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: 8278591
• 负责人: THOMAS A KENSLER
• 金额: $ 50.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278591
• 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风险有关 发展几种类型的癌症。西兰花的某些品种含有单一升高的水平 葡萄糖苷，葡萄糖磷酸（GR），在水解后产生异硫氰酸硫酸硫素。两个都 硫烷和GR（作为西兰花发芽热水提取物）是啮齿动物中癌变的抑制剂。这 发现年轻的西兰花植物（3天芽）中GR水平最高的促进了假设 这些芽具有安全，有效，廉价且实用的手段，以实现化学预防。最初的临床 研究表征了人类西兰花发芽制剂的药代动力学，并具有 在正常消费模式的情况下确定了这种食物的安全性。因此，目标 这个项目的是使用化学生物标志物评估化学预防干预措施的功效 中国Qidong的西兰花芽 有毒物质（烷基苯胺和多环芳烃）。项目4中的具体目的是（1） 比较在短期跨界临床试验中，从西兰花芽中的磺胺硫酸盐的生物利用度 两种形式：由肠道菌群从葡萄糖磷酸产生的肠道;或通过使用 Daikon植物的桃粒酶。葡萄磷酸/磺磷酸硫素代谢产物的尿液排泄 （二硫代氨基烷）将进行测量。 AIM 2将确定西兰花的药效学影响 使用质量对苯酚，四酚和苏联酸对酚类代谢的发芽干预 光谱法。 AIM 3将通过确定3个月的安慰剂对照来扩展这些发现， 随机西兰花发芽干预调节Qidong居民的生物标志物水平。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）以及次要终点 红细胞中的烷基苯胺 - 血红蛋白和包括烷基烷氨酸-DNA的排泄泌尿代谢产物 加合物（项目3），硫酸酸和苯哲二氟代谢产生的代谢产生。 将测量空气毒物。 AIM 4旨在监视和理解接触的来源 Qidong居民的烷基苯胺和3h苯胺。最后，AIM 5将评估药代动力学， 莫林加（Moringa oleifera 西非和印度的植物土著植物含有有效的酶诱导剂4-（鼠李糖酸糖） - 大鼠和小鼠模型中的苄基葡萄糖苷。这些临床前研究的结果将为 考虑在西非的高风险肝癌中对基于辣木的干预措施 （项目2）。总的来说，这些研究将定义文化适当，负担得起的效用和功效 安全食品，用于对环境有毒物质的不可避免的人口干预措施。