Metabolic Mechanisms of Naphthalene Toxicity in Lung

萘毒性肺代谢机制

• 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
• 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

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，人类对其有广泛的接触。鼻炎引起鼻腔和肺 对成年大鼠和小鼠的毒性，包括肿瘤，已被归类为可能的人类致癌物质。 NA致癌的机制，可能涉及遗传毒性和非遗传毒性事件，但不是 安全。NA细胞毒性的先决条件是细胞色素P450(CYP)酶的生物激活。被动型 由环氧化钠(NAO)形成的代谢物可以消耗细胞内的谷胱甘肽并结合 共价结合到蛋白质上。在当前供资周期中进行的研究，重点是NA生物激活和 急性肺毒性，为人CYP2A13和2F1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活体肺毒性，以及对全身倾向之间相互作用的见解 吸入NA的靶组织生物活性及其对NA呼吸道毒性的影响。最初的新奇证据是 还获得了NA在体外产生稳定DNA加合物的能力，以及可能的作用 全身生成的NA代谢物在体内的肺毒性。在下一笔资金的拟议研究中 周期，我们将继续研究NA肺毒性的代谢机制：鉴定肝脏产生的 体内导致肺毒性的NA代谢物(目标1)，确定人细胞色素P450 2A6的能力 在小鼠肝脏中表达以介导吸入NA的呼吸道毒性(Aim 2)，并鉴定稳定的NA- 肺中的DNA加合物及其形成的代谢机制剖析(目标3)。中环 假设NA对人肺具有潜在的细胞毒性和遗传毒性，并且 NA在肺和肝脏中的代谢影响个体的中毒结果。我们将聘请一名 结合体内、体外和体外方法，并利用新的转基因或人源化 小鼠模型，以及人类肺细胞和肝脏微粒体，以解决特定的目标。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。这一结果有望改善对人类肺部疾病的评估 暴露在NA和其他相关化学品中的风险。