MICRONUTRIENT KINETICS IN HUMANS AT PHYSIOLOGIC DOSES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 饮食中微量营养素（维生素）的稳定供应是维持人体正常生化反应所必需的。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和维生素A的营养前体。过去通常使用稳定或放射性同位素以高剂量、非生理剂量对这些和其他微量营养素进行人体研究。虽然对人类使用是安全的，但稳定同位素产生的动力学信号在单次剂量后迅速接近天然同位素水平。放射性同位素标签具有足够的独特性，可以在较长时间内提供可追踪的水平，但辐射暴露的风险限制了此类用途，使其仅限于对可能的损害不太关心的人群，如老年人或体弱的男性。加速器质谱法在定量长寿命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，特别是育龄妇女中追踪14 C标记的微量营养素。 志愿者被给予微克剂量的14 C标记的化合物，辐射剂量为100-200 nCi（6-12 kBq）。在第一天或第二天期间，经常从手臂中的留置导管收集血液，以提供反映药代动力学的吸收和初始代谢阶段的高密度数据。在暴露后的前两周内，每天采集尿液和粪便，以提供化合物的定量生物利用度。然后在暴露后4-7个月内偶尔通过静脉穿刺采集血液。标记营养素的循环代谢物通过HPLC分离。通过AMS测量来自样品的至少0.5mg碳来量化所有样品的14 C浓度。 已经进行了研究，以检查各种营养素的代谢，包括：β-胡萝卜素，叶酸和维生素E。 房室模型设计的营养素的基础上，目前最好的理解的吸收，代谢和消除过程。然后修改模型，以适应密集的AMS测量数据集。这些模型提供了对志愿者体内最慢（因此也是最持久）的营养池的深入了解。

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. 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.