Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 8874543
• 负责人: Xinxin Ding
• 金额: --
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874543
• 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; 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

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.

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品毒性中的作用。我们的重点是CYP2A13，一种在人类呼吸道中选择性表达的酶，以及在4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）代谢激活中最有效的人类P450酶，NNK是一种主要的烟草衍生的呼吸道前致癌物。众所周知，CYP2A13还能代谢许多其他重要的呼吸道毒物。我们的假设是，CYP2A13在人类烟草相关的肺癌发生中起重要作用，最近的一项流行病学研究结果支持了这一假设，并证实CYP2A13蛋白在人肺中表达，在那里它在NNK的代谢激活中活跃，并且肺中的p450而不是肝脏中的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，CYP2A13的表达被炎症下调，这解释了为什么在患者来源的肺活检样本中检测到的CYP2A13蛋白水平如此之低，并表明在完整、健康的肺中CYP2A13水平可能要高得多。在这里，我们提出了三个系列的实验来克服无法直接研究P450在完整健康人类肺中的表达或活性的困难。我们将1)研究CYP2A13人源化小鼠模型，为CYP2A13介导nnk诱导的人类肺肿瘤发生的潜力提供原理证明；2)开展进一步的研究，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)发现导致基因表达改变的常见CYP2A13基因变异（及其潜在机制），为未来流行病学研究提供生物学基础，进一步确认CYP2A13在不同种族或职业人群中吸烟引起的肺癌或其他化学毒性中的作用。我们认为我们提出的研究是新颖的，预期的结果将与人类肺部化学致癌和其他化学毒性的机制高度相关。