Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 8307420
• 负责人: Xinxin Ding
• 金额: $ 24.15万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307420
• 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

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（由申请方提供）：长期目标是确定呼吸道细胞色素P450（P450或CYP 1A 1）酶在靶组织代谢活化和环境化学品毒性中的作用。我们的重点仍然是CYP 2A 13，一种在人呼吸道中选择性表达的酶，以及在4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）（一种主要的烟草源性呼吸道原致癌物）代谢活化中最有效的人P450酶。CYP 2A 13还已知代谢许多其他重要的呼吸道毒物。我们的假设，即CYP 2A 13在人类烟草相关的肺癌发生中起重要作用，得到了最近流行病学研究结果的支持，并得到了证实CYP 2A 13蛋白在人肺中表达的报告的支持，在人肺中，CYP 2A 13蛋白在NNK的代谢活化中具有活性，并且肺中的P450而不是肝脏中的P450对于小鼠模型中NNK诱导的肺肿瘤发生是必不可少的。此外，我们的初步发现，CYP 2A 13的表达受到炎症的下调，为为什么在患者来源的肺活检样本中检测到的CYP 2A 13蛋白水平如此低提供了解释，并表明完整的健康肺中的CYP 2A 13水平可能要高得多。在这里，我们提出了三个系列的实验，以克服与不能直接研究P450在完整的，健康的人肺的表达或活性相关的困难。我们将1）研究CYP 2A 13人源化小鼠模型，以便为CYP 2A 13介导人类NNK诱导的肺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理解炎症诱导的肺中NNK基因表达抑制的性质和范围;和3）鉴定引起基因表达变化的常见CYP 2A 13遗传变异（和基本机制），为进一步证实CYP 2A 13在吸烟中的作用提供生物学基础，在不同种族或职业群体中诱发肺癌或其他化学毒性。我们相信，我们提出的研究是新颖的，预期的结果将是高度相关的化学致癌和其他化学毒性在人类肺部的机制。公共卫生相关性：对CYP 2A 13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（如肺癌）中涉及的环境和遗传因素的理解，这是导致癌症的主要原因-确认CYP 2A 13在人类呼吸道毒性风险中的重要作用可能会导致新的策略，通过酶抑制进行化学预防。