2-Amino-9H-pyrido[2,3-b]indole: a potential colorectal carcinogen formed in tobac

2-Amino-9H-pyrido[2,3-b]indole：烟草中形成的潜在结直肠致癌物

• 批准号: 8426255
• 负责人: Robert J. Turesky
• 金额: $ 30.84万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426255
• 关键词: Aberrant crypt foci; Aflatoxin B1; Aromatic Amines; Aromatic Polycyclic Hydrocarbons; Biochemical; Biological Markers; Biological Monitoring; Blood; Blood Proteins; Carcinogens; Chemicals; Chemistry; Chronic; Cigarette; Cohort Studies; Colorectal; Colorectal Cancer; DNA; DNA Adduction; DNA Adducts; Development; Dose; Enzymes; Epidemiology; Exposure to; Feces; Future; Gastrointestinal tract structure; Goals; Grant; Half-Life; Hemoglobin; Hemoglobin C; Hepatocyte; Human; Incidence; Indoles; Investigation; Kinetics; Leukocytes; Life; Link; Liquid Chromatography; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Maps; Mass Spectrum Analysis; Measurement; Measures; Metabolic Activation; Metabolic Pathway; Metabolism; Methods; Mission; Mus; Neoplasms; Pathway interactions; Population; Primary carcinoma of the liver cells; Proteins; Public Health; Reaction; Reporting; Research; Risk; Risk Factors; Rodent; Role; Safety; Sampling; Serum Albumin; Smoker; Smoking; Staging; Tissues; Tobacco; Tobacco smoke; Tobacco smoking; Toxic effect; Toxicology; United States; Urine; Validation; adduct; carcinogenicity; cigarette smoking; citrate carrier; cohort; detoxication; gastrointestinal; genotoxicity; heterocyclic aromatic amines; non-smoker; parent grant; population based; prospective; repaired; smoking cessation; tandem mass spectrometry; uptake; urinary

DESCRIPTION (provided by applicant): Tobacco smoking is a risk factor for cancers of the GI (gastrointestinal) tract, including hepatocellular carcinoma that has seen increasing incidence in the United States. However, little is known about the tobacco constituents that are potentially responsible for the development of GI cancers in human smokers. Using a population sample, we reported that the heterocyclic aromatic amine, 2-amino-9H-pyrido[2,3-b]indole (A¿C), a rodent GI carcinogen, is present in the urine of tobacco smokers in a dose-dependent manner while nonsmokers are devoid of the compound in their urine. We hypothesize that high exposure to A¿C through smoking of cigarettes, and the propensity of A¿C to undergo bioactivation by enzymes expressed in the liver and the colorectum, provides a biochemical mechanism for the development of GI tract cancer in smokers. Our long-term goal is to determine if A¿C in tobacco smoke is causally related to GI tract cancer in smokers, and to elucidate the mechanistic pathways underlying this exposure-cancer relationship. The original 3 aims of the parent grant are: 1) to determine the extent of exposure to A¿C, by measuring the levels of A¿C in urine and stool of tobacco smokers participating in a smoking cessation study; 2) to evaluate the genotoxicity of A¿C in the colorectum of mice, by measurement of DNA adducts and aberrant crypt foci, recognized early biomarkers of neoplasia; and 3) to characterize the major pathways of A¿C metabolism in mice and humans, especially as they relate to DNA adduct formation at the target tissue. The above studies are essential in understanding the biochemical toxicology of A¿C in GI tract cancers. However, in order to definitively establish a causal link between A¿C exposure and cancer in human smokers using existing population-based cohorts with baseline biospecimens, biomarkers of A¿C that reflect the stable profile of exposure in subjects need to be in place. The objectives of this grant revision are: 1) to examine the reaction products of the carcinogenic metabolites of A¿C with serum albumin and hemoglobin, in order to develop A¿C adducts of these blood proteins as biomarkers, and 2) to develop analytical mass spectrometry methods for sensitive and precision measurements of A¿C-blood protein biomarkers, for future use in large-scale, population-based cohort studies. This proposed research is relevant to NIH's mission on public health and directly relates to assessing the safety of an over-looked carcinogen that exists in high levels in tobacco smoke. The proposed research will establish a set of biomarkers of A¿C reflecting a smoker's stable exposure profile that can be used in epidemiologic cohort studies to definitively link A¿C exposure to human cancers. The biomarkers also will provide a means to measure and compare the toxicity and carcinogenicity of different tobacco products. PUBLIC HEALTH RELEVANCE: 2-Amino-9H-pyrido[2,3-b]indole (A¿C) is the most abundant of the aromatic amine carcinogens formed in tobacco smoke. There is mounting evidence that it may be an important causal agent for the development of GI (gastrointestinal tract) tract cancers in smokers, including the rapidly fatal hepatocellular carcinoma that has seen increasing incidence in the United States during the past three decades. Characterization of the metabolic pathways involved in bioactivation and detoxication of A¿C in humans as they relate to GI tract cancers, in conjunction with the development and validation of long-lived biomarkers of A¿C for use in large scale, prospective cohort studies would serve to definitively establish the causal role between A¿C exposure and smoking-related GI tract cancers in humans.

