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3 Metabolic Modeling Services, 7201 Blenheim, New Zealand and 4 USDA-Agricultural Research Service, Robert W. Holley Center for Agriculture and Health, Ithaca, NY 14853
* To whom correspondence should be addressed. E-mail: wastneym{at}metabolic-modeling-services.com.
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ABSTRACT |
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 TOP ABSTRACT IntroductionExperimental ProceduresModel Fitting and ResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionExperimental ProceduresModel Fitting and ResultsDiscussionLITERATURE CITED |
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Many biological functions of Zn are associated with proteins (12) and there has been an explosion of information concerning proteins involved in Zn uptake and release by cells via Zn transporters (13–15), as well as the storage of Zn within cells by metallothionein (MT)5 (16,17). Two major isoforms of this protein, MT-I and MT-II, assimilate Zn in tissues in rodents (18,19). Although the genes are induced by a number of factors, including hormones, stress, and administration of metals (20), mice lacking gene expression for MT-I and MT-II appear to grow and reproduce normally (21,22) and the physiological role of MT remains unclear (23,24), although it appears to be important during times of stress (25).
Possible roles for MT in Zn metabolism have been explored with tracer studies in MT-knockout mice (26,27). Following subcutaneous administration of Zn tracer, low levels (1–2%) of tracer were detected in the small intestine and it was concluded that an absence of MT in the pancreas contributed to more Zn secretion in exocrine secretions. Studies on the mice used, however, have been questioned (23), because the control and knockout mice may not have had identical genetic backgrounds. The pancreas has one of the highest concentrations of MT (28,29) and because in vitro (30) and in vivo studies (31) indicate that MT can accept and donate Zn, MT may have a role in exocrine functions by regulating or modulating Zn utilization.
The aim of the current study was to develop a multicompartmental model for Zn kinetics in mice by administering tracer and sampling multiple tissues over several days. The objectives were to provide baseline values for Zn kinetics in mice under replete dietary conditions and to then quantify differences in Zn metabolism between normal mice and those lacking MT.
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Experimental Procedures |
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TOPABSTRACTIntroductionExperimental ProceduresModel Fitting and ResultsDiscussionLITERATURE CITED |
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In separate groups of mice, aged 9 or 34 wk, 15 mice of each genotype were food deprived for 12–14 h, anesthetized, and a blood sample was obtained from the tail. A glucometer (FastTake, LifeScan) was used to determine blood glucose concentration. A radioimmunoassay kit (no. SRI-13K, Linco Research) was used to measure insulin in small samples of plasma (
20 µL).
Isotope administration and sampling. Non-food-deprived mice were given by oral gavage 18.5 kBq (0.5 µCi) of 65ZnCl2 (DuPont de Nemours; 88.5 mBq/µg Zn) in 0.1 mL of deionized water. Immediately after 65Zn was given, some mice were assayed for radioactivity in a custom-built "whole-body" gamma scintillation spectrometer described previously (34). Subsequently, mice were assayed and whole-body retention of 65Zn was measured daily until the mice were killed. At 10 time points after isotope administration (0.5, 1, 2, 3, 6, 12, 24, 48, 96, and 192 h), 3–5 mice of each strain were anesthetized and blood was collected by cardiac puncture into heparinized tubes. These mice were then killed by CO2 anesthesia and dissected to obtain organs and tissue samples. Daily food consumption was measured and urine and feces were collected separately each day on the mice killed at 96 and 192 h (8–10 mice per strain).
Blood samples were centrifuged and plasma and formed elements were separated. The entire liver, kidneys, adrenal glands, spleen, heart, lungs, pancreas, brain, eyes, reproductive tract, and gastrointestinal tract were removed from each mouse. Additionally, the pelt, samples of bone (femur), and skeletal muscle were collected from each mouse; the pelt, which included the ears, was removed as nearly as completely as possible. The gastrointestinal tract was divided into the following anatomical segments: stomach, duodenum (proximal 8 cm of small intestine), jejunum (mid-region of small intestine), ileum (distal 8 cm of small intestine), cecum, and colon. The reproductive tract included the vagina, left and right uterine horns, oviducts and ovaries; fat and supporting mesentery were removed. All remaining parts of the carcass were pooled and saved.
