Quantitation of Tocopherol Metabolism in Humans

人类生育酚代谢的定量

• 批准号: 7637872
• 负责人: ANDREW JOSEPH CLIFFORD
• 金额: $ 20.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637872
• 关键词: Adult; Affect; Antioxidants; Apolipoproteins B; Atherosclerosis; Attention; Behavior; Bile fluid; Biological; Biological Availability; Biological Process; Blood; Blood Platelets; Cardiovascular Diseases; Catabolism; Chemicals; Child; Cholesterol; Chronic Disease; Data; Data Set; Dose; Ensure; Enzymes; Equilibrium; Erythrocytes; Extrahepatic; Feasibility Studies; Feces; Flying body movement; Folate; Food; Generic Drugs; Goals; Hepatocyte; High Pressure Liquid Chromatography; Human; Human body; Hypertension; Intake; Isotopes; Kidney; Kinetics; Label; Laboratories; Learning; Life; Link; Lipids; Lipoproteins; Liver; Location; Lymphocyte; Malignant Neoplasms; Measures; Metabolic; Metabolism; Methods; Milk; Modeling; Names; Olive oil preparation; Oral Administration; Phase; Physiological; Plasma; Play; Pregnant Women; Process; Protocols documentation; Radiation; Radioactive; Recommendation; Recruitment Activity; Reporting; Research; Risk; Role; Sampling; Scientist; Single Nucleotide Polymorphism; Solid; Stable Isotope Labeling; Stereoisomer; Study Subject; Testing; Time; Tissues; Tocopherols; Tracer; Urine; Vitamin E; Vitamins; Woman; absorption; accelerator mass spectrometry; atherogenesis; base; density; design; experience; extracellular; healthy volunteer; human tissue; improved; in vivo; men; nutrition; oxidation; prevent; public health relevance; residence; stable isotope; vitamin metabolism; volunteer

DESCRIPTION (provided by applicant): There is growing evidence that a-tocopherol, the active form of vitamin E, may help minimize the risk of certain chronic diseases such as cardiovascular disease, hypertension and cancer. Still, more research on vitamin E is needed to fully understand its metabolism and function(s). The IOM/NAS has listed key research recommendations for vitamin E. The list included quantifying vitamin E metabolism; determining whether mass balance is feasible and vitamin E requirements can be estimated using stable isotope-labeled vitamin E; determining whether vitamin E metabolism as it occurs in vivo in humans can be quantified; determining how, where, and how fast vitamin E is degraded; identifying the metabolic intermediates during metabolism; and determining whether they have biological function. The long term goal of this application is to quantify the dynamic and kinetic behavior of vitamin E metabolism as it might occur in vivo in humans using kinetic modeling of the fate of true tracer doses of 14C-vitamin E that ensure steady state conditions of vitamin E metabolism that are relevant and useful to nutrition, and where our study subjects are not asked to accept risks significantly greater than those experienced in everyday life; i.e., radiation exposures < those obtained in flying for 1-4 h, a common radiation exposure, even for young children and pregnant women. The following specific aims will achieve our long term goal. Specific aim # 1: Determine the absorption, accretion, distribution, and elimination of RRR-a-TOC in humans. To accommodate this, we will quantify the transfer of 14C-RRR-a-TOC among various lipoprotein classes and its metabolites by time since dose. Specific aim # 2: Construct a dynamic and kinetic model of 14C-RRR-a-TOC metabolism as it might occur in vivo in humans to test the hypothesis whether EHT-a-TOC is eliminated by a "reverse a-TOC transfer" process. The null hypothesis is that EHT-a-TOC eliminated through "reverse cholesterol transfer." Plasma lipoproteins play key roles in delivering RRR-a-TOC to and from EHT. For this purpose 12 volunteers, 6 women and 6 men, will be recruited and administered a single dose of 14C-RRR-a-tocopherol (100 nCi) that will be added to a cup containing a whipped mix of 10.5 g olive oil and 30 g skim milk. We will follow the 14C tracer over a 60-day period. The long term goal of this project is to quantify the dynamic/ kinetic behavior of vitamin E metabolism in vivo in humans of the RRR-a-TOC and of its 2R stereoisomer forms using a test re-test design. In addition, using a mechanistic model of tocopherol metabolism we can determine whether or not single nucleotide polymorphisms (SNPs) in tocopherol-relevant enzymes affects the kinetic behavior of human tocopherol metabolism as we recently show for folate Clifford et al. 2006. Baseline blood (10 mL) will be taken just before dosing and at various intervals until 60 days post dose to ensure that the 14C labeled a-tocopherol is fully equilibrated into the slowest turning over a-tocopherol pool that can affect the plasma kinetics late in a study. The lipoprotein classes will be separated using a new protocol. Erythrocytes, lymphocytes, and platelets will also be separated. Urine and feces will be collected until 30 days post dose. The 14C content of each biological sample will be measured at the Center for the Accelerator Mass Spectrometry at Lawrence Livermore National Laboratory (Livermore, CA). Chemical identity of the 14C in plasma and plasma lipoprotein samples will also be determined, 14C-RRR-a-tocopherol, a-CEHC, a-CPHC plus 4 more unknowns by using non-radioactive standards in an HPLC. We will construct a dynamic/kinetic model of a-tocopherol metabolism, we have already demonstrated the feasibility of our approach. We will use a high sampling density of plasma over a relatively long time since dosing to acquire a much more detailed/complete dataset than any already existing dataset. Then if specific metabolic functions for a-tocopherol can be stipulated, it will be possible to determine a minimum intake of a-tocopherol to sustain these critical functions, such as, preventing oxidation of lipoproteins, which has been linked to atherogenesis, and therefore minimizing the risk of atherosclerosis. PUBLIC HEALTH RELEVANCE: Vitamin E is a generic name for a group of lipid-soluble compounds known as tocopherols that have different formulas. These Vitamin E formulas occur naturally in many foods and act as biological antioxidants. Previous studies have shown differences in the way humans metabolize vitamin E. Since metabolism of the vitamin is poorly understood especially at normal physiological levels, in vivo studies under physiological conditions are needed in humans to understand it. Therefore, UC Davis Scientists are conducting a study with approximately 12 healthy volunteers to evaluate the metabolism of a single oral administration of tracer amounts of the RRR- (natural form) of vitamin E to learn more about how the human body utilizes this vitamin. Particular attention will be directed to the absorption phase. The results are expected to provide information about vitamin E biopotency and eventually improved Dietary Recommendations.

