DYNAMIC AND KINETIC BEHAVIOR OF FOLATE METABOLISM

叶酸代谢的动态和动力学行为

• 批准号: 6380761
• 负责人: ANDREW JOSEPH CLIFFORD
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380761
• 关键词: analytical chemistry; bioimaging /biomedical imaging; carbon; chemical kinetics; clinical chemistry; clinical research; female; folate; gastrointestinal nutrient absorption; gender difference; human middle age (35-64); human subject; male; mass spectrometry; mathematical model; model design /development; nutrient bioavailability; nutrition related tag; radionuclide imaging /scanning; radionuclides; radiotracer; vitamin metabolism; young adult human (21-34)

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.

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态的了解还不够。 至少十分之一的美国人叶酸营养状况处于边缘或较差状态，与多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（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功能障碍；因此，叶酸体内代谢的定量信息已成为科学优先事项。 新的同位素示踪方法采用放射性碳标记的叶酸，结合加速器质谱 (AMS) 检测，有望彻底改变人类体内示踪剂研究。 使用这种方法，在单次生理（35 杯）口服剂量后长达 200 天内，可以可靠地检测到血浆、红细胞、尿液和粪便中阿托摩尔浓度（摩尔 x 10-18）的[14C]叶酸。 在这些敏感性水平下，剂量实际上是非放射性的，允许对健康受试者和叶酸依赖性疾病的高危亚群进行测试。 我们的长期目标是根据调节叶酸相关疾病的发生和进展的已知遗传和环境因素来了解人类叶酸代谢的动态。 相关例子包括遗传物质的紊乱，例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）如何可能导致同型半胱氨酸血症，或者怀孕如何影响体内叶酸储备的动员和利用。 为了实现这一目标，我们建议使用[14C]叶酸和AMS检测进行长期（7个月）示踪剂研究，以确定健康女性和男性受试者的叶酸代谢动力学。 这些研究将填补有关叶酸代谢的关键知识空白。 动力学方法提供了一种精确的模式来定量叶酸个体反应中吸收、分布和消除的相对重要性。动力学数据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对高危人群和个人进行调查的参考点。