Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 7214161
• 负责人: Xinxin Ding
• 金额: $ 48.04万
• 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 2009-08-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214161
• 关键词: 7alpha hydroxylase; A/J Mouse; A549; Adenoviruses; Adult; Affinity; Alcohols; Aldehydes; Alleles; Animals; Antibodies; Antigens; Backcrossings; Biological Assay; Blood; Breeding; Butanones; Cancer Etiology; Cell Line; Cells; Cessation of life; Chemoprevention; Cytochrome P450; DNA; DNA Adduction; DNA Sequence; Diethylnitrosamine; Digestion; Dose; Enzyme Inhibition; Enzyme Kinetics; Enzymes; Ethnic group; Exons; Fetal Development; Fetal Liver; Fetus; Frequencies; Future; Gel; Gene Frequency; Generations; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Green Fluorescent Proteins; Haplotypes; Health Status; High Pressure Liquid Chromatography; Human; In Vitro; Individual; Insecta; Knock-out; Knowledge; Lead; Lung; Lung Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measures; Messenger RNA; Metabolic Activation; Microsomes; Modeling; Monitor; Monoclonal Antibodies; Mus; Mutation; NADPH-Ferrihemoprotein Reductase; Newborn Infant; Nose; Numbers; Pathway interactions; Polymerase Chain Reaction; Protein Isoforms; Proteins; Recombinants; Recovery; Respiratory System; Respiratory Tract Diseases; Risk; Role; Site; Spottings; Structure of mucous membrane of nose; Structure of parenchyma of lung; System; Testing; Tetanus Helper Peptide; Time; Tissues; Tobacco; Toxic effect; Transgenic Mice; Variant; Week; Withdrawal; Xenobiotics; chemical carcinogenesis; congenic; cytochrome P-450 CYP2A6 (human); design; environmental chemical; environmental chemical exposure; ethnic difference; fetal; improved; in vivo; mRNA Expression; member; mouse model; mutant; novel; null mutation; polyacrylamide; reconstitution; restriction enzyme

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（由申请方提供）：长期目标是确定呼吸道细胞色素P450（P450）酶在靶组织代谢活化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，CYP 2A 13。初步研究表明：（a）CYP 2A 13 mRNA主要在呼吸道表达，在鼻粘膜和肺中的表达量远高于CYP 2A亚家族的另一个功能成员CYP 2A 6;（B）异源表达的CYP 2A 13在已知或怀疑引起实验动物和人的鼻癌和肺癌的几种化合物的代谢活化中具有高活性，如N-亚硝基二乙胺（NDEA）和4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）;和（c）CYP 2A蛋白在人胎儿鼻粘膜中的表达水平远高于在胎儿肝脏中的表达水平。因此，我们假设CYP 2A 13在人类鼻和肺组织中提供了一种独特的代谢活化途径，以启动化学致癌作用，并且该途径在胎儿发育期间已经活跃。两个具体目标（目标1和2）的目的是充分表征这种新的人P450酶的表达，其对人胎儿鼻和肺微粒体中已知呼吸道前致癌原（NNK）的代谢活化的贡献，以及其遗传多态性的程度和功能后果。此外（目的3），一种新的肺特异性NADPH-细胞色素P450还原酶（CPR）敲除小鼠模型将用于检验肺P450负责NNK代谢活化和NNK诱导的肺肿瘤的相关假设。拟议的研究将填补一个重要的知识空白，人类酶负责烟草相关的化学致癌作用在呼吸道，并将有助于更准确地预测胎儿和成人的环境化学品暴露的毒性的个人风险。它们还将有助于提高我们对呼吸道疾病（如肺癌）中涉及的遗传因素的理解，肺癌是美国癌症相关死亡的主要原因。