描述（由申请人提供）：越来越多的证据表明，维生素E的活性形式可能有助于最大程度地减少某些慢性疾病（例如心血管疾病，高血压和癌症）的风险。尽管如此，还需要对维生素E的更多研究来充分了解其代谢和功能。 IOM/NAS列出了维生素E的关键研究建议。该清单包括量化维生素E代谢；确定质量平衡是否可行，可以使用稳定的同位素标记的维生素E估算维生素E的需求；确定维生素E代谢是否可以在人体中进行体内发生；确定维生素E降解的速度，地点和多快；在代谢过程中识别代谢中间体；并确定它们是否具有生物学功能。该应用的长期目标是量化维生素E代谢的动态和动态行为，因为它在人类中可能发生在人体中，使用动力学模型对14c-vitamin e的命运进行动力学模型，以确保对维生素E代谢的稳态条件的稳定状态，而与我们的研究相关，并且在我们的研究中与营养相关，并且在某些情况下有意义，并且在某些情况下有用，并且能够将这些态度与营养相关，并且能够生活在某些情况下，并且能够将这些人的生活与营养相关。即，辐射暴露<在飞行中获得1-4 h的辐射暴露，即常见的辐射暴露，即使是针对幼儿和孕妇。以下特定目标将实现我们的长期目标。具体目的＃1：确定人类中RRR-A-TOC的吸收，积聚，分布和消除。为了适应这一点，我们将按照剂量以来的时间来量化14C-RRR-A-TOC在各种脂蛋白类别及其代谢物之间的转移。特定目的＃2：构建14C-RRR-A-TOC代谢的动态和动力学模型，因为它可能在人体中发生在人体中，以检验假设是否通过“反向A-TOC转移”过程消除EHT-A-TOC是否消除了EHT-A-TOC。零假设是通过“反向胆固醇转移”消除了EHT-A-TOC。血浆脂蛋白在向EHT提供RRR-A-TOC中起关键作用。为此，将招募和服用12名志愿者，6名女性和6名男性，单剂量的14c-rrr-a-托酚醇（100 NCI）将添加到杯中，其中包含10.5 g橄榄油和30 g脱脂牛奶的搅拌混合物。我们将在60天的时间内跟随14C示踪剂。该项目的长期目标是使用测试重新测试设计来量化RRR-A-TOC及其2R立体异构体形式的体内维生素E代谢的动态/动力学行为。此外，使用生育酚代谢的机械模型，我们可以确定与生育酚相关酶中的单核苷酸多态性（SNP）是否会影响人类托酚酚代谢的动力学行为，因为我们最近显示的是Fule Clifford等人。 2006。基线血液（10 mL）将在给药前，并在剂量后60天之前以不同的间隔进行，以确保标记为A托酚的14C完全平衡到最慢的A-Topopherol池的最慢的转移，从而在研究后期可能影响血浆动力学。脂蛋白类将使用新协议分开。红细胞，淋巴细胞和血小板也将分开。尿液和粪便将收集到剂量后30天。每个生物样品的14C含量将在Lawrence Livermore国家实验室（加利福尼亚州Livermore）的加速器质谱中心进行测量。还将确定14C和血浆脂蛋白样品中14C的化学身份，即通过在HPLC中使用非放射性标准，即14C-RRR-A-生育酚，A-CEHC，A-CPHC加4个未知数。我们将构建A-Topherol代谢的动态/动力学模型，我们已经证明了方法的可行性。自从给药以来，我们将在相对较长的时间内使用高的血浆采样密度来获取比任何已经存在的数据集更详细/完整的数据集。那么，如果可以规定A托酚的特定代谢功能，则可以确定A-Topherol的最低摄入量来维持这些关键功能，例如防止脂蛋白的氧化，这与动脉粥样硬化有关，从而与动脉粥样硬化的风险最小化。公共卫生相关性：维生素E是一组脂溶性化合物的通用名称，称为具有不同配方的生育酚。这些维生素E配方自然存在于许多食物中，并充当生物抗氧化剂。先前的研究表明，人类代谢维生素E的方式差异。由于维生素的代谢尤其是在正常的生理水平上鲜为人知，因此人类需要在生理条件下进行体内研究才能理解它。因此，加州大学戴维斯分校的科学家正在对大约12名健康志愿者进行一项研究，以评估维生素E单一口服示踪剂量的RRR-（自然形式）的代谢，以更多地了解人体如何利用这种维生素。特别注意的是吸收阶段。结果预计将提供有关维生素E生物能力的信息，并最终改善饮食建议。