Zinc and Health: Current Status and Future Directions

Transcription

1 Zinc and Health: Current Status and Future Directions Zinc Homeostasis in Humans 1 Janet C. King, 2 David M. Shames and Leslie R. Woodhouse USDA/ARS Western Human Nutrition Research Center, University of California, Davis, CA ABSTRACT Maintaining a constant state of cellular zinc nutrition, or homeostasis, is essential for normal function. In animals and humans, adjustments in zinc absorption and endogenous intestinal excretion are the primary means of maintaining zinc homeostasis. The adjustments in gastrointestinal zinc absorption and endogenous excretion are synergistic. Shifts in endogenous excretion appear to occur quickly with changes in intake just above or below optimal intake. The absorption of zinc responds more slowly, but it has the capacity to cope with large fluctuations in intake. With extremely low zinc intakes or with prolonged marginal intakes, secondary homeostatic adjustments may augment the gastrointestinal changes. These secondary adjustments include changes in urinary zinc excretion, a shift in plasma zinc turnover rates and, possibly, an avid retention of zinc released from selected tissues, such as bone, in other tissues to maintain function. J. Nutr. 130: 1360S 1366S, KEY WORDS: zinc zinc homeostasis zinc absorption zinc kinetics zinc excretion The ability to maintain a constant internal state with varying external conditions is essential for survival. This is called homeostasis if the nutrient flow within an organism is in a state of equilibrium, and it is called homeorhesis if there is continual retention of the nutrient as occurs during growth, reproduction or lactation (Kirchgessner 1993). Changes in zinc absorption and excretion in the gastrointestinal tract are the primary mechanisms for maintaining zinc homeostasis. Adjustments in renal excretion also occur with extremely low or high intakes of zinc. Tissue and cellular redistribution of zinc may contribute further to the maintenance of zinc homeostasis. The purpose of this report is to describe how these adjustments in zinc homeostasis occur in animals and humans. Changes in zinc intake and whole body zinc content Studies in experimental rats demonstrate a capacity to maintain a relatively constant content of zinc in the whole body while dietary zinc intakes vary by as much as 10-fold (Kirchgessner 1993). When the zinc intakes of weanling experimental animals ranged from 10 to 100 mg/kg, the content 1 Presented at the international workshop Zinc and Health: Current Status and Future Directions, held at the National Institutes of Health in Bethesda, MD, on November 4 5, This workshop was organized by the Office of Dietary Supplements, NIH and cosponsored with the American Dietetic Association, the American Society for Clinical Nutrition, the Centers for Disease Control and Prevention, Department of Defense, Food and Drug Administration/Center for Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the NIH (Fogarty International Center, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institute of General Medical Sciences and the Office of Research on Women s Health). Published as a supplement to The Journal of Nutrition. Guest editors for this publication were Michael Hambidge, University of Colorado Health Sciences Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair, Nancy Krebs, University of Colorado School of Medicine, Denver. 2 To whom correspondence should be addressed. 3 Abbbreviation used: EFZ, endogenous fecal zinc. of the whole body zinc content remained constant at 30 mg/kg. Changes in the concentration of zinc in the whole body changed only when very low ( 10 mg/kg) or very high ( 100 mg/kg) intakes were consumed. The homeostatic mechanisms were insufficient to maintain body zinc content with these extremes in intake, and there was either a loss or an accumulation of zinc within the body. In humans, the effect of changes in dietary zinc on whole body zinc content cannot be measured directly. Measurements of zinc balance, however, provide a means for estimating changes in whole body zinc content with changes in intake. Typically, human zinc intakes range from 107 to 231 mol/d; this is equivalent to mg/kg for comparison with rat diets. These intakes support crude zinc balance (i.e., replace fecal and urinary losses) in healthy adults, but balance can be achieved when as little as 22 mol/d (2.8 mg/kg) or as much as 306 mol/d (40 mg/kg) is fed (Johnson et al. 1993). With these extreme reductions or increases in zinc intake, zinc losses either fell or increased during the first 6 12 d