DYNAMIC AND KINETIC BEHAVIOR OF FOLATE METABOLISM

鉴于叶酸在许多疾病发病机制中的重要性，我们目前对叶酸体内动力学的了解还不够。 至少有十分之一的美国人的叶酸营养状况差与几种慢性和发育性疾病有关，包括神经管缺陷，癌症和同型半胱氨酸血症，这是冠心病的独立危险因素。 病理学背后的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，叶酸体内代谢的定量信息已成为高度科学优先事项。 采用放射性碳标记的叶酸与加速器质谱（AMS）检测相结合的新同位素示踪方法有望彻底改变人体体内示踪剂研究。 使用这种方法，在单次生理（35 μ g）口服剂量后200天内，在血浆、红细胞、尿液和粪便中可靠地检测到阿托摩尔浓度（摩尔× 10-18）的[14 C]叶酸。 在这些敏感性水平下，剂量几乎是非放射性的，允许在健康受试者和叶酸依赖性疾病的风险亚群中进行测试。 我们的长期目标是了解人类叶酸代谢的动态，已知的遗传和环境因素，调节叶酸相关疾病的发病率和进展。 相关的例子包括遗传物质的紊乱，如常见的亚甲基四氢叶酸还原酶（MTHFR）基因多态性（一种关键的叶酸代谢酶）可能导致同型半胱氨酸血症，或怀孕如何影响动员和利用身体叶酸储存。 为了实现这一目标，我们建议使用[14 C]叶酸和AMS检测进行长期（7个月）示踪研究，以确定健康女性和男性受试者的叶酸代谢动力学。 这些调查将填补一个关键的知识缺口周围叶酸代谢。 动力学方法提供了一种精确的模式，定量的吸收，分布和消除的相对重要性，在个人对叶酸的反应。动力学数据的分析将有助于动力学模型的构建和代谢表型的建立;这一信息将作为未来在风险亚群和个体中进行研究的参考点。

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.