Isolation & Evaluation of Anticarcinogenic Glucosinolate

描述（由申请人提供）：诱导细胞2期酶（例如，谷胱甘肽转移酶、葡萄糖醛基转移酶、NAD(P)H：醌氧化还原酶）和谷胱甘肽水平升高，现在被认为是降低由亲电致癌物和活性氧引起的肿瘤发生风险的有效策略。第二阶段酶基因的转录激活是由九类化学试剂引起的，其中许多化学试剂存在于可食用植物中，并且已经在我们的饮食中广泛使用（异硫氰酸酯、酚类、醌类、苯丙烯、迈克尔反应受体）。最终目标是确定低毒性的膳食2期酶诱导剂，从而适合于快速评估功效和长期在人类中使用。该项目侧重于对新型硫代葡萄糖苷（异硫氰酸酯的稳定生物前体）进行详细评估，硫代葡萄糖苷被广泛消费并被认为是潜在的有价值的抗癌保护剂。Aim 1旨在识别含有大量硫代葡萄糖苷的可食用植物，其结构特征先前已被证明可产生高诱导剂效力；并分离，结晶和表征这些硫代葡萄糖苷的足够数量的生物评价细胞和动物。Aim 2提出了一种不寻常的鼠李糖氧基苯基硫代葡萄糖苷（其对应的异硫氰酸酯是一种非常有效的第二阶段诱导性物质）的分离和详细表征，这种物质丰富于泛热带的所有部分，完全可食用，广泛消费的鸡腿树（辣木）。相关的多重糖基化硫代葡萄糖苷也将从各种辣木物种中分离出来，检查其诱导活性，并在适当的细胞和动物模型中评估其对致癌的抑制作用。目标3将在健康志愿者中建立仔细表征的含有特别感兴趣的硫代葡萄糖苷的植物提取物的吸收、药代动力学、代谢和排泄，从鼠李糖氧基苄基硫代葡萄糖苷及其同源异硫氰酸酯开始。这些药代动力学研究将为开发安全有效的人类膳食化学保护剂奠定基础。

DESCRIPTION (provided by applicant): Induction of cellular Phase 2 enzymes (e.g.,glutathione transferases, glucuronosyltransferases, NAD(P)H:quinone oxidoreductase) and elevation of glutathione levels are now recognized as effective strategies for reducing the risk of developing neoplasms caused by electrophilic carcinogens and reactive forms of oxygen. Transcriptional activation of the genes of Phase 2 enzymes is evoked by nine classes of chemical agents, many of which are present in edible plants and already widely consumed in our diets (isothiocyanates, phenols, quinones, phenylpropenoids, Michael reaction acceptors). The ultimate goals are to identify dietary Phase 2 enzyme inducers with low toxicity and consequently suitable for rapid evaluation of efficacy and long-term use in humans. This project focuses on a detailed evaluation of novel glucosinolates (the stable biological precursors of isothiocyanates) which are widely consumed and recognized as potentially valuable protectors against carcinogenesis. Aim 1 is designed to identify edible plants that contain substantial quantities of glucosinolates with structural features that have been previously shown to result in high inducer potency; and to isolate, crystallize, and characterize these glucosinolates in adequate quantities for biological evaluation in cells and animals. Aim 2 proposes the isolation and detailed characterization of an unusual rhamnosyloxybenzyl glucosinolate (whose corresponding isothiocyanate is an exceedingly potent Phase 2 inducer) that is abundant in all parts of the pantropical, totally edible, and widely consumed drumstick tree (Moringa oleifera). Related multiply glycosylated glucosinolates will also be isolated from various Moringa species, examined for inducer activity, and assessed for inhibition of carcinogenesis in appropriate cell and animal models. Aim 3 will establish in healthy volunteers the absorption, pharmacokinetics, metabolism and excretion of carefully characterized plant extracts containing glucosinolates of special interest, beginning with the rhamnosyloxybenzyl glucosinolate and its cognate isothiocyanate. These pharmacokinetic studies will set the stage for the development of safe and effective dietary chemoprotectors for human use.