after the dietary change so that balance was achieved. Thus, humans appear to have the capacity to regulate whole body zinc content over a 10-fold change in intake, as has been observed in experimental animals. Intestinal regulation of zinc homeostasis The gastrointestinal tract is the major site for regulation of zinc homeostasis. The mechanism involves adjustments in both zinc absorption and endogenous excretion into the feces. It is important to remember, however, that zinc absorption and endogenous excretion cannot be measured directly in animals or humans. All determinations are based on models that cannot be validated. Nevertheless, consistent results across studies lend confidence to the validity of the estimates. In detailed metabolic balance studies in rats (Weigand and Kirchgessner 1978), the efficiency of zinc absorption decreased /00 $ American Society for Nutritional Sciences. 1360S

2 ZINC HOMEOSTASIS IN HUMANS 1361S from nearly 100% when a zinc-free diet was fed (group I) to 55% when 7 mol (0.5 mg) of zinc was fed daily (group IV) (Fig. 1). Endogenous fecal zinc (EFZ) 3 excretion varied 30- fold, from 0.1 to 3.0 mol/d, over the same range of intakes. In groups I, II and III, endogenous zinc represented the major portion of the total fecal zinc. From groups II to IV, each doubling of the dietary zinc intake caused a fourfold increase in EFZ. The excretion of endogenous zinc by the gastrointestinal tract is of major importance in maintaining zinc balance just above and below optimal intakes. However, it increases further with high intakes to fine tune the primary adjustment in zinc absorption. Adjustments in urinary zinc excretion were relatively minor in comparison with the gastrointestinal adjustments. Human studies of the gastrointestinal response to change in zinc intake are more limited, but the results available are consistent with the animal data. Using balance data in combination with an indicator dilution tracer model of intestinal secretion, Jackson et al. (1984) determined the changes in intestinal zinc absorption and endogenous excretion in a man consuming 110, 230 or 473 mol zinc/d during three consecutive 8-d periods. With each increase in dietary zinc, endogenous zinc excretion increased promptly (i.e., within the first 4 d of each study period), going from 46 to 68 mol/d from period I to II and to 96 mol/d in period III. Marked changes in zinc absorption also occurred, but this did not occur until the last 4 d of each period (Fig. 2). For example, during the first 4 d of period I, 58% of the zinc intake was absorbed; during the second 4-d period, it dropped to 47%. When zinc intake was doubled during the next 4 d in period II, 45% of the intake was absorbed during the first 4 d. This dropped to 32% in the second 4-d period. Because the changes in endogenous zinc excretion occurred promptly before the adjustment in zinc absorption, it appears that the regulation of gastrointestinal zinc endogenous excretion is independent of the regulation of absorption. Urinary zinc excretion was essentially unchanged during the three dietary treatments. These studies in both animals and humans demonstrate the synergistic action of gastrointestinal zinc absorption and endogenous excretion in establishing zinc homeostasis. Endogenous excretion responds immediately but by only a relatively small amount. The absorption of zinc, on the other hand, responds more slowly but has the capacity to cope with larger FIGURE 1 Changes in zinc losses with widely varying zinc intakes in rats. Adapted from Lee et al. (1993). FIGURE 2 Adjustments in zinc homeostasis with changes in intake in man. Adapted from Jackson et al. (1984). fluctuations in dietary zinc. The specific response of these two physiological adjustments to changes in intake is discussed in greater detail later. Adjustments in fractional zinc absorption Since the methodology for the use of stable zinc isotopic tracers to study zinc metabolism was developed, there have been a number of studies of fractional zinc absorption in humans (Lee et al. 1993, Turnlund et al. 1982, 1986, Wada et al. 1985) (Table 1). All of the studies were performed with healthy adults who consumed diets with adequate amounts of zinc before implementation of the study diet. Four studies compared the response to different levels of zinc intake. When the zinc intake was reduced from 252 to 85 mol/d in a study of six men (Wada et al. 1985), fractional zinc absorption increased from 25 to 49%. In another study, when zinc intake was reduced from 192 to 63 mol/d, fractional absorption increased from 44 to 63% (Lee et al. 1993). A