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

描述(由申请人提供)：吸烟是胃肠道癌症的危险因素，包括在美国发病率不断上升的肝细胞癌。然而，人们对可能导致人类吸烟者发生胃肠道癌症的烟草成分知之甚少。用人群抽样的方法，我们报道了杂环芳胺2-氨基-9H-吡啶并[2，3-b]吲哚(A？C)在吸烟者的尿液中呈剂量依赖性地存在于尿液中，而不吸烟者的尿液中没有这种化合物。我们假设，通过吸烟而高暴露于A？C，以及A？C被肝脏和结肠中表达的酶生物激活的倾向，为吸烟者发生胃肠道癌症提供了一种生化机制。我们的长期目标是确定烟草烟雾中的A？C是否与吸烟者的胃肠道癌症有因果关系，并阐明这种暴露-癌症关系的机制。家长基金最初的三个目标是：1)通过测量参与戒烟研究的烟草吸烟者的尿液和粪便中的A？C水平，确定A？C的暴露程度；2)通过测量DNA加合物和异常隐窝病灶，评估A？C在小鼠结直肠中的遗传毒性，这是公认的肿瘤早期生物标志物；以及3)描述A？C代谢的主要途径，特别是它们与靶组织DNA加合物形成有关的途径。上述研究对于了解A？C在胃肠道癌症中的生化毒理作用是必要的。然而，为了利用现有的以人群为基础的队列和基线生物标记物确定吸烟者接触A？C与癌症之间的因果联系，需要建立反映受试者接触A？C的稳定情况的A？C生物标记物。这项资助修订的目的是：1)检查A？C致癌代谢物与血清白蛋白和血红蛋白的反应产物，以开发这些血液蛋白的A？C加合物作为生物标记物，以及2)开发A？C-血液蛋白生物标记物的灵敏和精确测量的分析质谱学方法，以便将来用于大规模的基于人群的队列研究。这项拟议的研究与NIH的公共健康使命相关，并直接与评估一种被忽视的致癌物质的安全性有关，这种致癌物质存在于烟草烟雾中的高水平。这项拟议的研究将建立一套反映吸烟者稳定暴露情况的A？C生物标记物，可用于流行病学队列研究，明确A？C暴露与人类癌症之间的联系。生物标志物还将提供一种手段来测量和比较不同烟草产品的毒性和致癌性。 与公共健康相关：2-氨基-9H-吡啶并[2，3-b]吲哚(A？C)是烟草烟雾中形成的最丰富的芳香胺致癌物质。越来越多的证据表明，它可能是吸烟者胃肠道癌症发生的重要原因，包括在过去30年里在美国发病率不断上升的快速致命性肝细胞癌。当A？C与胃肠道癌症有关时，表征A？C在人体内的生物激活和解毒所涉及的代谢途径，结合A？C生物标志物的开发和验证以用于大规模前瞻性队列研究，将有助于最终确定A？C暴露与人类与吸烟相关的胃肠道癌症之间的因果关系。

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.