Clinical Trial of Watercress in Detoxification of Environmental Toxicants and Carcinogens

西洋菜解毒环境毒物和致癌物的临床试验

• 批准号: 10459454
• 负责人: DOROTHY K HATSUKAMI
• 金额: $ 61.31万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-03 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459454
• 关键词: 2-butenal; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; Acetylcysteine; Acrolein; Air; Benzene; Beverages; Blood; Carcinogens; Cells; Chemoprevention; Chemopreventive Agent; Cigarette Smoker; Clinical Research; Clinical Trials; Consumption; Crossover Design; DNA Adducts; Diet; Disease; Dose; Drug Metabolic Detoxication; Environmental Carcinogens; Excretory function; Exposure to; Food; Freeze Drying; Fruit; Glutathione; Glutathione S-Transferase; Goals; Health; Individual; Isothiocyanates; Juice; Link; Liquid Chromatography; Malignant Neoplasms; Masks; Mastication; Medicine; Metabolic; Metabolic Activation; Minnesota; Mus; Oral; Parents; Phenethyl Isothiocyanate; Placebos; Population; Powder dose form; Preparation; Prevalence; Publishing; Rattus; Saliva; Sampling; Signal Transduction; Smoker; Source; Standardization; Testing; Time; Toxic Environmental Substances; Transferase; Urine; Vegetables; Watercress; Weight; cancer chemoprevention; cancer prevention; capsule; design; dietary; dietary constituent; environmental agent; environmental stressor; exposed human population; glutathione S-transferase M1; inhibitor; lung cancer prevention; lung carcinogenesis; non-smoker; propylene oxide; recruit; tandem mass spectrometry; tobacco specific lung carcinogen; toxicant

Clinical Trial of Watercress in Detoxification of Environmental Toxicants and Carcinogens Summary In a recently completed clinical trial, we observed that 2-phenethyl isothiocyanate (PEITC) enhanced the detoxification of the environmental toxicants and carcinogens benzene, acrolein, and crotonaldehyde, as determined by increased excretion of the corresponding mercapturic acids in the urine of subjects who took 40 mg of PEITC orally per day. The significant enhancing effect was particularly strong in individuals who were null for the glutathione-S-transferase genes GST-T1, GST-M1, or both. These exciting results, which signal enhanced detoxification of commonly occurring environmental agents in subjects exposed to PEITC, led to the design of the current clinical trial of watercress, a common vegetable which is an abundant and practically unique natural dietary source of PEITC. When watercress is chewed or otherwise macerated, PEITC is released from its parent constituent gluconasturtiin. Thus, consumption of 10 grams wet weight of watercress exposes one to about 3 mg of PEITC. We hypothesize that watercress can enhance the detoxification of multiple environmental toxicants and carcinogens, thus emerging as an inexpensive and plentiful dietary constituent with potential for prevention of cancer and possibly other environmentally linked diseases. Therefore, we propose a clinical study of watercress with the following specific aims: 1. Prepare and standardize a watercress-derived beverage or capsules and appropriate placebo for the study. Two approaches will be investigated. A). Freeze-dry the watercress to obtain a powder which will be added to a mixture of fruit juices to mask the bitter watercress flavor. Subjects will drink this juice 10 min after mixing. B). Homogenize the watercress followed by freeze drying to produce a PEITC-containing powder which will be formulated into capsules. 2. Perform a clinical trial with 350 subjects to determine the effects of the watercress preparation on detoxification of environmental toxicants and carcinogens. Using a crossover design, subjects will consume the watercress beverage or capsules, or placebo, 3 times per day for 2 weeks with a 4 week washout period between watercress and placebo treatment. The target dose will be 40 mg/day of PEITC, as in our previous study. Urine, oral cells, saliva, and blood will be collected. 3. Using liquid chromatography-tandem mass spectrometry, analyze urine samples for mercapturic acids of specific toxicants (e.g. benzene, acrolein, crotonaldehyde, propylene oxide, etc.) and for mercapturic acids generally. Our hypothesis is that detoxification of these toxicants by conjugation with glutathione, as indicated by mercapturic acid levels in urine and DNA adduct levels in oral cells, will be significantly elevated compared to placebo in subjects who consumed the watercress preparation and are null for GSTM1, GSTT1, or both. The results of this study will provide a critical test of the use of watercress as a vehicle for isothiocyanates such as PEITC which can enhance detoxification of environmental toxicants and carcinogens. If the results of the trial support our hypothesis, watercress could emerge as a cheap and convenient food for cancer prevention, consistent with the concepts of “green chemoprevention and frugal medicine.”

