KINETIC ANALYSIS OF ZN METABOLISM IN HUMANS

我们开发了一种人体锌代谢模型，用来测量锌 吸收、分布、排泄和分泌。使用我们已有的模型 最近确定了3个新的锌代谢调节位点(与 RBC，从肌肉释放并分泌到肠道)除了吸收 来自肠道和尿液的排泄。我们用10个以上的数据做了这件事 通过数学建模进行分析。我们现在打算1)使用一个 来自正常受试者的65锌数据的大型唯一数据库，以定义 动态分析每个监管地点，并研究监管如何变化 在老化过程中，2)利用体外RBC锌交换数据对模型进行改进 (3)利用该模型对70Zn数据进行了调查。1)~(65)Zn数据为 采集自正常受试者，年龄18-84岁。受试者被给予口服 测定血浆、红细胞、尿液、粪便、全身和组织中的~(65)Zn和~(65)Zn。 在肝脏和大腿上持续9个月。然后给予口服锌负荷(100 mg/d) 持续了9个月，测量还在继续。人体锌负荷过程中锌的排泄 “年长”(70岁以上)的受试者增加了7倍，而“年轻人” 受试者(40岁以下)只有3倍，这表明锌的调节 老化过程中的变化。用隔室模型拟合的数据显示 有5个调控部位。每个站点的参数将为 确定并比较了这一变化及其机理。2)我们 在1个调控位点RBC交换上收集体外数据。装订和 全红细胞和再密封幽灵对锌摄取的关系 对不同浓度的锌白蛋白、球蛋白、组氨酸、甘氨酸和 螯合剂。该模型将被扩展以表征结合和 红细胞对锌的摄取及各配体间相互作用的研究。3) 从6名受试者中收集了稳定同位素70Zn的数据，这些受试者分别给予70Zn和 65锌同时口服。血浆、红细胞、尿液和粪便中的活性 通过模型进行拟合，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 根据我们自己和其他文献中的70Zn数据确定的。这个 每一项研究的重要性是1)确定不同的代谢 锌与年龄的关系，可能有助于揭示锌在衰老中的作用；2) 了解锌在细胞系统(RBC)中的代谢及其影响 几个生理因素；以及3)不仅要使用稳定的同位素数据 以测量人体对锌的吸收，还包括锌的分布、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.