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Division of Nutritional Sciences, Cornell University, Ithaca, New York
2To whom correspondence should be addressed. E-mail: kk326{at}cornell.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • DMT1 • antagonism • interaction • iron • zinc
It is increasingly recognized that iron and zinc deficiencies occur together in various populations and may have to be addressed concurrently. Combined treatment with iron and zinc has been proposed as one solution. However, metabolic studies and supplementation trials suggest an antagonistic relationship between iron and zinc, in which zinc reduces the positive effects of iron supplementation and vice versa. For example, when given to adults in solution in ratios > 2:1 inorganic iron was found to compete for absorption with zinc (1). Zinc absorption in fasting pregnant Peruvian women administered Fe1 or Fe + Zn was significantly reduced compared with nonsupplemented women (2) (Fig. 1A). In women administered only Fe, plasma zinc concentrations were also lower, compared with controls. Conversely, there were smaller improvements in hemoglobin and serum ferritin concentrations in Indonesian children administered both Fe and Zn than in children given Fe alone (Fig. 1B) (3,4).
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Iron, Zinc, and the DMT1. The studies of iron and zinc competition at the DMT1 use the Caco-2 cell model derived from human colon carcinoma cells. The Caco-2 line is a good model for the study of iron homeostasis and regulation of Fe and Zn absorption because it is similar to human enterocytes in differentiation markers and yields absorption results comparable to those of human studies (7).
Two concepts must be distinguished when interpreting intestinal absorption studies. Apical uptake refers to the shuttling of metals across the apical membrane of the enterocyte from the intestinal lumen to the cytoplasm. In the case of iron, this is accomplished by the DMT1 (Fig. 2). Transepithelial transport refers to the transfer of metals across the basolateral membrane to be picked up and distributed by soluble transporters. Transepithelial transport of Fe involves the iron-regulated transporter (IREG1, also known as ferroportin) and hephaestin proteins and can be quantified by measuring metal concentrations in the basolateral incubation medium.
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This study implies that Zn uptake may be independent of the DMT1 mechanism. The reduction in zinc uptake did not occur in the absence of serum, which is important because only in its absence was DMT1 expression downregulated. If zinc relied on the DMT1 to enter the cell, its absorption should have decreased in the absence of serum, along with the decline in DMT1 expression. This study, however, did not manipulate the DMT1 directly. Either a knockout or overexpression of the transporter would provide more direct evidence concerning whether zinc enters the cell via DMT1 or competes with iron for absorption.
Yamaji et al. (9) examined the absorption of iron (1 µmol/L 55Fe+2) in the presence of 100 µmol excess zinc and the absorption of zinc (1 µmol/L 65Zn+2) in the presence of 100 µmol/L iron. Although Fe significantly inhibited the uptake of Zn, the reverse was not true. The study also assessed the effects of iron and zinc supplementation on DMT1 and IREG1 mRNA and expression, and on metal absorption. Iron loading decreased DMT1 expression and reduced subsequent Fe uptake but did not affect zinc absorption. Conversely, cell loading with zinc increased DMT1 mRNA levels and expression, increased Fe absorption, increased IREG1 expression, but did not change Zn absorption.
Evidence that Zn Does Not Reduce Fe Absorption. The optimal function of DMT1 in Caco-2 cells is pH dependent. Lower pH enhances its ion-transport properties, whereas higher pH compromises its functional integrity. At pH 7.4, excess zinc (molar ratio 500:1) reduced 55Fe+2 uptake by 67% compared with controls (10). Under acidic conditions (pH 5.5), however, zinc did not interfere with iron uptake. The reduction of iron absorption by zinc at a neutral, but not acidic pH, suggests that under conditions favorable to the functioning of the DMT1, iron is absorbed without significant competition from zinc, even at very high Zn:Fe ratios.
Finally, Tandy et al. (11) raised Caco-2 cells in an iron-supplemented medium. After 5 d under these conditions, they found a 56% decrease in DMT1 expression, lower DMT1 mRNA levels, and a 30% reduction in iron uptake compared with cells grown in control medium. Changes in DMT1 expression did not affect zinc uptake, however. In a separate experiment, 1 µmol/L 55Fe+2 was incubated with 100-fold excess zinc, but no significant decrease in iron absorption was observed. Because the uptake of metals by DMT1 is thought to be dependent on cell membrane potential, the authors used high K+ solutions to depolarize the cells and demonstrated subsequent reductions in Fe uptake (42%) without changes in Zn absorption. Disrupting the function of DMT1 provided strong evidence that zinc does not depend on this transporter to enter intestinal cells and is unlikely to compete with iron for absorption at this site.
