Vitamin E Pharmacokinetics And Biomarkers In Normal And Obese Women

解释 维生素E(α-生育酚)对人类来说是必不可少的，但缺乏特定的生育酚依赖途径，使得制定人类的饮食需求变得困难。维生素E的推荐膳食摄入量(RDA)将在下一次审查时仔细修订。大约96%的美国妇女不符合2000年的建议，尽管没有明显的伤害。目前没有新的数据可用，这项研究试图填补这一空白。准确的α-生育酚需求可能会改善女性的健康，特别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，在正常体重和肥胖女性中，α-生育酚作为一种抗氧化剂与其组织储备物有关；通过缓释池的血浆α-生育酚周转动力学可以计算组织储存物的供给量；周转动力学是估计α-生育酚推荐膳食供给量的新方法。 1.证据表明，最相关的α-生育酚参数是来自缓释池的参数。因此，对于健康的瘦身和肥胖女性，将使用双稳定同位素标记的(氚)α-生育酚口服和静脉注射来表征这些特征。由于抗坏血酸(维生素C)浓度可能改变α-生育酚的药代动力学，受试者将首先在低维生素C浓度和高稳态维生素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。 A.在初步试验1中，将评估最佳吸收的脂肪含量，因为一餐的脂肪含量可能会改变维生素E的吸收。脂肪含量将是早餐一餐卡路里的0-40%。碳水化合物和脂肪会有所不同，蛋白质会保持不变。考试期间的剩余膳食将不会受到脂肪含量的限制。口服和静脉注射单剂维生素E 30毫克。 B.在初步试验2中，将使用初步试验1中的最佳脂肪含量，维生素E的剂量将有所不同。维生素E剂量可以非特异性地改变维生素E的动力学。因此，我们将确定在脂肪保持不变的情况下，不会非特定增加维生素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功能，α-生育酚药代动力学的测量将提供直接数据，可首次用于预测妇女对α-生育酚的需求，并为维生素E的摄入量设定新的建议。这些实验将提供周转数据，这对制造新的α-生育酚RDA至关重要。 3.我们将探索新的α-生育酚功能，特别是人类受试者中的基因转录是否受到维生素E状态与维生素C状态的关系的调节，以及相关基因是否存在单核苷酸多态(SNPs)，可能解释维生素E代谢和药代动力学的个体差异。 4.由于维生素E周转可能受维生素C浓度的影响，我们将使用维生素C耗竭-再枯竭研究设计来研究维生素C状态和维生素E周转之间的关系。 第一次初审于2014年底开始，目前仍在进行中。

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 when it is next due for review. 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. Preliminary trial one commenced at the end of 2014 and is on-going.