诱导剂- 丰富的食用植物将在实验室中生产的高度下， 标准化的条件下，他们的化学诱导剂将是 表征了 由于异硫氰酸酯萝卜硫素[1-异硫氰酸基-4-（4-氨基苯基）-1-甲基-2-甲基-2-甲基-1-苯基] （甲基亚磺酰基）丁烷]是一些主要的单功能诱导剂 十字花科植物（花椰菜），并阻止乳腺肿瘤的形成， 大鼠，一个主要的新方向是研究的机制， 异硫氰酸酯的抗癌作用（目的1.2）。 是什么 2期酶诱导和1期酶的相对重要性 抑制在阻断致癌作用中的作用，GST在 异硫氰酸盐代谢。 目标1.3旨在评估，在DMBA 大鼠乳腺肿瘤模型，莱菔硫烷的抗癌作用 和合成类似物，高诱导植物，和其他阶段2酶 将被分离或合成的诱导剂。 目标1.4是确定 与诱导剂反应的主要细胞信号蛋白， 阐明2相酶调节的分子机制， 诱导剂。 拟议的分子、细胞、植物和动物研究将 识别新的化学保护剂，阐明其机制，并评估 在动物身上的功效。 他们还将提供可食用的 项目中提出的富含诱导剂且适合人类研究的植物 号2.

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.