Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 9351480
• 负责人: Xinxin Ding
• 金额: $ 0.01万
• 依托单位: SUNY POLYTECHNIC INSTITUTE
• 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 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351480
• 关键词: 7alpha hydroxylase; Acute; Alleles; Butanones; CYP2B6 gene; Cancer Etiology; Carcinogenesis Mechanism; Carcinogens; Cessation of life; Chemoprevention; Chronic; Complex; Cytochrome P450; DNA Adducts; DNA lesion; Dose; Environmental Tobacco Smoke; Enzyme Inhibition; Enzymes; Female; Gene Cluster; Genetic Markers; Genotype; Glutathione; Goals; Grant; Hand; Human; Hyperplasia; Immunosuppression; In Vitro; Incidence; Individual; Inflammation; Knockout Mice; Knowledge; Lead; Link; Lung; Lung Inflammation; Lung Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Metabolic; Metabolic Activation; Microsomes; Modeling; Molecular Target; Mus; Nose; Oncogenic; Particulate; Pathologic; Play; Production; Recombinants; Resistance; Respiratory System; Respiratory tract structure; Risk; Risk Assessment; Role; Safety; Smoke; Smoker; Structure of parenchyma of lung; Testing; Tobacco; Tobacco smoke; Tobacco-Associated Carcinogen; Toxic effect; Tumor Promotion; Tumorigenicity; Xenobiotics; air filter; cancer risk; carcinogenesis; chemical carcinogenesis; cytotoxicity; design; environmental chemical; environmental tobacco smoke exposure; epidemiology study; humanized mouse; in vivo; lung carcinogenesis; lung tumorigenesis; male; peer; public health relevance; selective expression; sex; toxicant; tumor initiation; tumorigenic

 DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death in the U.S., and tobacco smoke (TS) exposure is the most important contributing factor. However, while much has been learned about the tumorigenic effects and the underlying mechanisms of many individual tobacco carcinogens, relatively little is known about the mechanisms of carcinogenesis induced by TS, the actual complex environmental mixture that many people are exposed to on a daily basis. The in vivo contribution of specific carcinogens and their bioactivation to TS-induced lung tumorigenesis, or to TS-induced pathologic changes that precede carcinogenesis, such as lung inflammation, is largely unknown; but such knowledge is critical for designing effective chemoprevention for TS-induced lung toxicity and for assessing the safety of new tobacco products. The long-term objective of this grant has been to determine the role of respiratory tract cytochrome P450 (P450 or CYP) enzymes in the metabolic activation and toxicity of environmental chemicals, with a focus on CYP2A13, a human enzyme selectively expressed in the respiratory tract. Our central hypothesis is that CYP2A13 plays a vital role in tobacco-related lung carcinogenesis. The ability of CYP2A13 to mediate lung tumorigenesis induced by a major tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is now well-documented, e.g., by our studies of CYP2A13-humanized mice. CYP2A13 also bioactivates many other TS toxicants/carcinogens. Epidemiologic studies of the CYP2A13*2 allele further support an important role of CYP2A13 in lung cancer risk in human smokers. A logical next step is to directly determine the role of CYP2A13 in TS-induced lung tumorigenesis. Thus, we will determine the in vivo role of human CYP2A13 and other P450 enzymes encoded by the mouse and human CYP2ABFS gene cluster in environmental tobacco smoke (ETS)-induced lung tumorigenesis (Aim 1) and lung inflammation (Aim 2); the latter is linked with both tumor initiation and tumor promotion. In Aim 1, we will test the hypothesis that deletion of mouse Cyp2abfs and addition of human CYP2A13 will lead to corresponding changes in the extent of lung tumorigenesis and the levels of O6-methylguanine (O6-mG) DNA adduct in the lung, in mice exposed chronically to ETS. In Aim 2, we will test the hypothesis that unique subsets of ETS constituents, which depend on CYP2A/B/F/S enzymes for bioactivation, enable ETS to cause lung inflammation in vivo. Our goal is to establish CYP2A13 as a valid genetic marker for lung cancer risk assessment and a logical molecular target for chemoprevention.

 描述（由适用提供）：肺癌是美国与癌症相关死亡的主要原因，烟草烟雾（TS）暴露是最重要的因素。然而，尽管许多单个烟草致癌物的肿瘤效应和潜在机制已经了解了很多，但对于TS引起的致癌机制的了解相对较少，许多人每天都暴露于实际的复杂环境混合物。特异性致癌物的体内贡献及其对TS诱导的肺肿瘤发生的生物活化，或对癌症发生之前的TS诱导的病理变化，例如肺部感染，在很大程度上是未知的。但是，这种知识对于设计有效的化学预防至关重要，以用于TS诱导的肺毒性和评估新烟草产品的安全性。该赠款的长期目标是确定呼吸道细胞色素P450（P450或CYP）酶在环境化学物质的代谢激活和毒性中的作用，重点是CYP2A13，一种在呼吸道中选择性表达的人类酶。我们的中心假设是CYP2A13在与烟草相关的肺癌中起着至关重要的作用。 CYP2A13介导由主要的烟草致癌物诱导的肺肿瘤发生的能力，4-（甲基硝基氨基氨基）-1-（3-吡啶基）-1-丁酮（NNK），例如，通过我们的CYP2A13-HUMANID-HUMAANIAD小鼠的研究，如今已有据可查。 CYP2A13还可以生物活化许多其他TS毒物/致癌物。 CYP2A13*2的流行病学研究进一步支持CYP2A13在肺癌风险中的重要作用。逻辑下一步是直接确定CYP2A13在TS诱导的肺肿瘤发生中的作用。这是，我们将确定由小鼠和人CYP2ABFS基因簇编码的人CYP2A13和其他P450酶在环境烟草烟雾（ETS）诱导的肺肿瘤发生（AIM 1）和肺损伤（AIM 2）中所编码的其他P450酶；后者与肿瘤起始和肿瘤促进均有联系。在AIM 1中，我们将检验以下假设：小鼠CYP2ABF的缺失和人CYP2A13的添加将导致肺肿瘤发生程度的相应变化以及肺中肺中肺中的O6-甲基鸟嘌呤（O6-mg）DNA加合物的水平，小鼠在长期向ETS暴露于ETS中。在AIM 2中，我们将检验以下假设：ETS的独特子集构成依赖于CYP2A/B/F/S酶进行生物活化的假设，使ETS能够在体内引起肺注射。我们的目标是将CYP2A13建立为肺癌风险评估的有效遗传标记，并且是化学预防的逻辑分子靶标。