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Metabolic Mechanisms of Naphthalene Toxicity in Lung

萘毒性肺代谢机制

基本信息

批准号：
9765706
负责人：
Xinxin Ding
金额：
$ 47.46万
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/9765706
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.

萘（NA）是一种普遍存在的污染物，人类广泛暴露于其中。NA导致鼻和肺对成年大鼠和小鼠的毒性，包括肿瘤，并已被归类为可能的人类致癌物。 NA致癌性的机制可能涉及遗传毒性和非遗传毒性事件，清楚NA细胞毒性的先决条件是通过细胞色素P450（CYP）酶的生物活化。反应性形成的代谢物，来自NA-环氧化物（NAO），可以消耗细胞谷胱甘肽并结合共价连接到蛋白质上。当前资助周期的研究，重点是NA生物活化和急性肺毒性，为人CYP 2A 13和2F 1介导NA的能力提供了令人信服的证据在人源化小鼠模型中的体内肺毒性，以及对全身处置之间相互作用的见解吸入NA的靶组织生物活化及其对NA气道毒性的影响。最初的新证据是还获得了NA离体产生稳定DNA加合物的能力，以及全身产生的NA代谢物在体内肺毒性中的作用。在下一次资助的拟议研究中，循环，我们将继续研究NA肺毒性的代谢机制，通过：导致体内肺毒性的NA代谢产物（目的1），确定人CYP 2A 6 在小鼠肝脏中表达，以介导吸入NA的气道毒性（目的2），并鉴定稳定的NA- 肺中的DNA加合物及其形成的代谢机制（目的3）。中央假设NA有可能在人肺中引起细胞毒性和遗传毒性， NA在肺和肝中的代谢影响个体基础上的毒性结果。我们将雇用一名本发明涉及体内、离体和体外方法的组合，并利用新的遗传修饰或人源化的方法，小鼠模型，以及人肺细胞和肝微粒体，以解决具体的目标。很长的- 这些研究的长期目标是确定影响NA介导的肺毒性的代谢机制，实验动物和人类。该结果有望改善对人类肺部疾病的评估暴露于NA和其他相关化学品的风险。