KINETIC ANALYSIS OF ZN METABOLISM IN HUMANS

我们开发了一个人体锌代谢模型， 吸收、分布、排泄和分泌。 利用我们现有的模型 最近定义了3个新的锌代谢调节位点（与 红细胞，从肌肉释放并分泌到肠道中） 从肠道和尿液中排出。 我们使用的数据超过10 通过数学建模进行分析。 我们现在打算1）使用 来自正常受试者的65 Zn数据的大型唯一数据库，以定义 从动力学上研究每个调节位点，并研究调节如何变化 在老化过程中，2）使用关于RBC Zn交换的体外数据来改进模型 （3）应用该模型对70 Zn数据进行了研究。 1)65 Zn数据为 从年龄18-84岁的正常受试者中收集。受试者口服 测定了血浆、红细胞、尿、粪便、全身和 肝脏和大腿9个月。 然后给予口服锌负荷（100 mg/d） 9个月，并继续测量。 在锌负荷期间， “老年”（大于70岁）受试者增加了7倍，“年轻”受试者增加了7倍， 受试者（小于40岁）只有3倍，这表明锌的调节 老化过程中的变化。 房室模型拟合的数据显示 有5个调节点。 每个站点的参数将是 确定和比较，以确定这种变化及其机制。 2)我们 在1个监管中心（RBC交换）收集体外数据。 结合和 测定了全红细胞和重封血影对锌的摄取， 不同浓度的锌白蛋白，球蛋白，组氨酸，甘氨酸和 螯合剂。 该模型将被扩展到表征绑定， 红细胞对锌的摄取，并表征每种配体的相互作用。 第三章 稳定同位素70 Zn数据已从给予70 Zn的6名受试者收集， 65锌口服同时进行。 血浆、RBC、尿液和粪便中的活性将 通过模型拟合，以确定两者代谢的相似性 同位素 锌的吸收、分布、排泄和分泌， 根据我们自己和文献中的其他70 Zn数据确定。 的 每项研究的重要性是1）确定代谢的差异， 锌与年龄的关系，这可能揭示了锌在衰老中的作用; 2） 了解锌在细胞系统（RBC）中的代谢以及 几个生理因素;和3）使用稳定同位素数据不仅 测量人体锌吸收，以及锌分布，排泄和 分泌物

We developed a model for Zn metabolism in humans that measures Zn absorption, distribution, excretion and secretion. Using the model we have recently defined 3 new sites of regulation of Zn metabolism (exchange with RBC, release from muscle and secretion into gut) in addition to absorption from gut and excretion in urine. We did this with data obtained over 10 yrs with analysis by mathematical modeling. We now intend to 1) use a large unique database of 65Zn data from normal subjects to define kinetically each site of regulation and to study how regulation changes during aging, 2) to refine the model using in vitro data on RBC Zn exchange and 3) to use the model to investigate 70Zn data. 1) The 65Zn data were collected from normal subjects, aged 18-84 yrs. Subjects were given oral 65Zn and 65Zn was measured in plasma, RBC, urine, feces, whole body and over liver and thigh for 9 mo. An oral Zn load (100 mg/d) was then given for 9 mo and measurements continued. During Zn loading Zn excretion in "older" (greater than 70 yr) subjects increased 7-fold, in "younger" subjects (less than 40 yr) only 3-fold, suggesting that regulation of Zn changes during aging. The data fitted by the compartmental model showed that there were 5 sites of regulation. Parameters at each site will be determined and compared to define this change and its mechanism. 2) We collected in vitro data on 1 regulatory site, RBC exchange. Binding and uptake of Zn by whole RBC and resealed ghosts were measured in relationship to varying concentrations of Zn albumin, globulins, histidine, glycine and chelators. The model will be extended to characterize the binding and uptake of Zn to RBC and to characterize interactions of each ligand. 3) Stable isotope 70Zn data have been collected from 6 subjects given 70Zn and 65Zn orally simultaneously. Activity in plasma, RBC, urine and feces will be fitted by the model to determine similarity in metabolism of the two isotopes. Absorption, distribution, excretion and secretion of Zn will be determined from our own and other 70Zn data in the literature. The importance of each study is 1) to identify differences in the metabolism of Zn with age which may shed light upon the role of Zn in aging; 2) to understand metabolism of Zn in a cellular system (RBC) and effects of several physiological factors; and 3) to use stable isotope data not only to measure human Zn absorption, but also Zn distribution, excretion and secretion.