Prophylactic Use of Vitamin E for Prevention of Occupational PAH-Induced Damage

预防性使用维生素 E 预防职业性 PAH 引起的损伤

• 批准号: 7532080
• 负责人: DEBBIE MUSTACICH
• 金额: $ 21.93万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-18 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532080
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Acute; Air; Antioxidants; Applications Grants; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Automobile Exhaust; Benzo(a)pyrene; Bile fluid; Biliary; Biological Markers; Breathing; Burn injury; Cigarette Smoker; Class; Coal; Coke; Complex Mixtures; DNA Adduction; DNA Adducts; DNA Damage; Data; Development; Disasters; Disease susceptibility; Dose; Drug Formulations; Drug Metabolic Detoxication; Environmental Pollutants; Environmental Tobacco Smoke; Enzymes; Excretory function; Exposure to; F2-Isoprostanes; Fire - disasters; Future; Goals; Hazardous Waste Sites; Health; Hepatic; Human; Individual; Kidney; Knowledge; Leukocytes; Life; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolism; Modeling; Multidrug Resistance Gene; Occupational; Occupational Exposure; Operative Surgical Procedures; Organ; Oxidative Stress; Pathology; Pathway interactions; Phase; Plants; Plasma; Play; Polycyclic Compounds; Polycyclic Hydrocarbons; Prevention; Proteins; Public Health; Qualifying; Range; Rattus; Recommendation; Regulation; Risk; Role; Route; Site; Suggestion; Supplementation; Tissues; Tocopherols; Tocotrienols; Toxic Environmental Substances; Toxic effect; Treatment Protocols; Urine; Vitamin E; Work; Xenobiotic Metabolism; Xenobiotics; adduct; base; cigarette smoking; concept; forest; improved; innovation; knowledge base; liver function; nutrition; oxidative DNA damage; prevent; prophylactic; protective effect; protein expression; response; superfund site; urinary

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs), including benzo(a)pyrene (BP), form a major class of environmental pollutants suggested to be causative factors in a variety of disease susceptibilities, including cancer. Virtually all PAH mixtures contain BP; a model compound that causes the formation of BP-DNA-adducts. Levels of BP-DNA adducts in cigarette smokers are decreased by vitamin E (a-tocopherol) administration. Although a-tocopherol's antioxidant activity has been the proposed mechanism for its protective effects, our recent provocative findings indicate that a-tocopherol also has a regulatory function in liver. Thus, a-tocopherol's action in eliminating BP-induced DNA damage likely involves regulation of hepatic detoxification and biliary excretion. There is, therefore, a need to evaluate a-tocopherol-dependent modulation of hepatic xenobiotic metabolism and disposition as mechanisms for the detoxification and elimination of PAHs. Our long-range goal is to determine the efficacy of prophylactic high dose vitamin E supplementation for prevention of DNA-adduct formation during occupational exposure to PAHs. Our objective in this R21 application is to identify the key mechanism(s) by which a-tocopherol supplementation alters the response of hepatic, lung and kidney tissues to PAHs utilizing BP as a model compound. Our central hypothesis is that pharmacologic a-tocopherol supplementation, in addition to providing increased antioxidant protection, increases xenobiotic metabolism and excretion pathways, thereby protecting the liver and other organs from PAH-induced DNA adduct formation by increasing detoxification and/or elimination of PAHs and their metabolites from the body. We propose to: Aim 1. Determine modulation of BP metabolism and excretion by a-tocopherol in rats. Our working hypothesis is that elevated levels of a-tocopherol will significantly increase: (1) metabolism of BP to non-DNA reactive metabolites and (2) increase BP and/or BP metabolite excretion. Aim 2. Identify the protective effects of a-tocopherol supplementation against BP-induced DNA damage. Our working hypothesis is that elevated levels of a-tocopherol will decrease BP-induced DNA damage in liver, lung and kidney by two synergistic mechanisms: (1) increased antioxidant protection against oxidative stress- induced damage and (2) decreased formation of covalent BP-DNA adducts. This proposal is innovative because it challenges the current paradigm that -tocopherol acts almost exclusively as an antioxidant, while supporting the paradigm that nutrition and dietary regiments can modulate toxicological insults and resultant pathologies. The public health relevance of these studies is that evidence that pathways other than antioxidant activity are functionally operative in a-tocopherol-mediated protection against environmental pollutants such as PAHs would be of considerable value in the ultimate development of protective strategies for acute occupational exposures to these and other environmental pollutants. Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure. PUBLIC HEALTH RELEVANCE: Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure.

