DYNAMIC AND KINETIC BEHAVIOR OF FOLATE METABOLISM

鉴于叶酸在许多疾病的发病机制中所起的重要作用，我们目前对叶酸体内动力学的了解还不够充分。至少十分之一的美国人叶酸营养状况极差，与多种慢性和发育性疾病有关，包括神经管畸形、癌症和同型半胱氨酸血症，同型半胱氨酸血症是冠心病的独立危险因素。病理机制被认为涉及叶酸代谢的动态和动力学行为的功能障碍；因此，关于叶酸在体内代谢的定量信息已成为高度科学的优先事项。使用放射性碳标记的叶酸与加速器质谱仪(AMS)检测相结合的新的同位素示踪方法有望给人体体内示踪研究带来革命性的变化。使用这种方法，在口服单次生理剂量(35杯)后的200天内，[14C]叶酸在血浆、红细胞、尿液和粪便中的阿托摩尔浓度(摩尔×10-18)可以可靠地检测到。在这种敏感性水平下，剂量实际上是非放射性的，允许在健康受试者和叶酸依赖型疾病的高危亚群中进行测试。我们的长期目标是根据调节叶酸相关疾病的发生和发展的已知遗传和环境因素来了解人类叶酸代谢的动态。相关的例子包括遗传物质的错乱，如常见的亚甲基四氢叶酸还原酶(MTHFR)基因多态(一种关键的叶酸代谢酶)如何导致同型半胱氨酸血症，或者怀孕如何影响体内叶酸储存的动员和利用。为了追求这一目标，我们建议进行长期(7个月)的示踪研究，使用[14C]叶酸和AMS检测来确定健康女性和男性受试者的叶酸代谢动力学。这些研究将填补围绕叶酸代谢的一个关键知识空白。动力学方法提供了一种精确的模式来量化个体对叶酸的反应中吸收、分配和消除的相对重要性。对动力学数据的分析将有助于建立动力学模型和确定代谢表型；这些信息将作为未来在高危亚群和个人中进行调查的参考点。

Our present understanding of the in vivo dynamics of folate is inadequate in light of the importance that folate plays in the pathogenesis of many diseases. The marginal to poor folate nutrition status of at least one in ten Americans is associated with several chronic and developmental diseases that include neural tube defects, cancer, and homocysteinemia, an independent risk factor for coronary heart disease. The mechanisms behind the pathology are believed to involve a dysfunction in the dynamic and kinetic behavior of folate metabolism; accordingly, quantitative information on the in vivo metabolism of folate has emerged as a high scientific priority. New isotope tracer methodologies employing radiocarbon tagged folates coupled with Accelerator Mass Spectrometry (AMS) detection promise to revolutionize in vivo tracer studies in humans. Using this approach, [14C]folate is reliably detected at attomole concentrations (moles x 10-18) in plasma, erythrocytes, urine and feces up to 200 days following a single, physiologic (35 mug) oral dose. At these levels of sensitivity, doses are virtually non-radioactive, permitting testing in both healthy subjects and at-risk subpopulations for folate-dependent disease. Our long-range goal is to understand the dynamics of human folate metabolism in terms of known hereditary and environmental factors that modulate incidence and progression of folate-related diseases. Relevant examples include how derangements of the genetic material, such as the common methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (a key folate metabolizing enzyme) may lead to homocysteinemia, or how pregnancy effects the mobilization and utilization of body folate stores. In pursuit of this goal, we propose long-term (7 month) tracer studies using [14C]folic acid and AMS detection to define the kinetics of folate metabolism in healthy female and male subjects. These investigations will fill a critical knowledge-gap surrounding folate metabolism. A kinetic approach offers a precise mode of quantitating the relative importance of absorption, distribution and elimination in the individual response to folic acid. Analysis of kinetic data will facilitate the construction of kinetic models and the establishment of metabolic phenotypes; this information will serve as a reference point for future investigations within at-risk sub-populations and individuals.