DETERMINANTS OF DIETARY RISK OF HETEROCYCLIC AMINES

杂环胺饮食风险的决定因素

• 批准号: 7602402
• 负责人: JAMES S. FELTON
• 金额: $ 2.1万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602402
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; Animal Model; Animals; Bile fluid; Biological Assay; Biological Markers; Carcinogens; Chinese Hamster Ovary Cell; Chronic; Computer Retrieval of Information on Scientific Projects Database; Cytochrome P450; Cytochromes; Cytogenetics; DNA Adduction; DNA Adducts; DNA Binding; DNA Damage; DNA Repair; Data; Diet; Dose; Drug Metabolic Detoxication; Extrahepatic; Failure; Female; Food; Funding; Genetic; Glucuronides; Glucuronosyltransferase; Goals; Grant; Heating; Heterocyclic Amines; Human; Hydroxylation; Incidence; Individual; Individual Differences; Ingestion; Institution; Intake; Isoenzymes; Literature; Malignant Neoplasms; Mediating; Metabolic Activation; Metabolic Biotransformation; Metabolic Pathway; Metabolism; Mus; Mutagens; Mutation; N hydroxylation; Nature; Numbers; Organ; Pathway interactions; Predisposition; Process; Program Research Project Grants; Proteins; Rattus; Reaction; Research; Research Personnel; Resources; Risk; Risk Assessment; Rodent; Rodent Model; Role; Site; Source; Specificity; System; Tissues; Toxicology; UDP-Glucuronosyltransferase 1A1; UGT1A1 gene; United States National Institutes of Health; Urine; Variant; Work; Xenobiotics; abstracting; accelerator mass spectrometry; animal tissue; cancer risk; cooking; dosimetry; feeding; glucuronide; heterocyclic aromatic amines; male; metabolic abnormality assessment; nonhuman primate; programs; repaired; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the last 15 years we have been studying the role of diet on cancer. The cooking, heat processing, and pyrolysis of protein-rich foods result in the formation of a group of structurally related heterocyclic aromatic amines that have been found to be potent mutagens in a number of assay systems. These same compounds produce tumors at multiple organ sites in both male and female mice and rats and 100 percent of non-human primates given one of these heterocyclic amines developed hepatocarcinomas after a very short latency. Given these very compelling data, it is important to determine the extent to which these dietary mutagens/carcinogens contribute to the human cancer incidence and to devise strategies to limit their impact. This NIH program project attempts to achieve these goals by: - Identifying and quantifying the human intake of these heterocyclic amines in the diet; - Understanding the chronic toxicology of these compounds by analysis of DNA binding, cytogenetic damage and mutational effects following chronic long-term feeding exposure of rodents; - Understanding the mechanistic relevance of animal studies for humans by characterizing important metabolic pathways (rodents, non-human primates, humans) with the additional goal of understanding the nature of the tissue specificity in tumor formation induced by these heterocyclic amines; - Understanding the dose-relevance of high dose animals studies for human risk assessment by assessing the dosimetry from ingestion of these potent mutagens at low doses; - Characterizing the structural features of carcinogens and DNA adducts that are correlated with mutation; - Predicting the importance of individual differences in repair and metabolism using CHO cells and rodent strains having genetic differences in DNA repair and metabolic activation; - Identifying and validating biomarkers that may be useful for human risk or susceptibility determinations and; - Evaluating data generated from this project and data from the literature to produce quantitative cancer-risk assessment. It is clear that the AMS resource is having a major impact on this NIH funded Program Project, as aspects of this work can