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效应的敏感性。 这个项目利用了许多化学物质 (一些存在于可食用植物中)防癌，也是诱导期 2解毒酶，如谷胱甘肽转移酶(GST)和NAD(P)H： (对苯二酚受体)氧化还原酶(对苯二酚还原酶；OR)，并升高 组织谷胱甘肽水平。这种细胞反应增强了 处理致癌物质。化学保护酶诱导剂有很多种 结构类型，要么是单功能(提升阶段2酶 选择性地)，或双功能(提高两个相1酶[细胞色素P- 450]和动物细胞和组织中的第二相酶[例如QR、GST]。 几乎所有的单功能诱导剂都是亲电的。在AIM 1.1中，诱导剂- 在高密度条件下，实验室将培育出丰富的可食用植物。 标准化的条件，它们的诱导剂的化学成分将是 特色化的。由于异硫氰酸酯类萝卜硫醚[1-异硫氰酸酯-4- (甲基亚硫基)丁烷]是一些 各种十字花科植物(西兰花)，并阻止乳腺癌的形成 大鼠，一个重大的新方向就是研究其作用机制。 异硫氰酸酯的抗癌作用(目标1.2)。什么是 2相酶诱导与1相酶的相对重要性 抑制癌变，以及GSTs在肿瘤发生中的作用 异硫氰酸酯代谢。在DMBA中，AIM 1.3旨在评估 萝卜硫素对大鼠乳腺肿瘤模型的抗癌作用 和合成类似物，高诱导性植物和其他相2酶 将被分离或合成的诱导剂。目标1.4是确定 与诱导剂反应的初级细胞信号蛋白(S)，并 阐明2相酶调控的分子机制 诱导者。拟议的分子、细胞、植物和动物研究将 确定新的化学保护剂，阐明其作用机制，并评估 它们在动物身上的功效。他们还将提供可食用的制剂 项目建议的富含诱导剂和适合人体研究的植物 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.