Zn and 65Zn analysis. Tissues, organs, excreta, and intestinal segments (with contents) from each mouse were assayed for 65Zn activity by a scintillation detector (Model 5530, Packard Instrument) and activity was expressed as a percentage of the oral dose. Tissues were then saved to determine total Zn content. Prior to chemical analysis, each intestinal segment was slit open along its horizontal axis and digesta removed by flushing with cold physiological saline. Organs, tissues, excreta, and diet samples were dried (70°C for 48–96 h), wet-digested in a mixture of HNO3 and HClO4 (9:1, v:v), and analyzed for Zn using inductively coupled plasma emission spectrometry (Trace Analyzer, Thermo Jarrell Ash). For all analyses, minerals measured in a standard reference material (no. 1577b, bovine liver, National Institute of Standards and Technology) were within certified ranges.
The total amount of 65Zn and Zn in whole organs or tissues was calculated from the 65Zn and Zn content of the samples combined with the measured or estimated weights of the organs. Literature values (6,29) were used to estimate volumes of plasma and RBC, and total weight and dry matter content of bone and muscle. Values used, expressed as a percentage of body weight, were: plasma, 2.1%; RBC, 3.2%; bone, 11.2%; and muscle, 38.8%. The 65Zn tracer data for each of the 21 tissues collected at each sampling time were expressed as a percentage of the amount administered.
Kinetic analysis. Changes in 65Zn distribution in the body were analyzed using compartmental analysis and the modeling software WinSAAM (35,36). Kinetic terms and symbols were as reported previously (1). Briefly, compartments represented pools of Zn in the body. The pools may represent Zn in different tissues or metabolic forms that differ kinetically. Transfer between compartments, L(i,j), was the fraction transferred per hour into compartment i from compartment j. M(i) represented Zn mass (µg) [Zn molecular weight is 65.4] in compartment i.
Statistics. Values were expressed as means ± SEM. Group means for the Zn and radiozinc data were compared using Student's t test. Similarly, blood glucose and plasma insulin concentrations were compared using a t-test procedure. Differences were considered significant at P < 0.05; actual P-values < 0.1 are reported.
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Model Fitting and Results |
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TOPABSTRACTIntroductionExperimental ProceduresModel Fitting and ResultsDiscussionLITERATURE CITED |
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10 d). Secretion pathways from plasma into the intestine, defined following i.v. tracer administration in rats (1), were retained in the mouse model. Summing all compartments (excluding urine and feces) fit the whole-body data. As described for rats, exchange with compartments in skin and muscle that turned over slowly, and not defined from these 8-d studies, was fixed by the measured Zn mass in the tissue (1). Absorption was calculated as the fraction of tracer entering plasma from each site in the intestine (compartments 24, 34, and 36) and the fractions were added to determine total absorption. For example, absorption from the duodenum was calculated as L(1,24)/(L(1,24)+L(34,24)). Absorption capacity from each was: duodenum, 3.8%; jejunum, 12.5%; and cecum, 9%. Based on the percent of dose arriving at each site, this translated into 4, 12, and 7% absorption, respectively, of the orally administered 65Zn dose for a total absorption of 23%. The time courses of tracer appearance in some tissues (Fig. 3) were compared with values calculated by the model (Fig. 1) of Zn metabolism in the mice.
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The body weight of MT–/– mice was greater than that of WT mice (Table 1). Blood glucose and plasma insulin concentrations were 20 and 27% higher, respectively, in MT-null mice than in the WT mice (Table 1). Following intraperitoneal glucose administration, glucose disappearance and insulin kinetics did not differ over time (data not shown). In 34-wk-old mice, differences between genotypes in fasting glucose (P = 0.065) and insulin (P = 0.086) were not significant and glucose tolerance did not differ (data not shown).
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10%. However, the amount and concentration of Zn in the pancreas differed more markedly between genotypes. The total amount of Zn in most tissues did not differ between genotypes, but in some tissues (brain, kidney, lung, pancreas, and reproductive tract), Zn content was lower in MT-null mice than in WT mice (Table 3). Muscle, by contrast, had higher total Zn mass in MT–/– than in WT mice. The Zn mass observed in each tissue was compared with the value calculated using the model and predictions were within 30% for most tissues (Table 3).
