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：
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
项目类别：
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

项目摘要

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（由申请人证明）：肺癌是与癌症相关死亡的主要原因。 TS诱导的癌变的机制每天暴露于特定的致癌物和TOS诱导的肺肿瘤发生的体内贡献。这是未知的，但这种知识对于设计有效的化学预防量至关重要CYP2A13的重点是，我们的呼吸道中有选择地表达的酶。 - 吡啶基）-1-丁酮（NNK），如我们对CYP2A13-Humanized小鼠的研究已得到充分记录，例如，CYP2A13*2等位基因的重要作用。吸烟者。 1将测试小鼠CYP2ABF的缺失和人类CYP2A13的添加将导致肺部肿瘤发生的相应变化和O6-甲基鸟嘌呤（O6-mg）DNA的水平在肺中成长为ETS中的ETS 2。检验以下假设：依赖CYP2A/B/F/S酶进行生物活化3作为肺癌风险评估的有效遗传标记和化学预防的逻辑分子靶标的UTS成分的独特子集。