Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 8869326
• 负责人: Xinxin Ding
• 金额: $ 8万
• 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/8869326
• 关键词: Human; CYP2A; respiratory; tract; xenobiotic

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）酶在目标组织代谢激活和环境化学物质的毒性中的作用。我们的重点继续放在CYP2A13上，CYP2A13是一种在人呼吸道中选择性表达的酶，以及在4-（甲基硝基氨基）的代谢激活中最有效的人P450酶-1-（3-吡啶基）-1-1-1-丁烷（NNK），（NNK），酶，主要的烟草呼吸道procarcinogen。 CYP2A13也已知可以代谢许多其他重要的呼吸道有毒物质。我们的假设是，CYP2A13在人类中与烟草相关的肺癌发生中起着重要作用，得到了最近一项流行病学研究的发现，并通过报道证实CYP2A13蛋白在人肺中表达，并在人类肺中表达。 NNK和肺中的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的表达被炎症降低，可以解释为什么在患者衍生的肺dung活检样本中检测到的CYP2A13蛋白水平如此之低，并表明CYP2A13水平在完整，健康，健康，健康，健康的可能性肺部高得多。在这里，我们提出了三个系列实验，以克服与无法直接研究完整，健康的人类肺中P450表达或活性相关的困难。我们将研究1）研究CYP2A13人性化的小鼠模型，以便为CYP2A13的潜力提供原则证明，以介导NNK诱导的人类中的肺肿瘤发生； 2）进行其他研究以更好地了解肺中CYP基因表达抑制炎症的性质和范围； 3）确定引起基因表达变化（以及潜在机制）的常见CYP2A13遗传变异，以便为未来的流行病学研究提供生物学基础，旨在进一步证实CYP2A13在吸烟诱导的肺癌或其他化学毒性中的作用各种种族或职业群体。我们认为，我们提出的研究是新颖的，预期的结果将与人肺中化学癌变和其他化学毒性的机制高度相关。