Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

基本信息

批准号：
8193257
负责人：
Xinxin Ding
金额：
$ 32.46万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8193257
关键词：
1-Butanol 7alpha hydroxylase A/J Mouse Affect Alleles Animals Autopsy Binding Biochemical Biological Biological Assay Biological Availability Biopsy Biopsy Specimen Butanones CYP2A5 gene Cancer Etiology Cessation of life Chemical Exposure Chemicals Chemoprevention Chinese People Clinical Research Code Cytochrome P450 DNA Adducts DNA Methylation Data Disease Disease susceptibility Dose Electrophoretic Mobility Shift Assay Elements Endotoxins Environmental Risk Factor Enzyme Inhibition Enzymes Epidemiologic Studies Ethnic group Exposure to Future Gene Expression Gene Frequency Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Goals Health Human Hypermethylation In Vitro Incidence Individual Inflammation Inflammatory Injection of therapeutic agent Intergenic Sequence Interleukin-6 Introns Knockout Mice Lead Lipopolysaccharides Liver Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Messenger RNA Metabolic Metabolic Activation Metabolism Mind Modeling Molecular Mouse Strains Mus Names Nature Nuclear Protein Nuclear RNA Occupational Groups Outcome Pathogenesis Patients Phenotype Play Population Predisposition Proteins Protocols documentation Regulation Relative (related person)Reporter Genes Reporting Research Design Respiratory System Respiratory Tract Diseases Respiratory tract structure Risk Role Saline Sampling Series Serum Single Nucleotide Polymorphism Smoker Smoking Structure of parenchyma of lung Testing Time Tissue Sample Tissues Tobacco Toxic effect Transgenic Organisms Wild Type Mouse Work Xenobiotics base chemical carcinogenesis cytokine environmental chemical genetic variant human population study improved in vivo insight lung carcinogenesis lung tumorigenesis mouse model novel promoter research study response selective expression toxicant tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long-term objective is to determine the role of respiratory tract cytochrome P450 (P450 or CYP) enzymes in target tissue metabolic activation and toxicity of environmental chemicals. Our focus continues to be on CYP2A13, an enzyme selectively expressed in human respiratory tract, and the most efficient human P450 enzyme in the metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major tobacco- derived respiratory tract procarcinogen. CYP2A13 is also known to metabolize numerous other important respiratory tract toxicants. Our hypothesis, that CYP2A13 plays an important role in tobacco-related lung carcinogenesis in humans, is supported by findings of a recent epidemiological study, and by reports confirming that CYP2A13 protein is expressed in human lung, where it is active in the metabolic activation of NNK, and that P450s in the lung, but not those in the liver, are essential for NNK-induced lung tumorigenesis in mouse models. Furthermore, our preliminary finding, that expression of CYP2A13 is down-regulated by inflammation, offers an explanation for why the levels of CYP2A13 protein detected in patient-derived lung biopsy samples were so low, and suggests the possibility that CYP2A13 levels in intact, healthy lungs are much higher. Here, we propose three series of experiments to overcome the difficulties associated with not being able to directly study P450 expression or activity in intact, healthy human lungs. We will 1) study a CYP2A13-humanized mouse model, in order to provide proof-of-principle for the potential of CYP2A13 to mediate NNK-induced lung tumorigenesis in humans; 2) perform additional studies to better understand the nature and scope of inflammation-induced suppression of CYP gene expression in the lung; and 3) identify common CYP2A13 genetic variants that cause changes in gene expression (and the underlying mechanisms), in order to provide biological basis for future epidemiological studies aimed at further confirming the role of CYP2A13 in smoking-induced lung cancer or other chemical toxicities in various ethnic or occupational groups. We believe that our proposed studies are novel, and the anticipated outcome will be highly relevant to mechanisms of chemical carcinogenesis and other chemical toxicities in human lung. PUBLIC HEALTH RELEVANCE: Continued studies on the regulation and genetic polymorphisms of the CYP2A13 gene will help to improve our understanding of the environmental and genetic factors involved in the diseases of the respiratory tract, such as lung cancer, which is the leading cause of cancer-related death in the U.S. Confirmation of a significant role of CYP2A13 in the risks of respiratory tract toxicity in humans may lead to new strategies for chemoprevention via enzyme inhibition.

描述（由申请人提供）：长期目标是确定呼吸道细胞色素P450（P450或CYP）酶在靶组织代谢激活和环境化学物质毒性中的作用。我们的重点仍然是 CYP2A13，一种在人类呼吸道中选择性表达的酶，以及在 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 代谢激活中最有效的人类 P450 酶，一种主要的烟草衍生呼吸道致癌物。 CYP2A13 还可以代谢许多其他重要的呼吸道毒物。我们的假设是，CYP2A13 在人类与烟草相关的肺癌发生中发挥着重要作用，这一假设得到了最近的一项流行病学研究结果的支持，并且有报告证实 CYP2A13 蛋白在人肺中表达，在肺中它在代谢激活中具有活性。 NNK 和肺中的 P450（而非肝脏中的 P450）对于小鼠模型中 NNK 诱导的肺肿瘤发生至关重要。此外，我们的初步发现，炎症使 CYP2A13 的表达下调，这解释了为什么在患者来源的肺活检样本中检测到的 CYP2A13 蛋白水平如此低，并表明完整、健康的 CYP2A13 水平可能肺要高得多。在这里，我们提出了三个系列的实验，以克服无法直接研究完整、健康人肺中 P450 表达或活性的困难。我们将1）研究CYP2A13人源化小鼠模型，以便为CYP2A13介导NNK诱导的人类肺部肿瘤发生的潜力提供原理证明； 2) 进行额外的研究，以更好地了解炎症诱导的肺部 CYP 基因表达抑制的性质和范围； 3）鉴定引起基因表达变化（及其潜在机制）的常见CYP2A13遗传变异，为未来的流行病学研究提供生物学基础，进一步证实CYP2A13在吸烟诱发的肺癌或其他化学毒性中的作用。不同种族或职业群体。我们相信，我们提出的研究是新颖的，预期结果将与人肺中化学致癌和其他化学毒性的机制高度相关。公共健康相关性：对 CYP2A13 基因的调控和遗传多态性的持续研究将有助于提高我们对呼吸道疾病（例如肺癌，这是癌症的主要原因）所涉及的环境和遗传因素的了解。 CYP2A13 在人类呼吸道毒性风险中的重要作用的确认可能会导致通过酶抑制进行化学预防的新策略。