DETERMINANTS OF DIETARY RISK OF HETEROCYCLIC AMINES

杂环胺饮食风险的决定因素

基本信息

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
项目类别：
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

项目摘要

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.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。在过去的15年中，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，热加工和热解会导致形成一组结构相关的杂环芳香胺，这些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以及100％的非人类灵长类动物中产生肿瘤，鉴于这些杂环胺之一在潜伏期很短之后就形成了肝癌。鉴于这些非常引人注目的数据，重要的是要确定这些饮食诱变剂/致癌物有助于人类癌症发病率的程度，并制定策略以限制其影响。这个NIH计划项目试图通过以下方式实现这些目标 - 在饮食中识别和量化这些杂环胺的人类摄入； - 通过分析啮齿动物的慢性长期喂养暴露后，通过分析DNA结合，细胞遗传学损伤和突变作用来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，非人类灵长类动物，人类），了解人类动物研究对人类的机理相关性，其其他目标是理解这些异质细胞胺引起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有效诱变剂的剂量测定法，了解高剂量动物研究的剂量 - 对人类风险评估的剂量相关； - 表征与突变相关的致癌物和DNA加合物的结构特征； - 使用CHO细胞和啮齿动物菌株在DNA修复和代谢激活方面预测个人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确定有用的生物标志物； - 评估从该项目产生的数据以及文献中产生的数据，以产生定量的癌风险评估。显然，AMS资源对NIH资助的计划项目产生了重大影响，因为这项工作的各个方面只能利用加速器质谱法完成。特别是，AMS使我们能够以低剂量的低剂量进行代谢和DNA损伤研究，从而影响我们计划项目赠款的每个子项目。当前的研究摘要：细胞色素P450介导的羟基化和UDP-葡萄糖醛酸酮基转移酶（UGT）催化的葡萄糖醛酸化是许多多种异生元素在内的生物转化的主要代谢途径，包括异源性细胞胺（HATE）。研究表明，在人类中，HA PHIP的生物活化高度依赖于细胞色素P4501A2介导的N-羟基化对相应的N-羟基苯基化。随后的N-葡萄糖醛酸化导致形成较低的反应性N-羟基-PHIP-N2-葡萄糖苷和N-羟基-PHIP-N3-葡萄糖醛酸糖苷，可以通过尿液或胆汁排出，或可以将其运输到肝外组织中，从而进一步发生代谢。最近的研究表明，在人类中，n-羟基果蝇的葡萄糖醛酸化是PHIP生物转化的主要途径，而UGT1A1同工酶是N-羟基酸酸性葡萄糖醛酸苷的主要贡献者。另外，几种UGT的多态性表达导致许多底物的代谢差异。 UGT表达中的这种个体间变化可能会改变某些个体中PHIP等phip的生物活化。因此，了解人类中pHIP和n-羟基的N-葡萄糖醛酸化尤其重要，因为葡萄糖醛酸化未能通过葡萄糖醛酸化结合N-羟基果皮，可以通过酯化反应来进一步激活。这些反应将导致高反应性化合物可以结合DNA，并可能导致突变。由于已经证明PHIP生物激活是为了使动物模型中多个组织中的DNA加合物形成，因此通过确定葡萄糖醛酸化对啮齿动物模型中PHIP的生物活化/解毒的作用，可以更好地理解PHIP代谢对整个动物的DNA促进形式的更好理解。通过使用加速器质谱法，我们可以分析肿瘤靶组织中的DNA加合物形成和饮食中相关剂量的PHIP。我们假设与具有增加的UGT活性增加的动物相比，肿瘤诱导的动物和/或组织将更容易受到PHIP诱导的DNA加合物的影响。