Isolation & Evaluation of Anticarcinogenic Glucosinolate

描述(由申请人提供)：诱导细胞第二相酶(例如谷胱甘肽转移酶、葡萄糖醛酸基转移酶、NAD(P)H：苯醌氧化还原酶)和提高谷胱甘肽水平现在被认为是降低由亲电致癌物和氧的活性形式引起的肿瘤风险的有效策略。第二阶段酶基因的转录激活是由九类化学试剂引起的，其中许多存在于可食用植物中，并已在我们的饮食中广泛消费(异硫氰酸盐、酚、苯醌、苯丙烯、Michael反应受体)。最终目标是确定低毒的饮食第二阶段酶诱导剂，从而适合于快速评估疗效和在人类身上长期使用。本项目的重点是对新的硫代葡萄糖苷(异硫氰酸酯的稳定生物前体)进行详细评估，这些化合物被广泛消费并被认为是潜在的有价值的抗癌保护剂。AIM 1旨在鉴定含有大量硫代葡萄糖苷的可食用植物，这些硫代葡萄糖苷具有先前已被证明具有高诱导剂效力的结构特征；并分离、结晶和表征足够数量的这些硫代葡萄糖苷以用于细胞和动物的生物学评价。目的2分离和详细鉴定了一种罕见的鼠李糖氧基苄基硫代葡萄糖苷(其对应的异硫氰酸酯是一种非常有效的第二相诱导剂)，该化合物在泛热带、完全可食用和广泛食用的鸡腿树(Moringa Oleifera)的所有部分都有丰富的存在。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，检查诱导剂活性，并在适当的细胞和动物模型中评估抑制致癌作用。目的3将在健康志愿者中建立包含特别感兴趣的硫代葡萄糖苷的仔细表征的植物提取物的吸收、药代动力学、代谢和排泄，首先是鼠李糖氧基苄基硫代葡萄糖苷及其同系物异硫氰酸盐。这些药代动力学研究将为开发安全有效的人类饮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.