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。通过其辅酶形式磷酸吡哆醛（PLP），B6在通过甘氨酸裂解系统和丝氨酸羟甲基转移酶获得和加工一碳（1C）单元、氨基酸的相互转化和催化、同型半胱氨酸的控制以及葡萄糖和半胱氨酸的产生中起重要作用。因此，B6营养与许多重要的细胞过程相关联，例如核苷酸和谷胱甘肽的合成，大多数氨基酸的代谢，包括含硫氨基酸，甲基化过程和维生素E生成。低B6状态可能会干扰许多这些过程。很大一部分人口，育龄妇女，已经损害了与使用口服避孕药（OC）相关的B6状态。拟议的研究将确定长期低B6状态的代谢后果以及使用OC的女性中有针对性的B6补充的影响。维生素B6营养，B6依赖性代谢和人类健康之间的联系构成了这些研究的总体原理。 在三个方案中，将在补充吡哆醇之前和之后对OC使用者进行动力学和代谢组学评估，以便对未补充的OC使用者和补充剂提供的代谢恢复进行全面的功能评估。目标1方案将采用标记的丝氨酸和甲硫氨酸来评估1C代谢和相关过程的体内动力学和功能状态，以及1C代谢和代谢产物生成之间的联系。目的2研究将使用标记的甘氨酸作为主要示踪剂，以确定体内甘氨酸代谢的速率，基于甘氨酸的1C单位的产生，并确定谷胱甘肽合成的速率。Aim 3方案将使用标记的甲硫氨酸示踪剂评估甲硫氨酸循环的功能状态（再甲基化、转甲基化和转硫化）。在目标4中，将对这些方案和同步代谢特征分析的数据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代谢和相关过程的探索性数学建模和模拟（目标5），以进一步了解长期使用OC的代谢效应和补充剂的影响。总的来说，这些研究将对与OC使用相关的长期低维生素B6状态的代谢作用以及适当补充维生素B6的恢复作用产生新的认识。这些发现将产生重要的新的见解，部分负责的机制，血管疾病的风险增加的主要部分育龄妇女。 公共卫生相关性：许多使用口服避孕药（OC）的妇女长期缺乏维生素B6营养状况，这可能与维生素B6摄入水平关系不大。慢性维生素B6缺乏与多种形式的血管疾病的风险增加有关，包括心血管疾病，静脉血栓形成和中风。这些研究将扩大我们对维生素B6不足对OC使用者的功能影响的理解，并将提供一种经代谢验证的补充策略，以缓解低B6状态并促进OC使用者的健康。

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.