study of a reduction to a very low intake (85 12 mol/d) caused fractional zinc absorption to increase to 93% (Taylor et al. 1991). Doubling the zinc intake from 109 to 224 to 472 mol/d caused fractional absorption to decline from 47 to 32 to 21%; the lower the intake of zinc, the higher the rate of fractional zinc absorption. Because fractional zinc absorption responds so dramatically to large changes in zinc intake, it is a gross indicator of the amount of zinc consumed. However, the fractional absorption of zinc varies sufficiently within a group of individuals fed the same amount of zinc that it becomes impossible to predict zinc intakes from the efficiency of absorption measured at a single time. The increase in the efficiency of zinc absorption with reductions in intake allows more zinc to be absorbed than would have been the case had there been no change in the efficiency of absorption. However, the total amount absorbed is always less than the amount absorbed before the reduction in intake. For example, the increase in fractional zinc absorption from 40 to 93%, when dietary zinc was reduced from 85 to 12 mol/d (Taylor et al. 1991), permitted 11 mol of zinc to be absorbed rather than only 4.5 mol if the fractional absorption had remained at 40%. This adjustment in the efficiency of zinc absorption provided an additional 6.5 mol of zinc to the tissues. When the zinc intake is very low, absorption occurs pri-

3 1362S SUPPLEMENT TABLE 1 Zinc absorption and endogenous losses with different levels of zinc intake in adult men Reference Day of study Diet zinc Total absorbed zinc % absorbed Endog fecal loss Urinary zinc Balance mol/d Wada et al., 1985, n Lee et al., 1993, n Taylor et al., 1991, n Jackson et al., 1984, n Turnlund et al., 1984, N Turnlund et al., marily by a carrier-mediated process (Cousins 1996). Kinetic studies performed in rats show that the increased efficiency in absorption that occurs with reductions in intake is due to an increase in the rate of transfer of zinc on the carrier across the mucosal membrane rather than a change in the affinity of the carrier for zinc. It is not known how this increased transfer of zinc by the carrier occurs. Several investigators have proposed that the exocrine pancreas secretes a ligand that enhances jejunal zinc absorption. When the ligand is unsaturated with zinc, it binds dietary zinc in the lumen of the intestine and somehow facilitates its absorption (Van Wouwe and Uijlenbroek 1994). It is thought that this ligand might be metallothionein (De Lisle et al. 1996, Finley et al. 1994, McClain 1990, Oberlas 1996, Van Wouwe and Uijlenbroek 1994). Adjustments in endogenous fecal zinc excretion Although fractional zinc absorption increases dramatically when zinc intakes are reduced, the shift in EFZ excretion conserves more zinc for tissue use than does the change in zinc absorption. The overall adjustment in EFZ excretion may reflect a reduction in the amount of zinc secreted into the gut as well as an increased reabsorption of the endogenous zinc due to the up-regulation of the carrier-mediated process. For example, when the dietary zinc was reduced from 85 to 12 mol/d (Taylor et al. 1991), EFZ dropped by 16 mol/d. The up-regulation of zinc absorption conserved only 6.5 mol/d. The larger decline in EFZ than that conserved by absorptive changes shows that the change in EFZ is not due to shifts in absorption alone. EFZ excretion is made up of two components of zinc metabolism: the inevitable metabolic, or obligatory, loss and the endogenous loss that is in excess of the obligatory loss and contributes to homeostasis by increasing or decreasing the retention of absorbed zinc (Weigand and Kirchgessner 1980). The obligatory EFZ loss can be estimated from the amount of zinc excreted in the stools when a zinc-free diet is fed; this is 6 8 mol/d (Baer and King 1984). The net effect of the adjustments in gastrointestinal absorption and endogenous excretion with changes in intake is an overall shift in the physiological capacity to provide zinc to the tissues. As dietary zinc declines, the efficiency in zinc utilization increases, allowing the reduced intake of zinc to be absorbed with a higher efficiency. Also, the lower total zinc absorption is associated with a lower endogenous excretion. These two actions result in an overall increased metabolic efficiency (Weigand and Kirchgessner 1980). Gastrointestinal regulation of zinc homeostasis in individuals with chronically low zinc intakes The zinc intake of most populations around the world falls below amounts considered to be adequate or desirable. The limited