MOLECULAR DOSIMETRY OF INGESTED PAHS AND HETEROCYCLIC AMINES

摄入多环芳烃和杂环胺的分子剂量测定

• 批准号: 5211306
• 负责人: PAUL T STRICKLAND
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5211306
• 关键词: acyltransferase; adduct; biomarker; blood chemistry; carbopolycyclic compound; carcinogens; colon polyp; colorectal neoplasms; cytochrome P450; human subject; isozymes; laboratory mouse; nitrogenous heterocyclic compound; nutrition related neoplasm /cancer; nutrition related tag; toxicant interaction; toxin metabolism; urinalysis

Project II: A major route of exposure to environmental carcinogens is through the diet. Epidemiological studies indicate that 20 to 50% of all human cancers can be attributed to dietary causes. The frequent consumption of animal fat, red meats, or barbequed/smoked meats has been associated with increased risk for cancers of the gastro-intestinal tract and pancreas. However, in contrast to the strong association between aflatoxin and liver cancer described in other projects in this program, the specific etiologic agents responsible for causing many diet- associated human cancers remain undetermined. Two classes of chemical carcinogens, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HAs), have been identified in cooked meats. These chemicals produce a variety of cancers in animal models including colon, stomach, breast, and liver cancers. The overall goals of this project are to investigate the molecular dosimetry of ingested PAHs and HAs from cooked meats in humans, and identify susceptibility factors (effect modifiers) that modulate the formation of DNA and protein adducts due to these dietary carcinogens. These studies will utilize controlled feeding protocols. Individual differences in the formation and persistence of carcinogen-DNA adducts in peripheral white blood cell fractions and carcinogen metabolites in urine will be investigated following ingestion of char-broiled meat. Relevant metabolic phenotypes (P450IA2, P450IIIA4 and acetyltransferase) will be assessed to determine their role in adduct and metabolite kinetics. A pilot case-control colon polyp study will also be initiated to examine selected biomarkers as indicators of cancer risk. This study will develop and evaluate biomarkers of exposure to cooking- induced dietary carcinogens. The study should yield insight into the biological basis for inter-individual variation in response to carcinogens associated with cooked meats. The identification of critical metabolic and dietary determinants of DNA and protein damage could provide methodologies for assessing increased susceptibility to cancer from ingested carcinogens. Ultimately, molecular biomonitoring may allow quantitation of biological dose from ingested carcinogens, thereby accounting for variation in exposure, cooking processes, and metabolism.

项目二：接触环境致癌物的一个主要途径是 通过饮食。 流行病学研究表明，20%至50%的人 人类癌症可归因于饮食原因。 频繁的 动物脂肪、红肉或烧烤/熏肉的消费 与胃肠道癌症风险增加有关 和胰腺。 然而，与之间的强关联相反 本计划其他项目中描述的黄曲霉毒素和肝癌， 导致许多饮食- 相关的人类癌症仍未确定。 两类化学品 致癌物、多环芳烃（PAH）和杂环 熟肉中已鉴定出胺 (HA)。 这些化学品 在动物模型中产生多种癌症，包括结肠癌、胃癌、 乳腺癌和肝癌。 该项目的总体目标是 研究从熟食中摄入的 PAH 和 HA 的分子剂量测定 人类的肉类，并确定易感因素（效应调节剂） 调节 DNA 和蛋白质加合物的形成 饮食中的致癌物质。 这些研究将采用控制喂养方案。 个人 致癌物-DNA 加合物的形成和持久性差异 外周血白细胞成分和致癌物代谢物 摄入炭烤肉后将对尿液进行检查。 相关代谢表型（P450IA2、P450IIIA4 和乙酰转移酶） 将进行评估以确定它们在加合物和代谢物中的作用 动力学。 还将启动试点病例对照结肠息肉研究 检查选定的生物标志物作为癌症风险的指标。 这项研究将开发和评估暴露于烹饪的生物标志物 诱发膳食致癌物。 该研究应该深入了解 个体间反应差异的生物学基础 与熟肉有关的致癌物质。 关键的识别 DNA 和蛋白质损伤的代谢和饮食决定因素可能 提供评估癌症易感性增加的方法 来自摄入的致癌物质。 最终，分子生物监测可能允许 对摄入的致癌物的生物剂量进行定量，从而 考虑暴露、烹饪过程和新陈代谢的变化。