BIOMARKERS TO MOLECULAR INTERVENTIONS IN AFLATOXIN EXPOSED INDIVIDUALS

对黄曲霉毒素暴露个体进行分子干预的生物标志物

• 批准号: 6467577
• 负责人: THOMAS W KENSLER
• 金额: $ 19.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6467577
• 关键词: China; DNA damage; aflatoxins; biomarker; cancer prevention; cancer risk; chemoprevention; chlorophyll; clinical research; deoxyguanosine; environmental toxicology; food contamination; glutathione; hepatocellular carcinoma; human subject; laboratory rat; nutrition related neoplasm /cancer; nutrition related tag; oltipraz; toxin metabolism

Project II. Development and application of biomarkers to molecular interventions in aflatoxin-exposed individuals. A major goal of public health practice is disease prevention. Recent advances in our understanding of the fundamental mechanisms of carcinogenesis have provided opportunities to reduce human cancer incidence through molecular, chemopreventive interventions. However, use of cancer endpoints in the evaluation of new intervention strategies ensures slow and costly progress. The development of intermediate biomarkers is essential to the timely development and maturation of the field of chemoprevention. The continuing goal of these studies is to determine whether biomarkers of aflatoxicosis caused by consumption of aflatoxin-contaminated foods can be modulated by ingestion of oltipraz or chlorophyllin. Both oltipraz and chorophyllin are effective inhibitors of aflatoxin-induced hepatocarcinogenesis in animal models, although their mechanisms of action appear to be distinct. It is our hypothesis that levels of biomarkers for the biologically effective dose of aflatoxin will be predictive for assessing the efficacy of chemopreventive interventions in aflatoxin-exposed individuals. Results in rats during the initial grant period suggest that measurements of the levels of aflatoxin-N7-guanine in urine and aflatoxin-albumin adducts in serum reflect aflatoxin-induced genotoxicity in target organs. Moreover, animals fed oltipraz exhibited marked reductions in the levels of these biomarkers in parallel with reductions in the levels of hepatic aflatoxin- DNA adducts and liver cancer incidence. Molecular epidemiology studies have also firmly established these biomarkers as indices of aflatoxin exposure in humans and for subsequent risk of developing hepatocellular carcinoma. The proposed studies seek to continue the development and application of biomarkers to chemoprevention in populations at high risk for aflatoxin exposure and liver cancer. An additional biomarker of considerable promise is 8-hydroxy-2 prime- deoxyguanosine (8-OHdG). Several laboratories have shown recently that treatment of animals with aflatoxin B1 elevates levels of 8-OhdG in hepatic DNA. The proposed studies will evaluate whether measurement of 8-OHdG excretion in urine is a useful, modulatable endpoint for assessing chemopreventive efficacy. These studies will utilize urine samples collected from rats and humans that have recently undergone chemopreventive interventions with oltipraz. These studies will also be extended by conducting a clinical intervention with the anticarcinogen chlorophyllin in individuals from Qidong, Peopl~s Repubic of China, who are exposed to aflatoxins in their diets and are subsequently at high risk for development of liver cancer.

项目二. 分子生物标志物的发展与应用 对黄曲霉毒素暴露者的干预措施。 公众的主要目标 健康实践就是预防疾病。 我们的最新进展 了解致癌的基本机制， 提供机会，以减少人类癌症的发病率， 分子和化学预防干预。 然而，使用癌症 新干预战略评估的终点确保缓慢 昂贵的进展。 中间生物标志物的发展是 对及时发展和成熟的领域至关重要， 化学预防 这些研究的持续目标是确定 是否由消费引起的黄曲霉毒素中毒的生物标志物 摄入奥替普拉可以调节黄曲霉毒素污染的食物 或叶绿酸。 奥替普拉和叶绿素都是有效的抑制剂 黄曲霉毒素诱导的肝癌动物模型，虽然 它们的作用机制似乎不同。 我们假设 黄曲霉毒素生物有效剂量的生物标志物水平 将对评估化学预防的有效性具有预测性 对黄曲霉毒素暴露者的干预措施。 在大鼠中的结果 最初的赠款期表明， 尿中黄曲霉毒素-N7-鸟嘌呤和血清中黄曲霉毒素-白蛋白加合物 反映了黄曲霉毒素在靶器官中诱导的遗传毒性。 此外，委员会认为， 喂食奥替普拉的动物表现出这些水平的显著降低 生物标志物与肝脏黄曲霉毒素水平的降低平行- DNA加合物与肝癌发病率 分子流行病学 研究也已经确定这些生物标志物作为 人体暴露于黄曲霉毒素， 肝细胞癌 拟议的研究旨在继续 生物标记物在化学预防中的开发和应用 暴露于黄曲霉毒素和肝癌的高风险人群。 一个 另一种前景可观的生物标志物是8-羟基-2-素数， 脱氧鸟苷（8-OHdG）。 几个实验室最近已经证明 用黄曲霉毒素B1治疗动物会提高8-OhdG的水平， 在肝脏DNA中。 拟议的研究将评估是否 尿中8-OHdG排泄的测量是一种有用的、可调节的 用于评估化学预防功效的终点。 这些研究将 利用最近从老鼠和人类身上收集的尿液样本， 接受了奥替普拉的化学预防干预。 这些研究 还将通过进行临床干预来扩展， 启东地区人群抗癌药叶绿酸含量的测定 在中国，他们在饮食中暴露于黄曲霉毒素， 随后处于肝癌发展的高风险中。