Metabolic mechanisms of naphthalene toxicity in lung

萘肺毒性的代谢机制

基本信息

批准号：
8852124
负责人：
Xinxin Ding
金额：
$ 33.32万
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/8852124
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）是一种无处不在的污染物，人类被广泛暴露于该污染物。 NA导致大鼠和小鼠的肿瘤，并已被归类为可能的人致癌。据信NA致癌性的机制涉及NA诱导的急性肺损伤和修复的反复循环。 NA细胞毒性的先决条件是其通过细胞色素P450（CYP）酶的生物活化。源自Na-环氧（Na-O）的反应性代谢产物会耗尽细胞谷胱甘肽（GSH），并且在较高浓度下，将其与组织蛋白共价结合。 NA-O可以由肺和肝脏产生。负责小鼠Na生物活化的主要酶包括CYP2A5和CYP2F2； CYP2F2-NULL小鼠对NA肺毒性具有高度抗性，而CYP2A5-NULL小鼠则受到部分保护，以防止NA鼻毒性。尽管微粒体NA代谢和生物活化的速率存在很大的个体间变化，但人肺和人肝都能够代谢NA。然而，尚不清楚人类CYP2A13和CYP2F1（小鼠CYP2A5和CYP2F2的直系同源物）在Na生物活化中的作用，并且肝p450功能对个人介导的NA介导的肺毒性的风险的潜在影响仍然是未定的。该应用的目标是定义CYP2A13和CYP2F1在CYP2A13/2F1人性化小鼠肺中NA生物活化和毒性中的作用；确定富含CYP2A13/2F1表达的人类肺部区域；并确定肝脏中P450介导的NA生物活化和/或排毒是否可能导致或以其他方式影响NA肺毒性。中心假设是NA具有引起人类肺毒性的潜力，而NA在肺和肝脏中的代谢都会在个人基础上影响结果。该假设将以两个具体目的进行检验，以1）定义CYP2A13和CYP2F1在肺中的生物活化和毒性中的作用； 2）定义肝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方法的组合，并利用许多转基因的小鼠模型以及人体组织和细胞来解决特定目的。这些研究的长期目标是定义影响NA介导的实验动物和人类肺毒性的代谢机制。