Vitamin E Pharmacokinetics And Biomarkers In Normal And Obese Women

解释 维生素E（α-生育酚）是人类必需的，但缺乏特定的生育酚依赖性途径，使人类的饮食需求难以确定。维生素E的推荐膳食供给量（RDA）将在2010年进行仔细修订。大约96%的美国妇女没有达到2000年的建议，尽管没有明显的危害。目前没有新的数据，本研究试图填补差距。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，α-生育酚作为一种抗氧化剂的功能与其在正常体重和肥胖妇女的组织商店;交付到组织商店可以计算从血浆α-生育酚周转动力学从缓慢释放池;和周转动力学是一种新的手段来估计α-生育酚推荐的膳食津贴。 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，这些将使用经口和静脉给予健康瘦型和肥胖女性的双稳定同位素标记（氘）α-生育酚进行表征。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，受试者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。 a. 在初步试验1中，将评估最佳吸收的脂肪含量，因为膳食的脂肪含量可能会改变维生素E的吸收。脂肪含量将是早餐中卡路里的0 - 40%。碳水化合物和脂肪会变化，蛋白质保持不变。测试日期间的剩余膳食不受脂肪限制。 口服和静脉注射30 mg维生素E。 B. 在初步试验2中，将使用初步试验1的最佳脂肪含量，维生素E剂量将有所不同。维生素E剂量可能非特异性地改变维生素E动力学。因此，我们将确定不会非特异性增加维生素E周转的最大剂量（2-30 mg），脂肪保持不变。 2. α-生育酚药代动力学的措施，作为脂质过氧化生物标志物的功能，将提供直接的数据，可用于第一次预测α-生育酚的妇女的需求，并制定新的建议，维生素E的摄入量。这些实验将提供周转率数据，这对于制备新的α-生育酚RDA至关重要。 3. 我们将探索新的α-生育酚功能，特别是在人类受试者的基因转录是否受维生素E状态与维生素C状态的关系，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，我们将使用维生素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。

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.