Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 7048521
• 负责人: Xinxin Ding
• 金额: $ 48.27万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048521
• 关键词: NADPH cytochrome c2 reductase; SDS polyacrylamide gel electrophoresis; chemical carcinogenesis; chemical related neoplasm /cancer; clinical research; cytochrome P450; embryo /fetus toxicology; environment related neoplasm /cancer; environmental exposure; enzyme activity; enzyme linked immunosorbent assay; genetic polymorphism; genetically modified animals; high performance liquid chromatography; human tissue; laboratory mouse; lung neoplasms; mass spectrometry; polymerase chain reaction; respiratory enzyme; respiratory epithelium; respiratory system; respiratory toxin; tobacco; toxin metabolism

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.

描述（由申请人提供）：长期目标是确定呼吸道细胞色素P450（P450）酶在目标组织代谢激活和环境化学物质的毒性中的作用。当前的重点是最近确定的人P450酶CYP2A13。初步研究表明，（a）CYP2A13 mRNA主要在呼吸道中表达，并且比CYP2A6在鼻粘膜和肺中比CYP2A6更丰富。 （b）异源表达的CYP2A13在实验动物和人类的几种已知或怀疑引起鼻癌和肺癌的代谢激活中高度活跃3-吡啶基）-L-丁酮（NNK）; （c）CYP2A蛋白在人类胎儿鼻粘膜中表达，其水平高于胎儿肝脏。因此，我们假设CYP2A13在人类鼻和肺组织中提供了独特的代谢激活途径，以启动化学癌变，并且该途径在胎儿发育过程中已经活跃。设计了两个具体的目标（目标1和2），以完全表征这种新的人类P450酶的表达，其对人类胎儿鼻和肺微染色体中已知呼吸道procarcinogen（NNK）的代谢激活的贡献以及程度其遗传多态性的功能后果。此外（AIM 3），一种新型的，肺特异性的NADPH-CYTOCHROME P450还原酶（CPR）基因敲除小鼠模型将用于检验相关的假设，即肺P450是NNK代谢激活和NNK诱导的肺肿瘤。拟议的研究将填补有关呼吸道中与烟草相关的化学癌变的人类酶的重要知识差距，并将有助于更准确地预测胎儿和成年人中环境化学物质暴露的毒性风险。它们还将帮助我们提高我们对呼吸道疾病涉及的遗传因素的理解，例如肺癌，这是美国与癌症相关死亡的主要原因