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）酶在靶组织代谢激活和环境化学品毒性中的作用。目前的重点是最近发现的人类P450酶CYP2A13。初步研究表明(a) CYP2A13 mRNA主要表达于呼吸道，在鼻黏膜和肺部的表达量远高于CYP2A6， CYP2A6是CYP2A亚家族的另一个功能成员；(b)异源表达的CYP2A13在实验动物和人类中已知或怀疑导致鼻癌和肺癌的几种化合物的代谢激活中高度活跃，如n -亚硝基二乙胺（NDEA）和4-（甲基亚硝胺）- 1 -（3-吡啶基）-l-丁酮（NNK）；(c) CYP2A蛋白在人胎儿鼻黏膜中的表达水平远高于胎儿肝脏。因此，我们假设CYP2A13在人类鼻和肺组织中提供了一种独特的代谢激活途径来启动化学致癌作用，并且该途径在胎儿发育期间已经激活。两个特定目标（目标1和目标2）旨在充分表征这种新的人类P450酶的表达，其对人类胎儿鼻和肺微粒体中已知呼吸道前致癌物（NNK）代谢激活的贡献，以及其遗传多态性的程度和功能后果。此外（Aim 3），将使用一种新型的肺特异性nadph -细胞色素P450还原酶（CPR）敲除小鼠模型来验证肺P450负责NNK代谢激活和NNK诱导的肺肿瘤的相关假设。拟议的研究将填补有关呼吸道中与烟草相关的化学致癌作用的人类酶的重要知识空白，并将有助于更准确地预测胎儿和成人接触环境化学物质的个体毒性风险。它们还将有助于提高我们对呼吸道疾病（如肺癌）的遗传因素的理解，肺癌是美国癌症相关死亡的主要原因

DESCRIPTION (provided by applicant): The long-term objective is to determine the role of respiratory tract cytochrome P450 (P450) enzymes in target tissue metabolic activation and toxicity of environmental chemicals. The current focus is on a recently identified human P450 enzyme, CYP2A13. Preliminary studies indicated that (a) CYP2A13 mRNA is expressed mainly in the respiratory tract and is much more abundant than CYP2A6, the other functional member of the CYP2A subfamily, in nasal mucosa and lung; (b) heterologously expressed CYP2A13 is highly active in the metabolic activation of several compounds known or suspected to cause nasal and lung cancers in experimental animals and in humans, such as N-nitrosodiethylamine (NDEA) and 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK); and (c) CYP2A proteins are expressed in human fetal nasal mucosa at levels much higher than in fetal liver. We thus hypothesize that CYP2A13 provides a unique metabolic activation pathway in human nasal and lung tissues to initiate chemical carcinogenesis and that this pathway is already active during fetal development. Two specific aims (Aims 1 and 2) are designed to fully characterize this new human P450 enzyme with respect to its expression, its contribution to metabolic activation of a known respiratory tract procarcinogen (NNK) in human fetal nasal and pulmonary microsomes, and the extent and functional consequences of its genetic polymorphisms. In addition (Aim 3), a novel, lung-specific NADPH-cytochrome P450 reductase (CPR) knockout mouse model will be used to test a related hypothesis that pulmonary P450s are responsible for NNK metabolic activation and NNK-induced lung tumors. The proposed studies will fill an important knowledge gap regarding human enzymes responsible for tobacco-related chemical carcinogenesis in the respiratory tract, and will contribute toward a more accurate prediction of individual risks of toxicity from environmental chemical exposure in fetuses and well as in adults. They will also help to improve our understanding of the genetic factors involved in the diseases of the respiratory tract, such as lung cancer, which is the leading cause of cancer-related death in the U.S.