Vitamin B6 Effects on One-Carbon Metabolism

维生素 B6 对一碳代谢的影响

• 批准号: 8301786
• 负责人: JESSE F. GREGORY
• 金额: $ 49.83万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301786
• 关键词: Age; Amino Acids; Biostatistical Methods; Carbon; Cardiovascular Diseases; Catabolism; Cell physiology; Chronic; Coenzymes; Computer Simulation; Contraceptive Usage; Cystathionine; Cysteine; Data; Evaluation; Generations; Gluconeogenesis; Glucose; Glutathione; Glutathione Metabolism Pathway; Glycine; Glycine Hydroxymethyltransferase; Goals; Health; Homocysteine; Homocystine; Human; Intake; Kinetics; Label; Link; Metabolic; Metabolic Control; Metabolism; Methionine; Methionine Metabolism Pathway; Methylation; Nutritional status; Oral Contraceptives; Pathway interactions; Pattern; Plasma; Play; Population; Process; Production; Protocols documentation; Pyridoxal Phosphate; Research; Risk; Role; Serine; Skeleton; Stroke; Sulfur Amino Acids; Supplementation; Testing; Tracer; Tryptophan; Tryptophan Metabolism Pathway; Vascular Diseases; Venous Thrombosis; Vitamin B 6 Deficiency; Vitamin B6; Woman; base; cardiovascular disorder risk; functional status; glucose-cysteine; glycine cleavage system; in vivo; insight; mathematical model; metabolomics; methyl group; nucleotide metabolism; nutrition; public health relevance; pyridoxine; reproductive; response; restoration; simulation; tool; transmethylation

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.

描述（由申请人提供）：足够的维生素B6状态对健康很重要，而低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。负责的机制是未知的，但风险很大程度上与血浆同型半胱氨酸浓度无关。通过其辅酶形成吡啶还毒素磷酸（PLP），B6通过甘氨酸裂解系统和丝氨酸羟基甲基转移酶，氨基酸的互化和分解代谢，对氨基酸的氨基酸，以及氨基酸的氨基酸，对氨基酸的氨基酸，以及药物构菌素的氨基酸对照，通过甘氨酸裂解系统和丝氨酸羟基甲基转移酶，氨基甲基转移酶，氨基甲基转移酶，以及类药物构成的氨基酸，对单碳（1C）单位发挥至关重要的作用。葡萄糖和半胱氨酸。因此，B6营养与许多重要的细胞过程有关，例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此类过程。大部分人口（生殖年龄妇女）损害了与使用口服避孕药（OC）相关的B6状态。拟议的研究将确定使用OC的妇女对慢性B6状态的代谢后果以及靶向B6复制的影响。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基本原理。 在三个方案中，将在补充吡ido醇之前和之后，在OC使用者中进行动力学和代谢组学评估，以允许对不受补充的OC使用者以及补充提供的代谢恢复进行彻底的功能评估。 AIM 1方案将采用标记的丝氨酸和蛋氨酸来评估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的示踪剂，以确定体内甘氨酸代谢的速率，基于甘氨酸的1C单元的产生，并确定谷胱甘肽合成的速率。 AIM 3方案将使用标记的蛋氨酸示踪剂评估蛋氨酸周期（再甲基化，转甲基化和转硫化）的功能状态。在AIM 4中，来自这些方案的数据和并发代谢分析将进行多元统计分析，以确定各种动力学通量和代谢物模式之间的关系，以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），以进一步了解慢性OC使用的代谢影响以及补充的效果。总体而言，这些研究将对与OC使用相关的慢性维生素B6状态的代谢作用以及适当的维生素B6补充的恢复作用产生新的了解。这些发现将产生对主要因生殖时代妇女的血管疾病风险升高的机制的重要新见解。 公共卫生相关性：许多使用口服避孕药（OC）的女性具有长期的维生素B6营养状况，这可能与维生素B6摄入水平无关。慢性维生素B6缺乏症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OC用户中维生素B6不足的功能影响的理解，并将提供一项代谢验证的补充策略，以减轻较低的B6状态并促进OC用户的健康状况。