Vitamin B6 Effects on One-Carbon Metabolism

描述（由申请人提供）：充足的维生素B6状态对健康很重要，而低维生素B6状态与心血管疾病、静脉血栓形成和中风的风险增加有关。其机制尚不清楚，但风险在很大程度上与血浆同型半胱氨酸浓度无关。B6通过辅酶形式磷酸吡哆醛（pyridoxal phosphate， PLP），在甘氨酸裂解系统和丝氨酸羟甲基转移酶对一碳（1C）单元的获取和加工、氨基酸的相互转化和分解代谢、同型半胱氨酸的控制以及葡萄糖和半胱氨酸的产生等方面发挥着重要作用。因此，B6营养与许多重要的细胞过程有关，如核苷酸和谷胱甘肽的合成、大多数氨基酸的代谢（包括硫氨基酸）、甲基化过程和糖异生。低B6状态可能会干扰许多这些过程。很大一部分人口，即育龄妇女，由于使用口服避孕药（OC）而降低了B6水平。拟议的研究将确定长期低B6状态的代谢后果以及使用OC的女性靶向B6补充的影响。维生素B6营养、B6依赖性代谢和人体健康之间的联系构成了这些研究的基本原理。在三个方案中，将对补充吡哆醇前后的OC使用者进行动力学和代谢组学评估，以便对未补充的OC使用者进行全面的功能评估和补充提供的代谢恢复。Aim 1方案将使用标记丝氨酸和蛋氨酸来评估1C代谢及相关过程的体内动力学和功能状态，以及1C代谢与糖异生之间的联系。Aim 2研究将使用标记的甘氨酸作为主要示踪剂来确定体内甘氨酸代谢速率、基于甘氨酸的1C单位生成以及谷胱甘肽合成速率。Aim 3方案将使用标记的蛋氨酸示踪剂评估蛋氨酸循环（再甲基化、转甲基化和转硫化）的功能状态。在Aim 4中，将对这些方案的数据和同时进行的代谢分析进行多变量统计分析，以确定各种动力学通量和代谢物模式之间的关系，从而深入了解代谢控制关系。还将进行1C代谢及相关过程的探索性数学建模和模拟（Aim 5），以进一步了解慢性使用OC和补充OC的代谢影响。总的来说，这些研究将对长期低维生素B6状态与OC使用相关的代谢影响以及适当补充维生素B6的恢复作用产生新的认识。这些发现将对在很大一部分育龄妇女中血管疾病风险升高的部分机制产生重要的新见解。

DESCRIPTION (provided by applicant): Adequate vitamin B6 status is important for health, whereas low B6 status is associated with increased risk of cardiovascular disease, venous thrombosis and stroke. The mechanisms responsible are unknown, but the risk largely is independent of plasma homocysteine concentration. Through its coenzyme form pyridoxal phosphate (PLP), B6 plays essential roles in the acquisition and processing of one-carbon (1C) units by the glycine cleavage system and serine hydroxymethyltransferase, inter conversion and catabolism of amino acids, control of homocysteine, and production of glucose and cysteine. Thus, B6 nutrition is linked many vital cellular processes such as the synthesis of nucleotides and glutathione, metabolism of most amino acids, including sulfur amino acids, methylation processes, and gluconeogenesis. Low B6 status potentially can interfere with many of these processes. A large segment of the population, women of reproductive age, has compromised B6 status associated with the use of oral contraceptives (OC). The proposed research will determine the metabolic consequences of chronically low B6 status and the effects of targeted B6-repletion in women using OC. The linkages between vitamin B6 nutrition, B6-dependent metabolism and human health constitute the overarching rationale for these studies. In three protocols, kinetic and metabolomic assessments will be conducted in OC users before and after supplementation with pyridoxine to allow a thorough functional evaluation of unsupplemented OC users and the metabolic restoration provided by supplementation. The Aim 1 protocol will employ labeled serine and methionine to assess the in vivo kinetics and functional status of 1C metabolism and related processes, and the linkage between 1C metabolism and gluconeogenesis. Aim 2 studies will use labeled glycine as the primary tracer to determine the rates of in vivo glycine metabolism, glycine-based generation of 1C units, and determine the rate of glutathione synthesis. The Aim 3 protocol will assess the functional status of the methionine cycle (remethylation, transmethylation and transsulfuration) using labeled methionine tracers. In Aim 4, the data from these protocols and concurrent metabolic profiling will be subjected to multivariate statistical analysis to determine the relationships among the various kinetic fluxes and metabolite patterns to gain insight into metabolic control relationships. Exploratory mathematical modeling and simulations (Aim 5) of 1C metabolism and related processes also will be conducted to gain further insight into the metabolic effects of chronic OC use and effects of supplementation. Overall, these studies will yield new understanding of the metabolic effects of chronically low vitamin B6 status associated with OC use and the restorative effects of appropriate vitamin B6 supplementation. These findings will yield important new insight into mechanisms responsible in part for elevated risk of vascular disease in a major segment of women of reproductive age. PUBLIC HEALTH RELEVANCE: Many women using oral contraceptives (OC) have chronically low vitamin B6 nutritional status, which may have little relation to vitamin B6 intake level. Chronic vitamin B6 deficiency is associated with increased risk of several forms of vascular disease including cardiovascular disease, venous thrombosis and stroke. These studies will expand our understanding of the functional impact of vitamin B6 inadequacy in OC users and will provide a metabolically validated supplementation strategy to alleviate low B6 status and promote health in OC users.