MICRONUTRIENT KINETICS IN HUMANS AT PHYSIOLOGIC DOSES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。维持人体内正常的生化反应需要饮食中微量营养素(维生素)的稳定供应。叶酸是维持嘌呤和嘧啶合成以及同型半胱氨酸代谢为蛋氨酸所必需的。胡萝卜素是一种常用的植物色素(多烯)，是一种生物抗氧化剂，也是维生素A的营养前体。过去，人们通常使用稳定或放射性同位素在人体内研究高剂量、非生理性的胡萝卜素和其他微量营养素。虽然稳定同位素在人类身上使用是安全的，但它会产生动力学信号，在单次剂量后迅速接近自然同位素水平。放射性同位素标签足够清晰，可以提供更长时间内的可追踪水平，但辐射暴露的风险将这种用途限制在对可能的损害不太关心的人群，如老年人或体弱的男性。加速器质谱仪在量化长寿同位素方面具有如此高的灵敏度，以至于现在可以在健康的年轻人中追踪到14C标记的微量营养素，特别是育龄妇女。志愿者被给予微克剂量的14C标记化合物，辐射剂量为100-200nCi(6-12kBq)。血液通常在头一两天从手臂的留置导管采集，以提供高密度数据，反映药物动力学的吸收和初始代谢阶段。在过去暴露的头两周内，每天收集尿液和粪便，以提供化合物的定量生物利用度。然后，在接下来的4-7个月里，偶尔通过静脉穿刺法采集血液。用高效液相色谱法分离标记营养素的循环代谢物。所有样品都通过AMS测量样品中至少0.5毫克的碳来量化14C浓度。研究人员对各种营养素的新陈代谢进行了研究，包括：β-胡萝卜素、叶酸和维生素E。在过去的一年里，叶酸新陈代谢的研究已经发表。根据目前对营养吸收、新陈代谢和消除过程的最好理解，设计了营养素的隔室模型。然后对模型进行修改以适应AMS测量的密集数据集。这样的模型提供了对志愿者体内最慢的(因此也是最持久的)营养池的洞察。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A steady supply of dietary micronutrients (vitamins) is needed to maintain normal biochemical reactions within humans. Folate is needed to maintain purine and pyrimidine synthesis, and metabolism of homocysteine to methionine. Carotene is a commonly consumed plant pigment (polyene) that is a biological antioxidant and a nutritional precursor of vitamin A. These and other micronutrients have generally been studied within humans at high, non-physiologic, doses in the past using stable or radioactive isotopes. While safe for use in humans, stable isotopes produce kinetic signals that quickly approach natural isotopic levels after a single dose. Radioisotopic labels are sufficicently distinct to provide traceable levels for longer periods, but the risks of radiation exposure limit such uses to populations that are less concerned with possible damage, such as elderly or infirm men. Accelerator mass spectrometry has such high sensitivity for quantifying long-lived isotopes that 14C-labeled micronutrients can now be traced in healthy young people, including particularly women of child-bearing age. Volunteers are given microgram doses of 14C-labeled compounds at radiative doses of 100-200 nCi (6-12 kBq). Blood is frequently collected from an indwelling catheter in the arm during the first day or two to provide high density data reflecting the absorption and initial metabolism phases of the pharmacokinetics. Urinary and fecal collections are made daily during the first two weeks past exposure to provide the quantitative bioavailability of the compound. Blood is then collected occasionally by venipuncture over the next 4-7 months post exposure. Circulating metabolites of the labeled nutrient are seprarted by HPLC. All samples are quantified for 14C concentration by AMS measurement of at least 0.5 mg carbon from the sample. Studies have been performed to examine the metabolism of various nutients including: beta-carotene, folate and vitamin E. This past year the studies of Folate metabolism have been published. Compartmental models are devised for the nutrient based on present best understanding of the absorption, metabolism, and elimination processes. The models are then modified to fit the dense data set of AMS measurements. Such models provide insight into the slowest turning ( and thus the most sustained) pools of nutrients in the volunteers.