Relating New Evidence to Existing Knowledge. The seminal study by Gunshin and colleagues (6) demonstrated the affinity of DMT1 for iron and other divalent metals. Frog oocytes were perfused with solutions containing various divalent cations, and the currents evoked by these metals were recorded. Like iron, zinc produced large inward currents in oocytes expressing DMT1, and this was cited as evidence that zinc, like iron, employs the DMT1 for cellular transport. This method, however, did not demonstrate directly that any given metal was taken up by the DMT1 (11); the actual transport of Zn across the apical membrane was not measured in the study of Gunshin et al. (6). Recently, the absorption of 65Zn+2 was compared in frog oocytes injected with DMT1 and controls (12). Neither group showed any appreciable uptake of zinc, suggesting that DMT1 does not transport zinc.
In further support of this argument, a family of human intestinal Zn transporters (ZIP) was identified recently, suggesting separate mechanisms for iron and zinc absorption. Two such zinc transporters, hZIP1 and hZIP2 are expressed in various tissues of the body but are not thought to participate in iron transport (13). Another ZIP protein, hZIP4, expressed on the apical membrane of enterocytes, is defective in acrodermatitis enteropathica and regulated by dietary zinc but, again, is not involved in iron uptake (14,15).
On the basis of the evidence gathered to date, a model of the likely relationship between iron and zinc can be constructed. Although we have evidence that Fe interferes in the absorption of Zn, we do not have evidence that Zn interferes in the absorption of Fe. Furthermore, the above studies dispute the dependence of zinc on DMT1 for transport into cells and the physiological basis for absorptive competition between iron and zinc, at least at this particular site.
However, we must be cautious in interpreting cell culture studies. It is possible that an in vitro model of Fe and Zn absorption may not be easily translated into biochemical outcomes of a supplementation study and that a direct correspondence may not be achieved. One reason is that in vitro studies often use ion concentrations and molar ratios that are not physiologically feasible. Although Zn absorption is inhibited by iron at a 100:1 or 500:1 mol/L ratio in Caco-2 cells, supplements are usually given to people at ratios closer to 1:1. Furthermore, the effects and interactions of micronutrients given in a supplement may depend on the dietary context. Fe and Zn absorption is inhibited by phytate, but Fe absorption is enhanced by ascorbic acid and cysteine. Because iron and zinc form complexes in the lumen with other food constituents, such as carboxylic acids, their availability to absorptive mechanisms may be affected. It is possible that instead of a physiological competition, supplementation studies observed a physiochemical competition between iron and zinc (J. L. Beard, Penn State, personal communication).
Work in animal models of intestinal iron and zinc absorption may help bridge the gap between in vitro studies and the results of human supplementation trials. In a 2 x 3 factorial design, piglets were dosed with 2 different concentrations of elemental Fe (100 and 200 mg/kg) and 3 concentrations of zinc carbonate (25, 50, and 100 mg/kg) (16). The absorption and retention of 65Zn was measured in vivo at several time points. Elemental iron, irrespective of dose, did not affect 65Zn absorption. However, although the absorption of 65Zn did not differ, the retention of zinc was lower when given along with ferrous sulfate, due to increased zinc excretion. These results reveal a real difficulty in comparing and interpreting studies that use different treatment formulations, such as elemental vs. ferrous iron. In addition, they suggest the possibility of postabsorptive competition between Fe and Zn.
Other Interaction Sites. Most of our thinking about the potential competition between Fe and Fe as a possible interpretation of supplementation trials has focused on intestinal absorption. There exists, however, the possibility of an antagonism or interplay between iron and zinc at other sites in the body because the localization of metal transporters or the function of micronutrients is not limited to intestinal cells. Several sites of Fe and Zn interactions would be relevant to the outcomes most often assessed in supplementation trials. What follows is a brief description of the current knowledge of Fe and Zn function in the brain. The focus on neural tissues is relevant in light of increasing interest in the effects of iron and zinc, and their deficiencies, on the cognitive and behavioral development of children. A clear point of physiologic interplay between Fe and Zn has not been identified in neural tissues because most research to date has examined only the separate functions of these metals. Therefore, the following is intended as a springboard to move beyond the enterocyte in interpreting the results of supplementation trials.
Iron in the Brain. The mechanisms of Fe transport in the brain commonly involve transferrin and transferrin receptors (TfR), as well as the DMT1 (17). Iron in neurons is stored as ferritin (18). Iron deficiency (ID) has been associated with decreased tissue Fe, reduced ferritin, and increased serum transferrin and TfR concentrations (19–21) in the majority of brain regions examined, regardless of its duration and timing. Some brain regions, however, are better able to conserve iron than others. The mechanisms of this regulation are not clear but may depend on the distribution of Fe receptors and transporters, as well as Fe status of brain tissues.
