RESEARCH PROJECT 4: Biomarker-based Evaluation of Human Interventions

人们普遍认为，高水平的蔬菜消费与较低的风险有关。 发展成几种癌症。某些品种的花椰菜含有异常高水平的 芥子油苷，萝卜硫苷（GR），其在水解时产生异硫氰酸酯萝卜硫素。两 萝卜硫素和GR（作为花椰菜芽热水提取物）是啮齿类动物致癌作用的抑制剂。的 一项发现是，GR水平在年轻的花椰菜植株（3天大的芽）中最高，这一发现促使了这一假设 芽苗菜是安全、有效、廉价和实用的化学预防方法。初始临床 研究已经表征了花椰菜芽制剂在人体内的药代动力学， 在正常消费模式下确定了这种食品的安全性。因此，目标 该项目的目的是使用化学生物标志物来评估化学预防干预的有效性， 中国启东暴露于高水平食物（黄曲霉毒素）和空气传播的西兰花芽 有毒物质（烷基苯胺和多环芳烃）。项目4的具体目标是：（1） 在一项短期交叉临床试验中， 两种形式：通过肠道微生物菌群从萝卜硫苷肠内产生;或通过用 白萝卜中的黑芥子酶。萝卜硫苷/萝卜硫素代谢产物的尿排泄 （二硫代氨基甲酸酯）将被测量。目标2将确定西兰花的药效学影响 芽期激素对菲代谢为酚类、四醇类和巯基尿酸影响 光谱法目标3将通过确定3个月安慰剂对照， 随机西兰花芽干预调节启东居民的生物标志物水平黄曲霉毒素-DNA 尿液中的黄曲霉毒素-赖氨酸加合物和血清中的黄曲霉毒素-赖氨酸加合物（项目1），沿着次要终点 红细胞中的烷基苯胺-血红蛋白和排泄的尿液代谢物，包括烷基苯胺-DNA 加合物（项目3）以及巯基尿酸和菲四醇代谢物， 将测量空气中的有毒物质。目标4的目的是监测和了解暴露源， 启东市居民的烷基苯胺和菲。最后，目标5将评价药代动力学， 辣木（"鼓槌"树）的药效学作用和化学预防功效， 原产于西非和印度的一种植物，含有有效的酶诱导剂4-（鼠李吡喃糖基氧基）- 苄基芥子油苷，在大鼠和小鼠模型。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开展基于辣木的干预措施 （项目2）。总的来说，这些研究将确定文化上适当的，负担得起的， 为不可避免地暴露于环境毒物的人群提供安全食品。

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.