Metabolic Mechanisms of Naphthalene Toxicity in Lung

萘毒性肺代谢机制

基本信息

批准号：
10403995
负责人：
Xinxin Ding
金额：
$ 41.95万
依托单位：
UNIVERSITY OF ARIZONA
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403995
关键词：
Acute Address Adult Affect Animals Binding CYP2A5 gene CYP2F2 gene Carcinogens Cells Chemicals Cytochrome P450 DNA DNA Adducts Data Detection Dose Environmental Pollutants Enzymes Epoxy Compounds Event Exposure to Female Funding Generations Glutathione Goals Hepatic Human In Vitro Individual Inhalation Intervention Knockout Mice Label Liver Liver Microsomes Lung Lung diseases Mediating Metabolic Metabolism Microsomal Epoxide Hydrolase Monkeys Mus Naphthalene Nose Occupational Outcome Outcome Study Pattern Plasma Predisposition Proteins Publishing Rattus Research Respiratory System Risk Role Structure of parenchyma of lung System Techniques Testing Time Tissues Toxic effect Toxicokinetics Transgenic Mice Variant Wild Type Mouse Work accelerator mass spectrometry adduct carcinogenesis carcinogenicity cytotoxicity design disorder prevention disorder risk exposed human population genotoxicity humanized mouse improved in vivo insight liver metabolism male metabolic abnormality assessment mouse model novel pollutant toxicant tumor vapor

项目摘要

Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. NA causes nasal and lung toxicities, including tumors, in adult rats and mice and has been classified as a possible human carcinogen. The mechanism of NA carcinogenicity, which may involve both genotoxic and non-genotoxic events, is not clear. A prerequisite for NA cytotoxicity is bioactivation by cytochrome P450 (CYP) enzymes. The reactive metabolites formed, which derive from the NA-epoxide (NAO), can deplete cellular glutathione and bind covalently to proteins. Research in the current funding cycle, which was focused on NA bioactivation and acute lung toxicity, provided compelling evidence for the ability of human CYP2A13 and 2F1 to mediate NA’s lung toxicity in vivo in a humanized mouse model, and insights on the interplay between systemic disposition and target tissue bioactivation of inhaled NA and its impact on NA’s airway toxicity. Initial novel evidence was also obtained for the ability of NA to produce stable DNA adducts ex vivo, and for a possible role of systemically generated NA metabolites in lung toxicity in vivo. In the proposed studies for the next funding cycle, we will continue to study the metabolic mechanisms of NA lung toxicity by: identifying liver-generated NA metabolites that contribute to lung toxicity in vivo (Aim 1), determining the ability of human CYP2A6 expressed in the mouse liver to mediate airway toxicity of inhaled NA (Aim 2), and identifying the stable NA- DNA adducts in the lung and dissecting metabolic mechanisms of their formation (Aim 3). The central hypothesis is that NA has the potential to cause both cytotoxicity and genotoxicity in human lung, and that the metabolism of NA in both lung and liver influences the toxic outcome on an individual basis. We will employ a combination of in vivo, ex vivo, and in vitro approaches, and utilize novel genetically modified or humanized mouse models, as well as human lung cells and liver microsomes, 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. The outcome is expected to improve assessment of human lung disease risks from exposures to NA and other related chemicals.

nachthalene（NA）是无处不在的抛光，而whumans则广泛暴露。成年大鼠和小鼠和哈斯的毒性，包含肿瘤，并被归类为可能的人癌。 Na致癌性的机制可能涉及遗传毒性和非生物毒性事件，不是 NA细胞毒素的先决条件是细胞色素P450（CYP）酶的生物活化形成的代谢产物，源自na-氧化物（NaO），可以耗尽细胞谷胱甘肽并结合结合结合结合结合结合结合结合在当前的资金周期中共同研究，该研究的重点是急性肺毒品，提供了人类CYPA13和2F1介导Na的能力的竞争证据人性化小鼠模型中体内的肺毒性，以及有关全身性分配的洞察力的见解并靶向吸入NA的生物活化及其对NA气道毒理性的影响。还可以获得NA促进稳定DNA成瘾者的能力，并可能发挥作用在体内的肺毒性中系统地产生了NA代谢。循环，我们将继续研究Na肺毒性的代谢机制：识别肝脏生成的在体内有助于肺毒性的Na代谢产物（AIM 1），确定人CYP2A6的能力在小鼠肝脏中表达以介导吸入NA的气道毒性（AIM 2），并鉴定稳定的Na- 肺中的DNA加合物并解剖其形成的代谢机制（AIM 3）假设是NA有可能停止人类肺中的细胞毒和遗传毒性，并且您 NA在肺和肝脏中的代谢都会在个人基础上影响毒性结果。体内，体内和体外方法的结合，并利用新颖的遗传修饰或人性化的小鼠模型以及人肺细胞和肝微粒体，长期您的任期目标是影响Na介导的肺毒性的代谢机制实验动物和人类的结果是预期人暴露于NA和其他相关化学物质的风险。