Human CYP2A and respiratory tract xenobiotic toxicity

 描述（由申请人提供）：肺癌是美国癌症相关死亡的主要原因，而烟草烟雾暴露是最重要的影响因素。然而，虽然已经了解了很多关于致瘤作用和许多个别烟草致癌物的潜在机制，相对较少的是已知的致癌机制诱导TS，实际复杂的环境混合物，许多人每天都暴露在。特定致癌物及其生物活化对TS诱导的肺肿瘤发生或致癌前TS诱导的病理变化（如肺部炎症）的体内贡献在很大程度上是未知的;但这些知识对于设计有效的TS诱导的肺毒性化学预防和评估新烟草产品的安全性至关重要。这项资助的长期目标是确定呼吸道细胞色素P450（P450或CYP 13）酶在环境化学品代谢活化和毒性中的作用，重点是CYP 2A 13，一种选择性表达于呼吸道的人类酶。我们的中心假设是CYP 2A 13在烟草相关的肺癌发生中起着至关重要的作用。CYP 2A 13介导由主要烟草致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的肺肿瘤发生的能力现已得到充分证实，例如，通过我们对CYP 2A 13人源化小鼠的研究。CYP 2A 13还可生物活化许多其他TS毒物/致癌物。CYP 2A 13 *2等位基因的流行病学研究进一步支持CYP 2A 13在人类吸烟者肺癌风险中的重要作用。合乎逻辑的下一步是直接确定CYP 2A 13在TS诱导的肺肿瘤发生中的作用。因此，我们将确定人CYP 2A 13和其他P450酶编码的小鼠和人CYP 2ABFS基因簇在环境烟草烟雾（ETS）诱导的肺肿瘤发生（目标1）和肺部炎症（目标2）的体内作用;后者与肿瘤的启动和肿瘤的促进。在目标1中，我们将测试的假设，删除小鼠Cyp 2abfs和添加人CYP 2A 13将导致相应的变化，在肺肿瘤的程度和水平的O 6-甲基鸟嘌呤（O 6-mG）DNA加合物在肺中，在小鼠长期暴露于ETS。在目标2中，我们将检验以下假设：依赖于CYP 2A/B/F/S酶进行生物活化的ETS组分的独特子集使ETS能够在体内引起肺部炎症。我们的目标是建立CYP 2A 13作为肺癌风险评估的有效遗传标记和化学预防的合理分子靶点。

 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.