西洋菜对环境毒物、致癌物解毒作用的临床试验 总结 在最近完成的一项临床试验中，我们观察到2-苯乙基异硫氰酸酯（PEITC）增强了 环境毒物和致癌物苯、丙烯醛和巴豆醛，通过增加排泄测定 每天口服40 mg PEITC的受试者尿液中相应的巯基尿酸。的重大 增强作用在谷胱甘肽-S-转移酶基因GST-T1无效的个体中特别强， GST-M1或两者。这些令人兴奋的结果，这标志着增强解毒的常见环境 在暴露于PEITC的受试者中的药物，导致了目前对豆瓣菜（一种常见蔬菜）的临床试验的设计 其是PEITC的丰富且实际上独特的天然膳食来源。当豆瓣菜被咀嚼或以其他方式 浸软后，PEITC从其母体成分中释放出来。因此，消耗10克湿重的 豆瓣菜使人暴露于约3 mg的PEITC。我们假设西洋菜可以增强 多种环境毒物和致癌物，因此成为一种廉价且丰富的膳食成分， 预防癌症和其他可能与环境有关的疾病的潜力。因此，我们建议临床 研究豆瓣菜，具体目标如下： 1.制备并标准化豆瓣菜衍生饮料或胶囊和适当的安慰剂用于研究。两 将研究各种方法。A）。将豆瓣菜冷冻干燥以获得粉末，该粉末将被添加到以下物质的混合物中： 果汁来掩盖豆瓣菜的苦味。受试者将在混合后10分钟饮用该果汁。B）。均匀化 豆瓣菜，然后冷冻干燥以产生将被配制成胶囊的含PEITC的粉末。 2.对350名受试者进行临床试验，以确定西洋菜制剂对解毒的影响。 环境毒物和致癌物。使用交叉设计，受试者将饮用豆瓣菜饮料或 胶囊或安慰剂，每天3次，持续2周，豆瓣菜和安慰剂之间有4周的洗脱期 治疗目标剂量将是40 mg/天的PEITC，与我们先前的研究相同。尿液、口腔细胞、唾液和血液 将被收集。 3.使用液相色谱-串联质谱法，分析尿液样本中的特定巯基尿酸 有毒物质（如苯、丙烯醛、巴豆醛、环氧丙烷等）以及通常用于巯基尿酸。我们 假设是这些毒物通过与谷胱甘肽结合而解毒，如巯基尿酸所示 在受试者中，与安慰剂相比，尿液中的DNA水平和口腔细胞中的DNA加合物水平将显著升高， 食用豆瓣菜制剂，并且GSTM 1、GSTT 1或两者均为零。 这项研究的结果将提供一个关键的测试使用豆瓣菜作为媒介物的异硫氰酸酯，如PEITC 其可增强环境毒物和致癌物的解毒。如果试验结果支持我们的 假设，豆瓣菜可能成为一种廉价和方便的癌症预防食品，符合 “绿色化学预防和节约医药。”

项目成果

Preparation of a Beverage Containing Freeze-Dried Watercress for a Clinical Trial of Carcinogen and Toxicant Detoxification.

• DOI: 10.1158/1940-6207.capr-21-0473
• 发表时间: 2022-03-01
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Bonorden MJL;Carmella SG;Ballinger OT;Williams J;Dorn I;Vanderloo H;Fujioka N;Hatsukami DK;Hecht SS
• 通讯作者: Hecht SS