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、葡萄糖醛酸基转移酶、NAD（P）H：醌氧化还原酶）和谷胱甘肽水平的升高现在被认为是降低发生由亲电子致癌物和活性形式的氧引起的肿瘤的风险的有效策略。第二阶段酶的基因的转录激活由九类化学试剂引起，其中许多存在于可食用植物中，并且已经在我们的饮食中广泛消费（异硫氰酸酯、酚类、醌类、苯丙烯类、迈克尔反应受体）。最终目标是确定具有低毒性的饮食2期酶诱导剂，从而适合于快速评估功效和长期用于人类。该项目的重点是详细评估新的芥子油苷（异硫氰酸酯的稳定生物前体），这是广泛消费和公认的潜在有价值的保护剂，防止致癌。目的1旨在鉴定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导致高诱导剂效力;并分离、结晶和表征这些硫代葡萄糖苷的足够数量，用于细胞和动物的生物学评价。目的2提出了一种不寻常的鼠李糖基氧基苄基芥子油苷（其相应的异硫氰酸酯是一个非常有效的第2阶段诱导剂），是丰富的泛热带，完全可食用，广泛消费的鼓槌树（辣木）的所有部分的分离和详细的表征。还将从各种辣木属物种中分离相关的多重糖基化芥子油苷，检查诱导剂活性，并在适当的细胞和动物模型中评估对致癌作用的抑制。目标3将建立在健康志愿者的吸收，药代动力学，代谢和排泄的仔细表征的植物提取物含有特别感兴趣的硫代葡萄糖苷，从鼠李糖氧基苄基硫代葡萄糖苷及其同源异硫氰酸酯。这些药代动力学研究将为人类使用的安全有效的饮食化学保护剂的开发奠定基础。

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.