Metabolic Mechanisms of Naphthalene Toxicity in Lung

萘毒性肺代谢机制

基本信息

批准号：
10612426
负责人：
Xinxin Ding
金额：
$ 42.09万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612426
关键词：
7alpha hydroxylase Acute Address Adult Affect Animal Experiments Binding CYP2A5 gene CYP2F2 gene Carcinogens Cells Chemicals Classification Cytochrome P450 DNA DNA Adduction DNA Adducts DNA Maintenance Data Detection Dose Environmental Pollutants Enzymes Epoxy Compounds Event Exposure to Female Funding Generations Glutathione Goals Hepatic Human In Vitro Incubated 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 secondary metabolite 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，人类广泛接触 NA 会导致鼻腔和肺部损伤。对成年大鼠和小鼠具有毒性，包括肿瘤，并已被列为可能的人类致癌物。 NA 致癌性的机制可能涉及基因毒性和非基因毒性事件，目前尚无定论。明确 NA 细胞毒性的先决条件是细胞色素 P450 (CYP) 酶的生物活化。形成的代谢物源自 NA-环氧化物 (NAO)，可以消耗细胞谷胱甘肽并结合当前资助周期的研究重点是 NA 生物激活和急性肺毒性，为人类 CYP2A13 和 2F1 介导 NA 的能力提供了令人信服的证据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 的靶组织生物活性及其对 NA 气道毒性的影响是最初的新证据。还获得了 NA 离体产生稳定 DNA 加合物的能力，以及可能的作用在下一次资助的拟议研究中，系统地产生了体内肺毒性的NA代谢物。循环中，我们将通过以下方式继续研究 NA 肺毒性的代谢机制：识别肝脏产生的体内导致肺毒性的 NA 代谢物（目标 1），决定人类 CYP2A6 的能力在小鼠肝脏中表达，介导吸入 NA 的气道毒性（目标 2），并鉴定稳定的 NA- 肺中的 DNA 加合物并剖析其形成的代谢机制（目标 3）。假设是 NA 有可能在人肺中引起细胞毒性和基因毒性，并且 NA 在肺和肝脏中的代谢会影响个体的毒性结果。结合体内、离体和体外方法，并利用新型转基因或人源化方法小鼠模型以及人类肺细胞和肝微粒体，以解决特定目标。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。实验动物和人类的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。