only be accomplished utilizing accelerator mass spectrometry. In particular, AMS allows us to conduct studies of metabolism and DNA damage at low dose that impacts every sub-project of our program project grant. Current study abstract: Cytochrome P450-mediated hydroxylation and UDP-glucuronosyltransferase (UGT)-catalyzed glucuronidation are major metabolic pathways in the biotransformation of many xenobiotics including heterocyclic amines (HAs). Studies have shown that, in humans, the bioactivation of the HA PhIP is highly dependent upon cytochrome P4501A2-mediated N-hydroxylation to the corresponding N-hydroxy-PhIP. Subsequent N-glucuronidation results in the formation of the less reactive N-hydroxy-PhIP-N2-glucuronide and N-hydroxy-PhIP-N3-glucuronide, which can be excreted through urine or bile, or can be transported to extrahepatic tissue where further metabolism can occur. Recent studies have shown that, in humans, glucuronidation of N-hydroxy-PhIP is a major pathway in the biotransformation of PhIP and that the UGT1A1 isozyme is a major contributor to N-hydroxy-PhIP glucuronidation. In addition, polymorphic expression of several UGTs has led to differential metabolism of many substrates. This inter-individual variation in UGT expression could potentially alter the bioactivation of pro-carcinogens such as PhIP in certain individuals. Therefore, understanding the N-glucuronidation of PhIP and N-hydroxy-PhIP in humans is especially important because the failure to conjugate N-hydroxy-PhIP by glucuronidation could result in further activation by esterifying reactions. These reactions would result in highly reactive compounds that can bind DNA, potentially causing mutations. Since PhIP bioactivation has been shown to be responsible for the formation of DNA adducts in multiple tissues in animal models, by determining the role glucuronidation has on tissue-specific bioactivation/detoxification of PhIP in rodent models, a better understanding of how PhIP metabolism contributes to DNA adduct formation in whole animals can be established. By using accelerator mass spectrometry we can analyze DNA adduct formation in tumor target tissues and dietary relevant doses of PhIP. We hypothesize that animals and/or tissues with diminished glucuronidation capacity will be more susceptible to PhIP induced DNA adducts in tumor target tissues than animals with increased UGT activity.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在过去的15年里，我们一直在研究饮食对癌症的作用。 富含蛋白质的食物的烹饪、热加工和热解导致形成一组结构相关的杂环芳族胺，这些杂环芳族胺在许多测定系统中被发现是有效的诱变剂。 这些相同的化合物在雄性和雌性小鼠和大鼠的多个器官部位产生肿瘤，给予这些杂环胺之一的非人类灵长类动物在非常短的潜伏期后100%发展为肝癌。鉴于这些非常令人信服的数据，重要的是要确定这些饮食诱变剂/致癌物在多大程度上有助于人类癌症的发病率，并制定战略，以限制其影响。 该NIH计划项目试图通过以下方式实现这些目标： - 识别和量化人体饮食中这些杂环胺的摄入量; - 通过分析啮齿类动物长期接触这些化合物后的DNA结合、细胞遗传学损伤和突变效应，了解这些化合物的慢性毒理学; - 通过表征重要的代谢途径（啮齿动物，非人灵长类动物，人类），了解动物研究对人类的机械相关性，并了解这些杂环胺诱导的肿瘤形成中组织特异性的性质; - 通过评估低剂量摄入这些强效诱变剂的剂量测定，了解高剂量动物研究对人类风险评估的剂量相关性; - 描述与突变相关的致癌物和DNA加合物的结构特征; - 使用CHO细胞和在DNA修复和代谢活化中具有遗传差异的啮齿动物品系预测修复和代谢中个体差异的重要性; - 识别和验证可能对人类风险或易感性测定有用的生物标志物; - 评估本项目产生的数据和文献数据，以产生定量癌症风险评估。 很明显，AMS资源对NIH资助的计划项目产生了重大影响，因为这项工作的某些方面只能利用加速器质谱法来完成。 特别是，AMS允许我们在低剂量下进行代谢和DNA损伤的研究，这些研究影响了我们计划项目资助的每个子项目。 当前研究摘要：细胞色素P450介导的羟基化和UDP-葡萄糖醛酸基转移酶（UGT）催化的葡萄糖醛酸化是杂环胺（HAs）等外源性化合物生物转化的主要代谢途径。研究表明，在人体中，HA PhIP的生物活化高度依赖于细胞色素P4501 A2介导的N-羟基化为相应的N-羟基-PhIP。随后的N-葡萄糖醛酸化导致形成反应性较低的N-羟基-PhIP-N2-葡萄糖醛酸苷和N-羟基-PhIP-N3-葡萄糖醛酸苷，其可通过尿液或胆汁排泄，或可转运至肝外组织，在那里可发生进一步代谢。最近的研究表明，在人体中，N-羟基-PhIP的葡萄糖醛酸化是PhIP生物转化的主要途径，UGT 1A 1同工酶是N-羟基-PhIP葡萄糖醛酸化的主要贡献者。此外，几种UGT的多态性表达导致许多底物的差异代谢。这种UGT表达的个体间差异可能会改变某些个体中致癌物（如PhIP）的生物活化。因此，了解PhIP和N-羟基-PhIP在人体中的N-葡萄糖醛酸化尤其重要，因为未能通过葡萄糖醛酸化偶联N-羟基-PhIP可能导致通过脱水反应进一步活化。这些反应将产生高活性化合物，可以结合DNA，可能导致突变。由于PhIP生物活化已被证明是负责在动物模型中的多个组织中形成DNA加合物，通过确定葡萄糖醛酸化对组织特异性生物活化/解毒的PhIP在啮齿动物模型中的作用，可以更好地了解PhIP代谢如何有助于在整个动物中形成DNA加合物。通过使用加速器质谱，我们可以分析肿瘤靶组织中DNA加合物的形成和饮食相关剂量的PhIP。 我们假设葡萄糖醛酸化能力降低的动物和/或组织比UGT活性增加的动物更容易受到PhIP诱导的肿瘤靶组织DNA加合物的影响。