Metabolic mechanisms of naphthalene toxicity in lung

萘肺毒性的代谢机制

基本信息

批准号：
8840377
负责人：
Xinxin Ding
金额：
$ 35.92万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-20 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840377
关键词：
Abbreviations Acute Lung Injury Address Adult Animals Binding Breathing CYP2A5 gene CYP2F2 gene Carcinogens Cells Coculture Techniques Cytochrome P450 Data Dose Drug Kinetics Drug Metabolic Detoxication Environmental Pollutants Enzymes Epithelial Cells Epoxy Compounds Event Exposure to Female Gender Genes Glutathione Goals Health Hepatic Hepatocyte Human In Vitro Individual Intervention Knockout Mice Liver Location Lung Mediating Mediation Messenger RNA Metabolic Metabolic Activation Metabolism Microsomes Mus Naphthalene Nose Orthologous Gene Outcome Oxidoreductase Proteins Rattus Resistance Risk Role Site System Testing Time Tissues Toxic effect Variant base carcinogenicity cell injury cytotoxicity design disorder prevention exposed human population high risk human SLC25A5 protein human tissue in vivo lung repair male mouse model pollutant toxicant tumor

项目摘要

DESCRIPTION (provided by applicant): Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. NA causes tumors in rats and mice, and has been classified as a Possible Human Carcinogen. The mechanism of NA carcinogenicity is believed to involve repeated cycles of NA-induced acute lung injury and repair. A prerequisite for NA cytotoxicity is its bioactivation by cytochrome P450 (CYP) enzymes; the reactive metabolites formed, which derive from the NA-epoxide (NA-O), can deplete cellular glutathione (GSH) and, at higher concentrations, bind covalently to tissue proteins. NA-O can be produced by both lung and liver. The major enzymes responsible for NA bioactivation in the mouse include CYP2A5 and CYP2F2; Cyp2f2-null mice are highly resistant to NA lung toxicity, whereas Cyp2a5-null mice are partially protected against NA nasal toxicity. Both human lung and human liver are capable of metabolizing NA, although large interindividual variations exist in the rates of microsomal NA metabolism and bioactivation. However, the roles of human CYP2A13 and CYP2F1 (orthologs of mouse CYP2A5 and CYP2F2, respectively) in NA bioactivation are not well understood, and the potential impact of variations in hepatic P450 function on an individual's risks of developing NA- mediated lung toxicity remains undefined. The objectives of this application are to define the role of CYP2A13 and CYP2F1 in NA bioactivation and toxicity in the lungs of CYP2A13/2F1-humanized mice; identify human lung regions that are enriched in CYP2A13/2F1 expression; and determine whether P450- mediated NA bioactivation and/or detoxification in the liver could contribute to, or otherwise influence, NA lung toxicity. The central hypothesis is that NA has the potential to cause lung toxicity in humans and that the metabolism of NA in both lung and liver influence the outcome on an individual basis. This hypothesis will be tested in two specific aims that will 1) define the role of CYP2A13 and CYP2F1 in NA bioactivation and toxicity in the lung; 2) define whether hepatic NA metabolism could influence the risks of NA lung toxicity. We will employ a combination of in vivo and in vitro approaches, and utilize a number of genetically modified mouse models, as well as human tissues and cells, to address the specific aims. The long-term goal of these studies is to define the metabolic mechanisms that influence NA-mediated lung toxicity in experimental animals and humans.

描述（由申请人提供）：萘（NA）是人类广泛接触的一种普遍存在的污染物。 NA 会导致大鼠和小鼠肿瘤，并被列为可能的人类致癌物。 NA致癌性的机制被认为涉及NA诱导的急性肺损伤和修复的重复循环。 NA 细胞毒性的先决条件是其被细胞色素 P450 (CYP) 酶生物激活；形成的反应性代谢物源自 NA-环氧化物 (NA-O)，可以消耗细胞谷胱甘肽 (GSH)，并且在较高浓度下与组织蛋白共价结合。 NA-O 可由肺和肝产生。小鼠中负责 NA 生物激活的主要酶包括 CYP2A5 和 CYP2F2； Cyp2f2缺失小鼠对NA肺毒性具有高度抵抗力，而Cyp2a5缺失小鼠对NA鼻毒性有部分保护。人类肺和人类肝脏都能够代谢 NA，尽管微粒体 NA 代谢和生物激活率存在很大的个体差异。然而，人类 CYP2A13 和 CYP2F1（分别是小鼠 CYP2A5 和 CYP2F2 的直系同源物）在 NA 生物激活中的作用尚不清楚，肝 P450 功能变化对个体发生 NA 介导的肺毒性风险的潜在影响仍不清楚。本申请的目的是确定 CYP2A13 和 CYP2F1 在 CYP2A13/2F1 人源化小鼠肺部 NA 生物激活和毒性中的作用；识别富含 CYP2A13/2F1 表达的人肺区域；并确定肝脏中 P450 介导的 NA 生物活化和/或解毒是否会导致或以其他方式影响 NA 肺毒性。中心假设是 NA 有可能对人类造成肺毒性，并且 NA 在肺和肝脏中的代谢会影响个体的结果。该假设将在两个具体目标中进行测试，这将 1) 定义 CYP2A13 和 CYP2F1 在 NA 生物激活和肺部毒性中的作用； 2) 确定肝脏NA代谢是否会影响NA肺毒性的风险。我们将采用体内和体外相结合的方法，并利用一些转基因小鼠模型以及人体组织和细胞来实现特定目标。这些研究的长期目标是确定影响实验动物和人类 NA 介导的肺毒性的代谢机制。