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

描述（由申请人提供）：多环芳烃（PAH），包括苯并（a）芘（BP），是一类主要的环境污染物，被认为是多种疾病易感性（包括癌症）的致病因素。几乎所有的PAH混合物都含有BP;一种导致BP-DNA加合物形成的模型化合物。吸烟者中BP-DNA加合物的水平通过给予维生素E（α-生育酚）而降低。虽然α-生育酚的抗氧化活性是其保护作用的建议机制，但我们最近的挑衅性研究结果表明，α-生育酚在肝脏中也具有调节功能。因此，α-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α-生育酚依赖的调节肝脏外源性代谢和处置的机制，为多环芳烃的解毒和消除。我们的长期目标是确定预防性的高剂量维生素E补充剂的有效性，以防止DNA加合物的形成，在职业暴露于多环芳烃。我们在该R21应用中的目的是利用BP作为模型化合物来确定α-生育酚补充改变肝、肺和肾组织对PAH的反应的关键机制。我们的中心假设是，药理学α-生育酚补充剂，除了提供增加的抗氧化保护，增加异生物质代谢和排泄途径，从而保护肝脏和其他器官从PAH诱导的DNA加合物的形成，通过增加解毒和/或消除多环芳烃及其代谢物从体内。我们建议：目标1。测定大鼠中α-生育酚对BP代谢和排泄的调节作用。我们的工作假设是，a-生育酚水平升高将显著增加：（1）BP代谢为非DNA反应性代谢物和（2）增加BP和/或BP代谢物排泄。目标二。确定α-生育酚补充剂对BP诱导的DNA损伤的保护作用。我们的工作假设是，升高的α-生育酚水平将通过两种协同机制减少BP诱导的肝、肺和肾中的DNA损伤：（1）针对氧化应激诱导的损伤的抗氧化保护增加和（2）共价BP-DNA加合物的形成减少。这一建议是创新的，因为它挑战了目前的范式，生育酚几乎完全作为一种抗氧化剂，同时支持的范式，营养和饮食方案可以调节毒理学的侮辱和由此产生的病理。这些研究的公共卫生相关性是，证据表明，抗氧化活性以外的途径在α-生育酚介导的对环境污染物（如多环芳烃）的保护中具有功能性作用，这在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中具有相当大的价值。苯并（a）芘是一种多环芳烃，在国家优先清单危险废物场址中发现的比任何其他多环芳烃都多。由于苯并（a）芘暴露导致的DNA损伤与职业暴露于这种致癌化合物的工人的肺癌发生相关。无处不在的环境和职业存在以及人类健康与接触苯并（a）芘之间的负面联系，增加了填补我们知识空白的紧迫性，即高风险工人以及生活在有毒物质泄漏、灾害现场和超级基金现场附近的人可能受到保护，免受苯并（a）芘接触的有害影响。公共卫生相关性：苯并（a）芘是一种多环芳烃，在国家优先清单危险废物场址中发现的比任何其他多环芳烃都多。由于苯并（a）芘暴露导致的DNA损伤与职业暴露于这种致癌化合物的工人的肺癌发生相关。无处不在的环境和职业存在以及人类健康与接触苯并（a）芘之间的负面联系，增加了填补我们知识空白的紧迫性，即高风险工人以及生活在有毒物质泄漏、灾害现场和超级基金现场附近的人可能受到保护，免受苯并（a）芘接触的有害影响。

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.