描述（由申请人提供）：多环芳烃（PAHs），包括苯并(a)芘（BP），是一类主要的环境污染物，被认为是包括癌症在内的多种疾病易感性的致病因素。几乎所有的多环芳烃混合物都含有BP；一种导致bp - dna加合物形成的模型化合物。服用维生素E （a-生育酚）可降低吸烟者体内BP-DNA加合物的水平。尽管a-生育酚的抗氧化活性一直是其保护作用的机制，但我们最近的研究结果表明，a-生育酚在肝脏中也具有调节功能。因此，a-生育酚在消除bp诱导的DNA损伤中的作用可能涉及肝脏解毒和胆汁排泄的调节。因此，有必要评估a-生育酚依赖的肝脏外源性代谢和处置的调节作为解毒和消除多环芳烃的机制。我们的长期目标是确定预防性高剂量维生素E补充对预防职业暴露于多环芳烃时dna加合物形成的功效。我们在R21应用中的目标是利用BP作为模型化合物，确定补充a-生育酚改变肝、肺和肾组织对多环芳烃反应的关键机制。我们的中心假设是，药理学补充a-生育酚，除了提供增强的抗氧化保护外，还增加了异种生物代谢和排泄途径，从而通过增加体内对多环芳烃及其代谢产物的解毒和/或消除，保护肝脏和其他器官免受多环芳烃诱导的DNA加合物形成的影响。我们建议：目标1。测定a-生育酚对大鼠血压代谢和排泄的调节作用。我们的工作假设是，a-生育酚水平的升高将显著增加：(1)BP对非dna反应性代谢物的代谢；(2)增加BP和/或BP代谢物的排泄。目标2。确定补充a-生育酚对bp诱导的DNA损伤的保护作用。我们的工作假设是，a-生育酚水平的升高将通过两种协同机制减少bp诱导的肝、肺和肾DNA损伤：(1)增强抗氧化应激诱导损伤的抗氧化保护；(2)减少共价BP-DNA加合物的形成。这一建议是创新的，因为它挑战了目前的范式，即-生育酚几乎完全作为抗氧化剂起作用，同时支持营养和饮食方案可以调节毒理学损害和由此产生的病理。这些研究的公共卫生相关性在于，除抗氧化活性外，其他途径在a-生育酚介导的针对多环芳烃等环境污染物的保护中具有功能作用的证据，将对最终制定针对急性职业暴露于这些和其他环境污染物的保护策略具有相当大的价值。苯并(a)芘是一种多环芳香烃，在《国家重点清单》危险废物场址发现的苯并(a)芘比任何其他多环芳香烃都多。接触苯并(a)芘造成的DNA损伤与职业接触这种致癌化合物的工人发生肺癌有关。无处不在的环境和职业存在以及人类健康与接触苯并(a)芘之间的负面关联，使我们更加迫切需要填补我们对保护高风险工人以及居住在有毒泄漏、灾害现场和超级基金场址附近的人们免受接触苯并(a)芘有害影响的机制的知识空白。公共卫生相关性：苯并(a)芘是一种多环芳烃，在《国家重点清单》有害废物场址发现的苯并(a)芘比任何其他多环芳烃都多。接触苯并(a)芘造成的DNA损伤与职业接触这种致癌化合物的工人发生肺癌有关。无处不在的环境和职业存在以及人类健康与接触苯并(a)芘之间的负面关联，使我们更加迫切需要填补我们对保护高风险工人以及居住在有毒泄漏、灾害现场和超级基金场址附近的人们免受接触苯并(a)芘有害影响的机制的知识空白。