ID is thought to affect myelination, neurotransmitter metabolism, and Fe-containing enzymes [see (22 for review]. Rats with postweaning ID had significantly lower concentrations or activity levels of myelination markers than controls (23). Postweaning ID was also associated with changes in the PUFA content in myelin fractions (21,23). Both neonatal and postnatal ID in rats affected D1, D2 receptor and dopamine transporter (DAT) levels in the striatum and prefrontal cortex (24,25). Postnatal ID also reduced levels of locomotion, stereotypy, and exploratory activity. Lower D2 receptor levels in ID rats were linked to poorer behavioral outcomes. However, behavioral deficits and densities of D1 and DAT appeared resistant to Fe treatment after ID, despite correction of anemia. Other neurotransmitters also seem sensitive to ID. Rats with perinatal ID had significantly lower brain Fe levels, accompanied by elevated concentrations of glutamate and moderately higher 
-aminobutyric acid (GABA) (26).
Zinc in the Nervous System. Brain Zn concentrations show regional heterogeneity and developmental dependence (27). Zn in the adult brain is localized in the hippocampal region and cerebral cortex (28) and is found in presynaptic vesicles of glutamatergic neurons. The role of Zn2+ in these neurons is controversial but may include participation in the storage, release, and uptake of glutamate, and modulation of glutamate receptors (29). The following 3 types of Zn2+ signals have been proposed: 1) transmitter-like signals involving action potentials, the release of Zn2+ from synaptic vesicles, and its binding to glutamate or GABA receptors; 2) the flux of Zn2+ into postsynaptic neurons during long-term potentiation (LTP); and 3) intracellular signaling for sequestration of Zn2+ into vesicles (30).
The functions subserved by Zn-containing neurons and the role of synaptically released Zn2+ are unclear. The involvement of vesicular Zn in cognitive functions such as memory and learning has been suggested (28). Recent studies of zinc transporter3 (ZnT3) –/– mice showed that the absence of Zn from synaptic vesicles did not affect glutamatergic neurotransmission or impair learning or memory (31,32). However, high concentrations of a Zn-depleting chelator applied to hippocampal slices blocked the initiation of LTP in a mossy fiber (MF) pathway (33), suggesting that Zn enhances synaptic strength.
Iron and Zinc in the Brain. Studies of Fe and Zn interactions in neural tissues are scarce. One study examined the distribution of ferritin in the hippocampal region (glial cells of the MF system) in rats with postweaning ID. The effects of a 4-wk Fe and/or Zn treatment on neurotransmission were also assessed (34). ID delayed the development of ferritin-containing cells in this region. Although Fe or Zn alone was not effective in increasing the number of ferritin-containing MF cells, rats administered Fe + Zn had significantly higher numbers of these cells than all other treatment groups (except pair-fed controls). The MF of the hippocampus is thought to be involved in LTP, an electrophysiological model of memory and learning. Thus, studies showing the effects of ID and the effectiveness of combined Fe + Zn treatment on hippocampal anatomy are especially important. This study suggests a biological (micronutrient status) interdependence between iron and zinc in the brain. Elucidation of the mechanisms underlying this dependence is crucial for our understanding of the consequences of Fe and Zn deficiencies on brain development. Future research in this area would ideally include functional assessments, including hippocampus-dependent cognitive tasks and induction of LTP.
In conclusion, the molecular basis for the understanding of Fe-Zn interactions is increasingly important because deficiencies of these micronutrients often occur together, and combined Fe and Zn treatment may be one solution to this problem. Previous studies demonstrated an antagonism between Fe and Zn, citing absorptive competition between the 2 metals at the DMT1 as its basis. However, recent evidence does not support this explanation. These studies uphold the notion that Fe disrupts Zn absorption, not vice versa, but they also show that the DMT1 is not the primary intestinal transporter of zinc. This does not settle the debate over the existence of an absorptive antagonism between Fe and Zn. It does suggest, however, that DMT1 is an unlikely site for this competition.
In terms of Fe and Zn interactions in neural tissues, very few studies examining the combined roles of iron and zinc or their deficiencies on cognitive function or brain chemistry actually exist, and their lack is striking. There is a need for the consistent examination of the effects of timing, duration, severity, and reversibility of these deficiencies on neurochemistry and cognition. Furthermore, to link the biological and functional effects of Fe and Zn deficiencies, in addition to biochemical measures, future studies should ideally include theoretically grounded behavioral assessments related to specific brain regions of interest.
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FOOTNOTES |
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3 Abbreviations used: DAT, dopamine transporter; DMT1, divalent metal transporter 1, also known as DCT1 (divalent cation transporter 1) and Nramp2 (natural resistance-associated macrophage protein-2); GABA, -aminobutyric acid; hZIP, human ZIP; ID, iron deficiency; IREG, iron-regulated transporter, also known as ferroportin; LTP, long-term potentiation; MF, mossy fiber; TfR, transferrin receptor; ZIP, ZRT/IRT related protein.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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