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Discussion |
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TOPABSTRACTIntroductionExperimental ProceduresModel Fitting and ResultsDiscussionLITERATURE CITED |
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WT mice. This study provides basal values for Zn kinetics in normal, nutritionally replete female mice, which allows comparison to mice with differing dietary, genetic, or physiological conditions. The kinetic data agree with those of Sheline et al. (8) in that the relative turnover of Zn: 1) was most rapid in liver, pancreas, and kidney; 2) was the slowest in RBC, brain, skeletal muscle, and skin; and 3) was intermediate in spleen, gastrointestinal tract, adrenals, lungs, bone, heart, and thymus. Here we quantified the turnover rates and showed that some tissues (skin, muscle, and bone) contain both rapidly and slowly turning-over pools of Zn, as do those (RBC and liver) shown previously to have 2 pools in humans (3). Notably, the results of Sheline et al. (8) show much greater uptake of tracer by the liver following i.v. administration than in our study where tracer was administered orally. Zn absorption (23%) matched that (22%) determined by Cotzias et al. (9).
The additional Zn pools identified in mice are probably the result of being able to directly sample more tissues. Pool turnover times in mice were 5 times faster than those in rats (1). Studies in rats showed that the tracer curves of kidneys, spleen, and testes corresponded in shape to 3 previously unidentified pools in humans (1), indicating that Zn kinetics in rodents may assist in interpretation of human data. It is generally considered that refining existing models is more likely to improve prediction rather than inventing new models. Certainly when models do not fit a new set of data (37), those aspects not fitted need to be described before the model is abandoned, because the error may lie with either the original or the new data rather than the model per se. Our understanding of human Zn metabolism and its regulation has been assisted by kinetic studies during normal Zn intake (4,5,38), increased Zn intake where 5 sites were identified (4), and with Zn deficiency (39). However, our knowledge of the roles of specific proteins in these processes is limited. The kinetic results described here on the loss of MT from mice may provide insight into how metabolism is regulated. The approach could be generalized and applied to identify the role of specific proteins in the metabolism of other nutrients.
Zn concentrations in tissues are influenced by age, gender, diet, and genetic background and these factors may explain why Zn concentrations in some tissues in our study varied from values reported for other strains of mice. For example, total hepatic Zn and skeletal muscle Zn concentration measured here were lower than values reported for C57BL/6J mice (10,40,41). However, the total amount of Zn in other tissues, such as the pancreas, was similar to the amount in lean C57BL/6J mice (40).
MT–/– mice.
Although feed intake did not differ between groups, MT–/– mice were 5% heavier at 10 wk old than the WT mice. Whereas a trend toward obesity was reported in 6-wk-old male MT-null mice of mixed genetic background (129/OLA and C57BL/6J) compared with control C57BL/6J mice (42), others (23) reported that MT did not affect body weight when mice of identical background were compared. The variation in body weight that we observed may be a carry-over effect from weaning weights. Duffy et al. (43) reported that the mean weight of pups at weaning from MT-null dams was higher than that of pups from WT dams (strain 129/Sv), but the degree of difference or ratio of gender was not given. We have observed (W. A. House, unpublished data) that the mean body weights of female MT-null and WT 129/Sv mice did not differ significantly when the mice were older (32–39 wk old). We suggest, therefore, that MT does not have a major role in the regulation of energy utilization in female mice fed a diet containing adequate Zn.
Generally, tissue concentrations of Zn were lower in the MT-null mice than in the WT mice, particularly in the pancreas, which agrees with an earlier report (44). Differences in tissue Zn concentrations of MT-null and WT mice would appear to support one of the suggestions proposed for the function of MT, namely that MT can serve as a transient reservoir for the storage of metals, including Zn (23,45). Whole-body Zn concentration, by contrast, was 28 µg/g body weight in both groups, suggesting that MT probably does not have a marked affect on Zn balance in nutritionally replete animals. Plasma glucose concentration in MT–/– mice has been reported to be either similar to (42,46) or lower than (47) that in WT mice. The higher values of fasting plasma glucose and insulin that we observed in the MT–/– mice may reflect different responses to stress between the genotypes.