data available suggest that zinc homeostasis is maintained differently in those populations than occurs among individuals with adequate intakes. Rat studies show that EFZ losses are affected by the whole body zinc status as well as by current zinc intakes (Johnson et al. 1988). Fractional zinc absorption, on the other hand, is only influenced by current zinc intake. This suggests that the adjustment to a high zinc intake by a population in marginal zinc status due to a typical diet that is low in zinc would alter EFZ losses differently than if the high zinc diet were fed to a population in good zinc status. A 6-mo study of low zinc intakes (63 mol/d) in men confirmed the findings in rats, i.e., that EFZ losses are affected more by long-term poor zinc intakes than is fractional zinc absorption (Lee et al. 1993) (Fig. 3). After the men had been on the low zinc diet for 2 mo, fractional zinc absorption increased 48%, from 44 to 65%. Although fractional absorption increased, the total absorbed zinc declined from 85 to 41 mol/d and endogenous fecal losses fell by 27%, from 65 to 48 mol/d. During the 6 mo the men were on the low zinc diet, fractional and total zinc absorptions remained relatively constant, but the endogenous zinc losses continued to decline from 65 mol/d during baseline to 48, 40 and 27 mol/d at 2, 4 and 6 mo, respectively. After 6 mo, this reduction in EFZ losses allowed the men to achieve a positive crude zinc balance on this very low zinc diet. Net crude balance was 4.7 mol/d at 6 mo. It is unlikely, however, that this was sufficient to replace zinc losses in the integument and semen. Data from this study suggest that adjustments in zinc homeostasis with

4 ZINC HOMEOSTASIS IN HUMANS 1363S absorption in a group of Amazonian women consuming low zinc diets support this hypothesis (Jackson et al. 1988). The women consumed only 129 mol zinc/d before and during full lactation; fractional zinc absorption increased from 59 to 84%. The amount of zinc absorbed increased by 30 mol/d, but the EFZ losses remained low to provide additional zinc for milk synthesis. FIGURE 3 Changes in intestinal zinc absorption and endogenous loss over six months while consuming a low zinc intake, 63 mol/d. Adapted from Lee et al. (1993). very low intakes do not occur rapidly; however, changes continue to occur for months, possibly until equilibrium is eventually established. The reduction in EFZ losses associated with the negative zinc balance may reflect a decrease in the size of rapidly turning over endogenous zinc pools. No functional consequences were reported associated with this loss of whole body zinc (Lee et al. 1993). Another study of the homeostatic response to a chronic intake of diets low in zinc was performed in two groups of Chinese women: a group of rural women habitually consuming 5.2 mg zinc/d (80 mol/d) and an urban group consuming 8.1 mg/d (125 mol/d) (Sian et al. 1996). Although the urban women consumed 35% more dietary zinc than the rural women, fractional zinc absorption did not differ between the two groups; the urban and rural women absorbed 34 and 31% of their intakes, respectively. Thus, the absolute amount of zinc absorbed by the urban women was higher than that of the rural women because they consumed more zinc: 42 versus 25 mol/d. This increased amount of zinc absorbed by the urban women (17 mol/d) was nearly balanced by the increased amount of endogenous zinc excreted in the feces: 15 mol/d (i.e., 35 versus 20 mol/d). Thus, the rural women, who were consuming only 80 mol zinc/d, achieved homeostasis and zinc balance by reducing EFZ losses rather than changing the fractional rates of zinc absorption. These two studies of low zinc intakes (Lee et al. 1993, Sian et al. 1996), as well as other studies performed in healthy, young infants (Krebs et al. 1993), show that the EFZ excretion is directly related to the total amount of zinc absorbed after individuals have established a state of equilibrium on the level of intake. If total zinc absorption is low, EFZ losses are also reduced. The quantity of zinc that is absorbed undoubtedly influences the amount of zinc in endogenous tissue pools, which in turn may be associated with the amount of endogenous zinc excreted in the feces. In situations in which the tissue demand for zinc is high, as occurs during lactation, this relationship between true zinc absorption and EFZ losses is likely to change. Fractional zinc absorption increases during lactation (Fung et al. 1997) to provide additional zinc for milk synthesis. Endogenous fecal losses may be unchanged. Data from a study of fractional zinc