RESEARCH PROJECT 4: Biomarker-based Evaluation of Human Interventions

研究项目 4：基于生物标志物的人类干预评估

• 批准号: 8376305
• 负责人: THOMAS A KENSLER
• 金额: $ 50.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376305
• 关键词: Acetylcysteine; Aflatoxins; Africa; Air; Anticarcinogenic Agents; Aromatic Polycyclic Hydrocarbons; Beverages; Biological Markers; Brassica; Broccoli - dietary; CYP1A1 gene; Cabbage - dietary; Carcinogens; Cauliflower; Chemicals; Chemoprevention; Chemopreventive Agent; China; Clinical Research; Clinical Trials; Consumption; DNA Adducts; Drug Kinetics; Edible Plants; Enzyme Induction; Enzymes; Erythrocytes; Evaluation; Excretory function; Exposure to; Food; Food Safety; GSTM1 gene; Genetic Crossing Over; Genotype; Glucosinolates; Glutathione S-Transferase; Goals; Hemoglobin; Human; Hydrolysis; India; Indigenous; Intervention; Intestines; Isothiocyanates; Lysine; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Methods; Metric; Molecular; Monitor; Moringa; Moringa oleifera; Myrosinase; Participant; Pattern; Pharmacodynamics; Phase; Phenols; Placebo Control; Plants; Population; Preparation; Primary carcinoma of the liver cells; Randomized; Raphanus; Rattus; Reactive Oxygen Species; Research Personnel; Risk; Rodent; Serum; Source; Sulforaphane; Taiwan; Toxic Environmental Substances; Transferase; Translating; Treatment Efficacy; Trees; Urine; Vegetables; Water; adduct; base; cancer type; carcinogenesis inhibitor; cytotoxic; design; glucoraphanin; gut microflora; high risk; mouse model; phenanthrene; preclinical study; toxicant; urinary

It is widely recognized that high levels of consumption of vegetables are associated with lower risks of developing several types of cancer. Certain cultivars of broccoli contain singularly elevated levels of the glucosinolate, glucoraphanin (GR), which yields the isothiocyanate sulforaphane upon hydrolysis. Both sulforaphane and GR (as a broccoli sprout hot water extract) are inhibitors of carcinogenesis in rodents. The discovery that GR levels are highest in young broccoli plants (3-day-old sprouts) prompted the hypothesis that sprouts are safe, effective, inexpensive, and practical means to achieve chemoprevention. Initial clinical studies have characterized the pharmacokinetics of broccoli sprout preparations in humans and have established the safety of this food under circumstances of normal consumption patterns. Therefore, the goals of this project are to use chemical biomarkers to assess the efficacy of chemoprevention interventions with broccoli sprouts in populations in Qidong, China exposed to high levels of food (aflatoxins) and air-borne toxicants (alkylanilines and polycyclic aromatic hydrocarbons). The specific aims in Project 4 are (1) to compare, in a short-term cross-over clinical trial, the bioavailablity of sulforaphane from broccoli sprouts in two forms: enterically generated from glucoraphanin by gut microflora; or pre-released by treatment with myrosinase from the plant daikon. Urinary excretion of glucoraphanin/sulforaphane metabolites (dithiocarbamates) will be measured. Aim 2 will determine the pharmacodynamic impact of the broccoli sprout intervention on phenanthrene metabolism to phenols, tetraols and mercapturic acids using mass spectrometry. Aim 3 will extend these findings by determining whether a 3-month placebo-controlled, randomized broccoli sprout intervention modulates biomarker levels in residents of Qidong. Aflatoxin-DNA adducts in the urine and aflatoxin-lysine adducts in the serum (Project 1) along with secondary endpoints of alkylaniline-hemoglobin in red blood cells and excreted urinary metabolites including alkylaniline-DNA adducts (Project 3) and mercapturic acids and phenanthrene tetraol metabolites resulting from exposures to air toxics will be measured. Aim 4 is designed to monitor and understand source for exposures to the alkylanilines and phenanthrenes in residents of Qidong. Lastly, Aim 5 will evaluate the pharmacokinetics, pharmacodynamic action and chemopreventive efficacy of Moringa oleifera ("Drumstick" tree), an edible plant indigenous to West Africa and India containing the potent enzyme inducer 4-(rhamnopyranosyloxy)- benzyl glucosinolate, in rat and mouse models. Results from these preclinical studies will provide impetus to consider conducting Moringa-based interventions in populations at high-risk for liver cancer in West Africa (Project 2). Collectively, these studies will define the utility and efficacy of culturally appropriate, affordable, safe foods for interventions in populations with unavoidable exposures to environmental toxicants.

人们普遍认为，高水平的蔬菜消费与较低的患病风险有关 患上了几种癌症。某些品种的西兰花含有异常高水平的 硫代葡萄糖苷，硫萝卜素(GR)，它在水解时产生异硫氰酸酯萝卜硫酸酯。两者都有 萝卜硫素和GR(作为一种西兰花芽热水提取物)是啮齿动物致癌的抑制剂。这个 发现花椰菜幼苗(3天大的芽)的GR水平最高，这促使了这一假说的提出。 芽苗是实现化学预防的安全、有效、廉价和实用的手段。初期临床 研究已经表征了西兰花芽制剂在人体内的药代动力学，并 确立了该食品在正常消费模式下的安全性。因此，目标是 该项目的主要目的是使用化学生物标记物评估化学预防干预措施的有效性。 启东地区花椰菜发芽人群中中国接触高水平食物(黄曲霉毒素)和空气传播 有毒物质(烷基苯胺和多环芳香烃)。项目4的具体目标是：(1) 在短期交叉临床试验中，比较从西兰花芽中提取的萝卜硫素的生物利用度 两种形式：由肠道微生物群通过肠道产生的葡萄糖胺；或通过处理预先释放 黛空植物中的黑芥子酶。萝卜素/萝卜硫素代谢物的尿排出 (二硫代氨基甲酸盐)将被测量。目标2将确定西兰花的药效学影响 质量法对菲对苯酚、四醇和硫代尿酸代谢的干预 光谱分析。AIM 3将通过确定为期3个月的安慰剂对照、 西兰花芽随机干预对启东市居民生物标记物水平的影响。黄曲霉毒素-DNA 尿液中的加合物和血清中的黄曲霉毒素-赖氨酸加合物(项目1)以及 红细胞和尿液代谢物中的烷基苯胺-血红蛋白 加合物(项目3)以及接触以下物质所致的硫代尿酸和菲四醇代谢物 空气中的有毒物质将被测量。AIM 4旨在监测和了解暴露于 启东市居民中的烷基苯胺和菲。最后，Aim 5将评估药物动力学， 食用辣木的药效学作用及化学预防效果 一种原产于西非和印度的植物，含有有效的酶诱导剂4-(鼠李糖基)- 苯硫代葡萄糖苷，在大鼠和小鼠模型中。这些临床前研究的结果将推动 考虑在西非肝癌高危人群中进行基于Moringa的干预 (项目2)。总而言之，这些研究将确定适合文化的、负担得起的、 对不可避免地暴露于环境毒物的人群进行干预的安全食品。