Human CYP2A and respiratory tract xenobiotic toxicity

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)酶在靶组织代谢激活和环境化学品毒性中的作用。我们的重点仍然是在人类呼吸道选择性表达的一种酶--细胞色素P2A13，以及在烟草中主要的呼吸道前致癌物质4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone的代谢激活过程中最有效的人类P450酶。已知的是，CYP2A13还能代谢许多其他重要的呼吸道毒物。我们的假设，即CYP2A13在人类与烟草相关的肺癌发生中发挥重要作用，得到了最近一项流行病学研究的发现的支持，并得到了以下报道的支持：在NNK诱导的小鼠模型中，肺中的P450蛋白是NNK诱导的肺肿瘤发生所必需的，并且在人的肺中表达，在NNK的代谢激活中活跃。此外，我们的初步发现，炎症下调了CYP2A13的表达，这解释了为什么在患者来源的肺活检样本中检测到的CYP2A13蛋白水平如此低，并表明完整、健康的肺中的CYP2A13水平可能要高得多。在这里，我们提出了三个系列的实验，以克服与无法直接研究完整、健康的人肺中P450的表达或活性相关的困难。我们将1)研究CYP2A13人源化的小鼠模型，以期为其在NNK诱导的人类肺肿瘤发生中的作用提供理论依据；2)开展更多的研究以更好地了解炎症诱导的CYP基因在肺中表达抑制的性质和范围；以及3)找出导致基因表达变化的常见的CYP2A13基因变体(及其潜在的机制)，以便为未来的流行病学研究提供生物学基础，这些研究旨在进一步证实CYP2A13在不同种族或职业群体中吸烟诱导的肺癌或其他化学毒性中的作用。我们相信，我们提出的研究是新颖的，预期的结果将与化学致癌和其他化学毒性在人类肺中的机制高度相关。

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.