Renal adjustments with changes in dietary zinc In comparison with the amount of zinc loss through the gastrointestinal tract, renal losses tend to be low, and they also remain constant over a wide range of intakes. Intestinal fecal losses vary by threefold, from 27 to 90 mol/d, on intakes ranging from 63 to 472 mol/d (Table 1); urinary losses range from8to11 mol/d. When zinc intake is very low, i.e., 50 mol/d, urinary losses decline. Johnson et al. (1993) measured the changes in urinary zinc excretion when diets providing 21.9, 37.5, 51.6 and 67.8 mol/d were fed. They found that urinary zinc excretion did not decline until zinc intake was reduced to 51.6 mol/d. The decline in urinary zinc occurs very rapidly, in 2 3 d, after the initiation of a very low zinc intake (unpublished data). The urinary excretion data from a young man fed a diet providing only 4.5 mol/d is shown in Figure 4. This decline in urinary zinc occurs before there are any changes in plasma zinc concentration or in fractional zinc absorption. The regulation of urinary zinc losses is not well understood. Studies in dogs showed that glucagon infusions increased urinary zinc without changing plasma zinc concentrations (Victery et al. 1981); this increase is inhibited by an infusion of insulin (Vander et al. 1983). These hormonal changes in urinary zinc excretion occurred without altering glomerular filtration rates. Also, there was no evidence that other cations were affected by glucagon or insulin infusions. Possibly, the shifts in urinary zinc excretion are mediated by adjustments in renal tubular zinc transport. Cysteine infusion has been shown to increase urinary zinc excretion dramatically by causing a rise in net tubular secretion (Abu-Hamdan et al. 1981). The fall in EFZ conserves much more zinc than the changes in urinary zinc with an acute decrease in zinc intake. A reduction in dietary zinc from 85 to 12 mol/d conserved 16 mol of endogenous fecal losses (Taylor et al. 1991), but only 2 6 mol zinc/d was conserved by adjustments in renal excretion. Although the changes in urinary zinc occur quickly and may be as much as 100-fold, the amount of zinc excreted FIGURE 4 Reduction in urinary zinc excretion in a single adult male fed a diet providing 5 mol/d (unpublished data).

5 1364S SUPPLEMENT FIGURE 5 Comparison of daily changes in fecal and urinary zinc losses with plasma zinc concentrations in an adult male fed 5 mol zinc/d (unpublished data). Bars depict zinc losses; line depicts plasma zinc. in the urine is much less than that excreted in the feces, so less is conserved. Because renal adjustments have a relatively small impact on zinc conservation, it seems logical that adjustments in renal conservation are not induced unless the intakes are extremely low. The rapid changes in endogenous fecal and urinary zinc losses with low zinc diets limit the drop in plasma zinc concentrations (unpublished data) (Fig. 5). When dietary zinc was reduced from 241 to 4 mol/d, fecal and urinary zinc losses dropped 75% by the end of the second week, whereas the plasma zinc concentrations were unchanged. When dietary zinc intake was reduced from 252 to 85 mol/d (Wada et al. 1985), fecal zinc losses declined markedly; there were no changes in plasma zinc concentrations. Plasma zinc concentrations change very slowly, if at all, with changes in zinc intake reducing the value of this measurement for assessing zinc status. Because the plasma must provide zinc to all of the tissues, maintaining relatively constant plasma zinc concentrations is essential to sustaining normal function and health. Other sources of zinc loss Additional zinc is lost daily in integumental losses (i.e., sweat and other surface losses), seminal emissions, menstrual losses and hair and nail growth. Whole body surface losses average 7 mol/d when zinc intake averages 130 mol/d (Milne et al. 1983). When zinc intakes were reduced to 55 mol/d, surface losses declined by 50%. Surface losses also tended to rise with high zinc intakes (518 mol/d). These adjustments in surface losses occurred even though plasma zinc remained within the normal range. It is not known how this adjustment in integumental zinc losses is made with changes in intake. Semen is rich in zinc and can represent a significant source of zinc loss with frequent ejaculations. One ejaculation contains 9 mol zinc. Semen zinc losses decline with zinc depletion; severe zinc depletion caused a 50% decrease in the amount of zinc per ejaculum (Baer and King 1984). This reduction in semen zinc seems to be due to a decrease in semen volume rather than a change in the concentration