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

描述(由申请人提供)：多环芳烃(PAHs)，包括苯并(A)芘(BP)，形成了一种主要的环境污染物，被认为是各种疾病易感性的致病因素，包括癌症。几乎所有的多环芳烃混合物都含有BP，这是一种导致BP-DNA加合物形成的模型化合物。吸烟者服用维生素E(a-生育酚)可降低BP-DNA加合物的水平。虽然α-生育酚的抗氧化活性一直被认为是其保护作用的机制，但我们最近的挑衅性发现表明，a-生育酚在肝脏中也具有调节功能。因此，α-生育酚消除BP诱导的DNA损伤的作用可能涉及调节肝脏解毒和胆汁排泄。因此，有必要评估α-生育酚对肝脏异物代谢和处置的调节作用，以此作为多环芳烃的解毒和消除机制。我们的长期目标是确定预防性大剂量维生素E补充在预防职业接触多环芳烃过程中DNA加合物形成的有效性。我们在R21应用中的目标是以BP为模型化合物，确定补充α-生育酚改变肝、肺和肾组织对多环芳烃反应的关键机制(S)。我们的中心假设是，补充药理的α-生育酚，除了提供增强的抗氧化保护外，还增加了异物代谢和排泄途径，从而通过增加对多环芳烃及其代谢产物的解毒和/或消除来保护肝脏和其他器官免受多环芳烃诱导的DNA加合物的形成。我们建议：目的1.测定α-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，α-生育酚水平的升高将显著增加：(1)BP代谢为非DNA反应性代谢物；(2)增加BP和/或BP代谢物的排泄。目的2.研究补充α-生育酚对BP诱导的DNA损伤的保护作用。我们的工作假设是，升高α-生育酚水平将通过两种协同机制减少BP诱导的肝、肺和肾脏的DNA损伤：(1)增加对氧化应激诱导的损伤的抗氧化保护；(2)减少共价BP-DNA加合物的形成。这一建议是创新的，因为它挑战了目前生育酚几乎完全作为抗氧化剂的范式，同时支持营养和饮食方案可以调节毒物侮辱和由此产生的病理的范式。这些研究的公共卫生意义在于，有证据表明，在α-生育酚介导的环境污染物(如多环芳烃)防护中，除抗氧化剂活性外的其他途径在功能上起作用，这将对最终制定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)芘是一种多环芳烃，比其他任何多环芳烃在更多的国家重点危险废物场所中被发现。在职业接触这种致癌化合物的工人中，接触苯并(A)芘造成的DNA损伤与肺癌的发生有关。无处不在的环境和职业的存在，以及人类健康与苯并(A)芘暴露之间的负相关，增加了填补我们关于高风险工人以及生活在有毒物质泄漏、灾害地点和超级基金地点附近的人免受苯并(A)芘暴露的有害影响的机制的知识空白的紧迫性。与公众健康相关：苯并(A)芘是一种多环芳烃，比任何其他多环芳烃在更多的国家优先清单危险废物地点被发现。在职业接触这种致癌化合物的工人中，接触苯并(A)芘造成的DNA损伤与肺癌的发生有关。无处不在的环境和职业的存在，以及人类健康与苯并(A)芘暴露之间的负相关，增加了填补我们关于高风险工人以及生活在有毒物质泄漏、灾害地点和超级基金地点附近的人免受苯并(A)芘暴露的有害影响的机制的知识空白的紧迫性。

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.