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

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.