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。目前的焦点是最近发现的一种人类P450酶，CYP2A13。初步研究表明：(A)CYP2A13mRNA主要在呼吸道表达，并且在鼻黏膜和肺中的表达比另一个功能成员--CYP2A6丰富得多；(B)异源表达的CYP2A13在几种已知或怀疑会导致实验动物和人类鼻癌和肺癌的化合物的代谢激活中具有很高的活性，如N-亚硝基二乙胺和4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone(NNK)；以及(C)在人胎鼻粘膜中的表达水平远远高于胎肝。因此，我们假设，在人类鼻腔和肺组织中，CYP2A13提供了一种独特的代谢激活途径来启动化学致癌，并且该途径在胎儿发育过程中已经很活跃。设计了两个特定的目标(目标1和2)，以全面描述这种新的人类P450酶的表达，它对人胎儿鼻腔和肺微粒体中已知的呼吸道原癌原(NNK)代谢激活的贡献，以及它的基因多态的程度和功能后果。此外(目标3)，一种新的肺特异的NADPH-细胞色素P450还原酶(CPR)基因敲除小鼠模型将被用来检验一个相关假设，即肺P450与NNK代谢激活和NNK诱导的肺癌有关。拟议的研究将填补关于人体酶在呼吸道中与烟草相关的化学致癌作用的重要知识空白，并将有助于更准确地预测环境化学暴露在胎儿和成人中的个体毒性风险。它们还将有助于我们更好地了解与呼吸道疾病有关的遗传因素，例如肺癌，肺癌是美国与癌症相关的死亡的主要原因。

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.