Development of a Compartmental Model of Zinc Kinetics in Mice

Abstract

To investigate zinc (Zn) kinetics in mice, tracer (65Zn) was administered orally to 9-wk-old female mice in the fed state and tracer and Zn concentration were measured in 21 tissues over the following 8 d. Data were analyzed by compartmental modeling using WinSAAM. A published model for Zn kinetics in rats was modified to fit the data from mice and to calculate transfer rates and pool sizes of Zn. Parallel studies were performed in mice lacking genes for metallothionein (MT), MT-I and MT-II (MT−/−), to quantify differences in Zn kinetics in the absence of these proteins in vivo. We confirmed that tracer time course in most tissues was similar in wild-type mice and those lacking MT, except for the pancreas of MT−/−, which retained less tracer. By fitting tissue and intestinal data simultaneously, we found that intestinal tracer could be explained by unabsorbed isotope and loss of Zn from pancreas went through plasma. Differences in pancreatic data in MT−/− were explained by Zn turning over twice as fast in this tissue (4 h) compared with wild type (9 h). These kinetic studies provide parameter values for normal, fed mice that can be used to assess Zn kinetics in abnormal conditions, as demonstrated by the higher turnover of Zn in the pancreas of MT knockout mice.

Dietary Zinc Reduction, Pyruvate Supplementation, or Zinc Transporter 5 Knockout Attenuates β-Cell Death in Nonobese Diabetic Mice, Islets, and Insulinoma Cells3

“…Pancreatic Zn 2+ concentrations are required for insulin packaging (1 mg Zn 2+ /kg diet potentiated NOD diabetes incidence). This explains why the b-cell Zn 2+ pool is one of the last labile, stainable Zn 2+ pools to be depleted during ZnR [for review, see (57)]. However, 60 mg Zn 2+ /kg diet increased NOD diabetes incidence compared with 2 mg Zn 2+ /kg diet, demonstrating a sharp susceptibility curve for dietary Zn 2+ and ongoing T1DM.…”

Zinc and diabetes — clinical links and molecular mechanisms

“…An interesting finding is the increased loss of zinc from the pancreas of mice lacking the genes for MT-I and MT-II. This zinc loss seems to be mediated through the plasma and could be explained by a higher turnover of zinc in the pancreas of mice lacking the MT genes providing an example of the pivotal role of MT for zinc homeostasis [75].…”

Deficiency of metallothionein-1 and -2 genes shortens the lifespan of the 129/Sv mouse strain

“…In addition, MTs have the capacity to bind metals. MTs contribute to zinc homeostasis, and MT deficiency causes changes in zinc turnover (Wastney and House, 2008). Zinc is an essential trace element for animals and plants and plays many biological roles.…”