描述（由适用提供）：吸烟是GI（胃肠道）癌症的危险因素，包括美国发病率在增加的肝细胞癌。但是，对烟草构成的烟草构成的众所周知，这些烟草可能导致人类吸烟者中GI癌的发展。使用人群样本，我们报道说，杂环芳香胺，2-氨基-9H-吡啶[2,3-B]吲哚（A¿我们假设通过吸烟吸烟对AC的高度接触，并且A c进行了在肝脏和大肠杆菌中表达的酶进行生物活化的希望，为吸烟者中胃肠道癌的发展提供了生化机制。我们的长期目标是确定烟草烟中的A c与吸烟者中的胃肠道癌有时是否与胃肠道有关，并阐明这种暴露癌症关系的机械途径。父母赠款的最初3个目标是：1）通过测量参加戒烟研究的尿液和粪便吸烟者的尿液和粪便中的A级水平来确定暴露于A c的程度； 2）通过测量DNA加合物和异常的隐窝灶来评估小鼠结肠菌的遗传毒性，识别出肿瘤的早期生物标志物； 3）表征小鼠和人类A c代谢的主要途径，尤其是与目标组织的DNA加合物形成相关时。上述研究对于理解胃肠道癌中A c的生化毒理学至关重要。但是，为了定义现有基于人群的同类群体与基线生物测量的现有同类群体的A c暴露与癌症之间的因果关系，A c的生物标志物反映了受试者中稳定的暴露状况的生物标志物。 The objectives of this grant revision are: 1) to examine the reaction products of the carcinogenic metabolites of A¿ C with serum album and hemoglobin, in order to develop A¿ C adducts of these blood proteins as biomarkers, and 2) to develop analytical mass spectrometry methods for sensitive and precision measurements of A¿ C-blood protein biomarkers, for future use in large-scale, population-based cohort studies.这项拟议的研究与NIH关于公共卫生的使命有关，直接与评估烟草烟雾中高水平的过度致癌物的安全有关。拟议的研究将建立一组A¿C的生物标志物，反映了吸烟者的稳定暴露概况，可用于流行病学队列研究，以确定地将A c暴露与人类癌症联系起来。生物标志物还将提供一种方法来测量和比较不同烟草产品的毒性和致癌性。 公共卫生相关性：2-Amino-9H-Pyrido [2,3-B]吲哚（A¿C）是烟草烟雾中形成的芳香胺致癌物中最丰富的。有越来越多的证据表明，它可能是吸烟者中GI（胃肠道）癌（胃肠道）癌的重要因果因子，包括在过去三十年中在美国发生的迅速致命的肝细胞癌癌。 Characterization of the metabolic pathways involved in bioactivation and detoxication of A¿ C in humans as they relate to GI tract cancers, in conjunction with the development and validation of long-lived biomarkers of A¿ C for use in large scale, prospective cohort studies would serve to definely establish the causal role between A¿ C exposure and smoking-related GI tract cancers in humans.