of zinc in the semen (Hunt and Johnson 1990). Typical hair and nail growth account for only 0.5 mol zinc loss/d (Baer and King 1984). Shifts in tissue zinc concentrations to conserve whole body zinc Zinc, the most abundant intracellular element, is found in all body tissues, with 85% of the whole body zinc in muscle and bone (Table 2). Another 11% is found in the skin and liver. The remaining 2 3% of the whole body zinc is in all of the other tissues (Jackson 1989). When the dietary zinc supply is very low or if a marginal intake is consumed for a long period of time, homeostatic adjustments may not be sufficient to replace zinc losses and a negative zinc balance occurs. With severe zinc deficiency, i.e., 0.06 mol/g diet, the whole body zinc content of experimental animals decreased to 30% of that of control animals (Jackson et al. 1982), but zinc loss was not uniform across all tissues. Hair, skin, heart and skeletal muscle zinc concentrations remained constant, whereas plasma, liver, bone and testes zinc concentrations dropped significantly. After the low zinc diet was fed for 80 d, plasma zinc was 45% lower than that of controls, testes zinc was 53% lower, bone zinc was 64% lower and liver zinc was 19% lower. It is interesting that hair zinc concentrations did not change in this study of experimental animals. Hair zinc has been used as a measure of zinc status in humans (Hambidge 1982). Possibly, hair zinc concentrations change with long-term, marginal intakes but not with severe depletion as was studied in these experimental animals. A set of tissue zinc measurements from three patients in whom zinc metabolism was abnormal provides unique information about the effect of zinc depletion on tissue zinc concentrations in humans (Jackson et al. 1982). In one patient, hair and skeletal muscle samples were collected; in a second patient, skin and plasma samples were collected before death and tissue samples were removed postmortem. In the third patient, an 11-y-old boy with thalassemia treated with a zincchelating agent, liver, bone, testes, hair, heart and quadriceps muscle were removed postmortem and analyzed for zinc. As was observed in experimental rats, hair, skin, skeletal muscle and heart zinc concentrations were unchanged in these patients, but bone, liver, testes and plasma zinc levels were significantly below normal values. Bone zinc was 1.68 mol/g dry weight (normal range, mol/g dry weight). Liver zinc was 1.01 mol/g dry weight (normal range, mol/g dry weight). Testes zinc was 0.49 mol/g dry weight (normal range, mol/g dry weight), and plasma zinc ranged from 4.5 to 11.7 mol/l (normal range, mol/l). Tissue TABLE 2 Distribution of zinc within the body in a normal adult man (70 kg)1 Zn concentrate Percent of total body zinc g/g wet weight % Skeletal muscle Bone Skin 32 6 Liver 58 5 Brain Kidneys Heart Hair Blood plasma Adapted from Jackson 1989.

6 ZINC HOMEOSTASIS IN HUMANS 1365S These data from both experimental animals and humans show that even though the changes in whole body zinc are small with severe depletion, some tissues lose significant amounts of zinc. It is unclear why the bone, liver, testes and plasma give up zinc during deficiencies, whereas the concentration in muscle and skin are maintained. Possibly, the drop in plasma zinc after the initiation of a severely low zinc diet signals certain tissues to increase the release of zinc and other tissues to retain zinc. The bone contains about one third of the whole body zinc. Studies in experimental animals and humans suggest that it is a significant source of endogenous zinc when the dietary supply is low (Jackson et al. 1982). Bone is not a conventional zinc store, however, because there is no way to enhance the release of bone zinc during a deficiency. The decline in bone zinc with depletion may reflect a reduction in bone zinc uptake in response to the decrease in plasma zinc rather than an increased release. Recent research by Zhou et al. (1993) shows that the zinc released from bone comes primarily from a rapidly turning over pool that composes 10 20% of the total bone zinc. The second major pool turns over more slowly and does not release zinc as readily for use elsewhere in the body in times of zinc need. The bone can apparently accumulate zinc in times of excess. In studies of chicks, the administration of a high zinc diet before zinc depletion allowed the bone to accumulate zinc that was released later during zinc depletion. Chicks fed a high zinc diet before depletion survived for longer periods of time without developing any symptoms of zinc deficiency than did chicks fed