Zn kinetics: MT–/– vs. WT
Whole-body Zn kinetics were used to quantify differences in Zn metabolism between MT–/– and WT mice. In fed, female mice, lack of MT-1 and MT-II did not affect Zn absorption or Zn kinetics in most tissues. However, as observed previously (26,27), lack of MT did alter Zn kinetics in the pancreas. In our study, this difference between mouse genotypes, explained through modeling, was a 2-fold faster rate of turnover of Zn in the pancreas of MT–/– mice compared with WT mice. We did not observe other differences (Zn tracer in liver, muscle, and skin) that were reported in the food-deprived mice (26). Based on samples collected at 2 time points, Rofe et al. (26) concluded that the MT-null mice secreted more Zn into the intestine via pancreatic, bile, or intestinal secretions than did WT mice. However, it cannot be determined from observations at 2 time points whether the rate of Zn secretion into intestine is higher or rate of removal is altered. Although Zn efflux from the pancreas to the small intestine is considered an important pathway (48–50), we were not able to define this pathway kinetically from either our earlier studies in rats (1) or our current study where tracer was administered orally. Others (5) have included a separate pathway from tissues to the intestine to represent endogenous loss and separate absorption pathways. Interestingly, absorption from the 2 sites in the small intestine, calculated using their (5) parameter values, was similar (15%) in the fed subjects. Our model simulations for mice indicated that the major Zn loss from pancreas was via plasma. In support of this, endogenous fecal excretion was not reduced after pancreatectomy in control mice (26).
Interpretation: Zn kinetics in the pancreas in the presence and absence of MT
About 1% of the pancreas consists of Islet cells (composed of glucagon-secreting 
cells and insulin-secreting β cells) that may contain up to 20 times the amount of Zn found in the other cell type, the acinar cells [see (51)]. About one-third of the Zn in rat Islet cells is associated with insulin (i.e. in the granules) (52).Tracer studies in rats showed that acinar cells take up Zn rapidly and it then turns over in 24 h whereas Islet cells continue to retain high tracer levels beyond 92 h (51). We were able to identify only a single pancreatic Zn pool from our in vivo data and this pool presumably represents the more slowly exchanging Zn in Islet cells. As some investigators (50) reported that Islets in mice, in contrast to rats (53), do not contain MT, the difference we observed in pancreatic Zn kinetics between WT and MT–/– mice may likely be due to Zn kinetics in the acinar cells (47,54). However, others have found similar levels of MT in mice and rat Islets (47). We could speculate that the difference in Zn mass in pancreas of WT and MT–/– mice is the proportion of Zn bound to MT (23%) in the fed female mice. However, with the existence of Zn transporters, including one specific to the pancreas (55–57), this interpretation may be too simplistic. Namely, MT may facilitate movement of Zn into a specific cellular pool, enzyme, or storage form so that the difference in kinetics represents these other forms of Zn rather than MT-bound Zn. Experimental measurements of the location of Zn tracer in pancreas 15–45 h after gavage may indicate the form or location of Zn resulting from the presence of MT. In our model, the pancreatic pool, therefore, represents Zn in both acinar and Islet cells.
Our study provides baseline values for Zn kinetics in fed mice. These baseline values can be used to evaluate roles of specific proteins in Zn metabolism in vivo. By comparing Zn kinetics in MT- knockout and WT control mice with the same genetic background, we have confirmed that the pancreas is the primary tissue affected by the absence of MT-I and MT-II. Under replete dietary conditions, Zn in the pancreas of MT-null mice turns over twice as fast as Zn in WT mice. More detailed studies are required to determine how lack of MT alters Zn metabolism within the pancreas. In addition, an expansion of the Zn model to include intracellular metabolism and movement of Zn and MT within Islet and acinar cells (58) and parallel modeling of the dynamics of MT and Zn metabolism will further unravel the roles of these compounds.
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FOOTNOTES |
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2 Author disclosures: W. A. House and M. E. Wastney, no conflicts of interest.
5 Abbreviations used: MT, metallothionein; MT–/–, MT-null or mice lacking metallothionein isoforms I and II; WT, wild-type or mice with metallothionein isoforms I and II.
6 Mention of a trade name or a proprietary product does not constitute a guarantee or warranty of the product by USDA or imply its approval to the exclusion of other products or vendors that may be suitable.
Manuscript received 17 April 2008. Initial review completed 12 May 2008. Revision accepted 7 August 2008.
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