Vitamin E Pharmacokinetics And Biomarkers In Normal And Obese Women

正常和肥胖女性的维生素 E 药代动力学和生物标志物

• 批准号: 8939611
• 负责人: MARK A LEVINE
• 金额: $ 18.33万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939611
• 关键词: Accounting; Affect; American; Antioxidants; Ascorbic Acid; Biological Markers; Calories; Carbohydrates; Data; Deuterium; Diabetes Mellitus; Dose; Drug Kinetics; Fatty acid glycerol esters; Genes; Genetic Transcription; Human; Individual Differences; Inflammation; Intake; Kinetics; Lipid Peroxidation; Measures; Metabolism; Obesity; Oxidative Stress; Pathway interactions; Plasma; Proteins; Recommendation; Recommended Dietary Allowance; Research Design; Single Nucleotide Polymorphism; Stable Isotope Labeling; Testing; Time; Tissues; Tocopherols; Vitamin E; Weight; Woman; Women' s Health; absorption; alpha Tocopherol; dietary requirement; experience; human subject; improved; meetings; research study

Explanation Vitamin E (alpha-tocopherol) is essential for humans, but lack of a specific -tocopherol-dependent pathway has made setting human dietary requirements difficult. The recommended dietary allowance (RDA) for vitamin E will have to be carefully revised in 2010. Approximately 96% of American women do not meet the 2000 recommendation, although without apparent harm. No new data are currently available, and this study seeks to fill the gap. Accurate alpha-tocopherol requirements may improve the health of women, especially obese women who experience high levels of inflammation and oxidative stress, because vitamin E is an antioxidant. We hypothesize that alpha-tocopherol functions as an antioxidant as related to its tissue stores in normal weight and obese women; that delivery to tissue stores can be calculated from plasma alpha-tocopherol turnover kinetics from slow release pools; and that turnover kinetics are a new means to estimate an alpha-tocopherol recommended dietary allowance. 1. Evidence indicates that the most relevant alpha-tocopherol parameters are those from the slow release pools. Therefore, these will be characterized using dual stable-isotope labeled (deuterium) alpha-tocopherols administered orally and intravenously to healthy lean and obese women. Because ascorbic acid (vitamin C) concentrations may alter alpha-tocopherol pharmacokinetics, subjects will be studied first at low and then high steady state vitamin C concentrations. Before this main study is initiated, two preliminary trials will be performed. a. In preliminary trial 1, fat content for optimal absorption will be assessed because fat-content of a meal may alter vitamin E absorption. The fat content will be 0 - 40% of calories in the breakfast meal. Carbohydrate and fat will vary, and protein will remain constant. Remaining meals during test days will not be restricted in fat. A single vitamin E dose of 30 mg will be given orally and intravenously. b. In preliminary trial 2, optimal fat content from preliminary trial 1 will be used, and the vitamin E dose will be varied. Vitamin E dose amount could non-specifically alter vitamin E kinetics. We will therefore determine the largest dose (2-30 mg) that does not non-specifically increase vitamin E turnover, with fat held constant. 2. Measures of alpha-tocopherol pharmacokinetics, as a function of lipid peroxidation biomarkers, will provide direct data that can be used for the first time to predict alpha-tocopherol requirements for women and set new recommendations for vitamin E intakes. These experiments will provide turnover data, essential for making new alpha-tocopherol RDAs. 3. We will explore new alpha-tocopherol functions, specifically whether gene transcription in human subjects is regulated by vitamin E status in relation to vitamin C status, and whether single nucleotide polymorphisms (SNPs) exist in relevant genes and perhaps account for inter-individual differences in vitamin E metabolism and pharmacokinetics. 4. Because vitamin E turnover may be affected by vitamin C concentrations, we will use a vitamin C depletion-repletion study design to investigate the relationship between vitamin C status and vitamin E turnover.

解释 维生素 E（α-生育酚）对人类至关重要，但缺乏特定的 α-生育酚依赖性途径使得设定人类饮食需求变得困难。维生素 E 的建议膳食摄入量 (RDA) 必须在 2010 年进行仔细修订。大约 96% 的美国女性没有达到 2000 年的建议，尽管没有明显的危害。目前没有新的数据可用，本研究旨在填补这一空白。准确的α-生育酚需求可以改善女性的健康，尤其是经历高水平炎症和氧化应激的肥胖女性，因为维生素 E 是一种抗氧化剂。 我们假设α-生育酚作为抗氧化剂发挥作用，与其在正常体重和肥胖女性的组织储存有关。可以根据缓释池的血浆α-生育酚周转动力学计算向组织储存的递送；周转动力学是估计α-生育酚推荐膳食摄入量的新方法。 1. 有证据表明，最相关的α-生育酚参数来自缓释池。因此，将使用双稳定同位素标记（氘）α-生育酚对健康瘦和肥胖女性进行口服和静脉注射来表征。由于抗坏血酸（维生素 C）浓度可能会改变 α-生育酚的药代动力学，因此将首先在低稳态维生素 C 浓度下进行研究，然后在高稳态维生素 C 浓度下进行研究。 在这项主要研究开始之前，将进行两项初步试验。 一个。 在初步试验 1 中，将评估最佳吸收的脂肪含量，因为膳食中的脂肪含量可能会改变维生素 E 的吸收。早餐中的脂肪含量为卡路里的0-40%。碳水化合物和脂肪会发生变化，而蛋白质将保持不变。测试期间剩余膳食将不限制脂肪含量。 维生素 E 单剂量为 30 毫克，可口服和静脉注射。 b. 在初步试验 2 中，将使用初步试验 1 中的最佳脂肪含量，并且维生素 E 剂量将发生变化。维生素 E 剂量可能会非特异性地改变维生素 E 动力学。因此，我们将确定在脂肪保持不变的情况下不会非特异性增加维生素 E 周转率的最大剂量（2-30 毫克）。 2. 作为脂质过氧化生物标志物的函数，α-生育酚药代动力学的测量将首次提供直接数据，可用于预测女性对α-生育酚的需求，并为维生素 E 摄入量制定新的建议。这些实验将提供周转数据，这对于制造新的 α-生育酚 RDA 至关重要。 3. 我们将探索新的α-生育酚功能，特别是人类受试者的基因转录是否受到与维生素C状态相关的维生素E状态的调节，以及相关基因中是否存在单核苷酸多态性（SNP），并可能解释维生素E代谢和药代动力学的个体间差异。 4. 由于维生素 E 周转率可能受到维生素 C 浓度的影响，因此我们将采用维生素 C 消耗-补充研究设计来研究维生素 C 状态与维生素 E 周转率之间的关系。