typical zinc intakes before depletion (Emmert and Baker 1995). Bone seems to function, therefore, as a passive reserve of zinc that is released, but not replaced, when the dietary supply is very low. No specific mechanisms for increasing the rate of bone zinc release have been identified. The rate of loss seems to be governed by normal rates of bone turnover. This is in stark contrast to the situation in the muscle in which zinc deposition is maintained at a rate that maintains a normal concentration. Zinc depletion and plasma kinetics Severe zinc depletion in growing, weanling rats causes a rapid fall in plasma zinc concentrations (Williams and Mills 1970). Plasma zinc concentrations also fall in humans in experimental zinc depletion studies (Baer and King 1984, Johnson et al. 1993, Taylor et al. 1991). Physiological signs of zinc depletion and changes in tissue zinc concentrations are not evident until a drop in plasma zinc concentration occurs. One can argue, therefore, that the fall in plasma zinc concentration may be part of a homeostatic mechanism to maintain critical levels of zinc in those tissues most susceptible to zinc depletion. This second line of defense may only come into play when there is a large drop in dietary zinc, when chronically low zinc intakes have been consumed for a long time or when zinc intakes are marginal in times of increased need, i.e., growth or lactation. Plasma zinc represents 0.1% of whole body zinc. In an adult, the plasma contains 3.5 mg of zinc. Because all of the absorbed zinc passes through the plasma, i.e., mol/d, the flux of zinc out of the plasma must be rapid to maintain a constant concentration. Using an intravenous stable isotopic tracer of zinc, 70 Zn, we measured indices of zinc kinetics in five men before and after 5 6 wk of severe zinc depletion ( 5 mol/d; unpublished data). At baseline, plasma zinc turned over 150 times/d, and 7400 mol of zinc was moved into and out of the tissues daily. This is roughly equivalent to one third of the whole body zinc. However, at the end of depletion when plasma zinc concentrations had declined by two thirds, from 12 to 4 mol/l, the fractional turnover rate increased about one third from 150 to 200 times/d. Plasma zinc mass fell more than the turnover rate increased, however, and the total amount of zinc moved into the tissues declined from 7400 to 4150 mol/d. This reduction in the amount of zinc available to the tissues was associated with the onset of the clinical symptoms of zinc depletion. Use of tissue zinc as a reserve in severe zinc depletion The rapid onset of the clinical symptoms of zinc deficiency with severe depletion indicates that there is no store for zinc like there is for energy or iron. In all growing species that have been studied, a marked reduction in dietary zinc is invariably followed quickly by a reduction in food intake and growth failure (O Dell and Reeves 1989). When weanling rats were force fed a zinc-deficient diet so that they were prevented from reducing their growth rates, the rats rapidly became ill and died. In contrast, rats fed similar diets ad libitum survive for several weeks longer, albeit with signs of zinc deficiency. They survived, however, at the expense of the use of their own tissue zinc. Typically, weanling animals fed zinc-deficient diets develop a cyclic pattern of food intake that is 3 4 d in length (O Dell and Reeves 1989). This cyclic pattern in food intake causes the catabolism of tissues containing zinc, such as muscle, and the release of that endogenous zinc for critical metabolic functions. The prevention of tissue catabolism by force feeding the animals seems to prevent a homeostatic response to an extremely low zinc diet, and survival is impaired. Zinc released from tissues during the catabolic phase is taken up and retained very efficiently by other tissues. This was demonstrated by Giugliano and Millward (1984). They measured the changes in weight and zinc concentrations in various organs after weanling rats had consumed a severely deficient diet for 24 d. During this period, the net gain in total muscle zinc was 25 mol. This was only 5 mol more than the amount of zinc lost from bone during the same period. Apparently, muscle tissue gained weight and maintained its zinc concentration by efficiently incorporating any zinc released by the bone and small amounts obtained from the diet. This avid retention of zinc in selected tissues during severe zinc deficiency contributes to the marked drop in endogenous zinc losses and the overall efficient use of dietary zinc. 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