Zinc is an essential nutrient that functions in growth, reproduction, tissue repair, and cellular immunity. Zinc recommendations of 5 mg/day for breast-fed infants are met from mobilization of liver stores and the approximately 2 mg of Zinc obtained each day in breast milk. Formula-fed infants have greater needs due to lesser bioavailability of Zinc from formula. Although high amounts of dietary iron have been shown to reduce Zinc absorption, the iron in fortified formulas does not appear to have a significant negative impact on Zinc status (National Research Council, 1989
Zinc can reduce the level of copper in the body, impair immune responses and decrease the level of protective high-density lipoproteins in the blood, often called the ‘good’ cholesterol. Folic acid can react badly with anticonvulsant medications and mask signs of a B12 deficiency. Iron supplements can be deadly to small children. In fact, the most common cause of poisoning deaths among children is not caustic cleaning agents or aspirin, but iron supplements intended for adult use”
Recent research implicated a number of CNS structures and neurotransmitter processes in the development and expression of individual differences in temperament. For example, some studies found a link between the expression of positive emotionality and the action of limbic system structures such as the amygdala, whereas studies of negative emotionality highlighted the role of the hippocampus. Researchers related individual differences in irritability to the hypothalamus and hypothalamic projections to other regions of the limbic system ( Rothbart et al., 1994).
In studies of neurotransmitter metabolism, serotonin was linked to variability in both negative emotionality and inhibition, dopamine was linked to variability in approach, monoamine oxidase (MAO) was linked to inhibition, and norepinephrin was linked to variability in self-regulation.
Role of Zinc
Zinc is essential for healthy growth and sexual maturation. Although there have been no controlled studies on the Zinc requirements of adolescents, growth retardation and hypogonadism in adolescent males with Zinc deficiency have been reported in developing countries. Body Zinc levels appear to decline during puberty, which may reflect either an increased need for Zinc during growth or a redistribution of plasma Zinc due to hormonal changes. Recommended levels for adolescents are the same as for adults.
The role of Zinc in protein synthesis and cell development makes it essential for fetal growth. A recent study revealed that pregnant women with low blood Zinc levels had a higher incidence of low-birthweight infants. The fetal need for Zinc is approximately 100 mg, with the daily accumulation increasing from about 0.1 mg per day during the first trimester to 0.7 g during the third trimester. The RDA for Zinc has been set at 15 mg per day; usual intakes among American women appear to be 8.8 to 14.4 mg per day. Although the typical dietary intake may be below the RDA, Zinc supplementation during pregnancy has not been recommended (Institute of Medicine, 1990).
Zinc deprivation in adolescence is a particularly interesting topic because of a series of studies conducted. A syndrome of severe growth retardation (“nutritional dwarfism”), lack of sexual development, and absence of epiphyseal closure was described in young Iranian and Egyptian men 19–20 years of age. This syndrome was reversed by a diet containing Zinc supplements, whereas an otherwise adequate diet lacking the supplement was not effective.
Zinc is an important essential trace element that is associated with protein in the diet. It is an active constituent of over 200 enzymes and also has a major structural role (“Zinc fingers”) in proteins. Although the exact etiology of the Mideast adolescent syndrome could not be established, the response to Zinc emphasized the potential importance of this essential trace element in adolescent development.
The influence of Zinc deprivation in the development and behavior of rhesus monkeys has been studied (Golub, Gershwin, & Hendrickx, 1995). These studies focused on periods of most rapid growth: late gestation (Golub, Gershwin, Hurley, Baly, & Hendrickx, 1984), early infancy (Golub, Gershwin, Hurley, Saito, & Hendrickx, 1984), and, more recently, adolescence. Two levels of Zinc deprivation have been used.
Marginal Zinc deprivation (4 micrograms of Zinc per gram of diet) does not influence growth or health of adult monkeys except during late gestation when a significant decline in plasma Zinc concentration occurs along with some changes in hematological and clinical chemistry and immune function measures. Offspring show a small amount of growth retardation at birth and a transient period of growth retardation after weaning. Moderate Zinc deprivation (2 micrograms of Zinc per gram of diet) leads to clear signs of Zinc deficiency in late pregnant dams and a more serious set of consequences in their infants
Beef is rich in Zinc. The National Cattlemen’s Beef Association states that the Zinc in meat, liver, eggs, and seafoods (especially oysters) more is available to the body than that in whole-grain products. Beef in the diet also improves the absorption of Zinc from other foods. Moreover, a study commissioned by the National Cattlemen’s Beef Association found that people who eat higher amounts of beef are more likely to meet 100% of the daily value for protein, iron, Zinc, and B vitamins than people who eat lower amounts of beef or no beef.
The USDA Grand Forks Human Nutrition Research Center in North Dakota compared the Zinc content in the diets of healthy young women who followed a lacto-ovo-vegetarian diet to women of a similar age who ate meat. “The lactoovovegetarian diet was associated with a 21% reduction in absorptive efficiency that, together with a 14% reduction in dietary Zinc, reduced the amount of Zinc absorbed by 35% (2.4 compared with 3.7 mg/d) and reduced plasma Zinc by 5% within the normal range. Zinc balance was maintained with both diets.” The researchers concluded that “although there is a greater risk of Zinc deficiency in persons consuming lactoovovegetarian compared with omnivorous diets, with inclusion of whole grains and legumes Zinc requirements can be met and Zinc balanced maintained”.
If dairy products have been eliminated, calcium and vitamin D should be taken in supplemental form. Parents should also be certain that their children consume adequate amounts of vitamin B12 and Zinc. The consequences of a B12 deficiency have already been noted. As for Zinc, inadequate amounts may cause “delays in cognitive development.” Further, “poor appetite and slowing of growth are the most evident clinical signs of Zinc deficiency in children, particularly during infancy and adolescence”.
Studies have been performed using oral tracer administration to define the absorption pathways and using intravenous administration to define the distribution and endogenous excretion pathways. Short-term studies (hours to days) have been used to examine the pools of Zinc that exchange rapidly with serum Zinc, whereas longer-term studies (weeks to months) have been used in addition to study the tissue pools that turnover more slowly. These studies have shown that there are multiple pools of Zinc that turnover within minutes to years. The faster pools are located in plasma, liver and red blood cells, and the slower pools are located in muscle and bone.
Zinc kinetics have been determined in healthy subjects consuming either normal or relatively high amounts of Zinc. By comparing the changes in the kinetics attributable to Zinc intake, it was found that processes at five sites, including absorption and excretion, are regulated to maintain tissue levels during high Zinc intake. By comparing kinetic data in healthy adults age 20–84 y, it was shown that although a few values changed while subjects consumed their normal dietary intake of Zinc, there were significant changes with age at four sites of Zinc regulation when the subjects consumed supplemental Zinc. The results may indicate either a reduced need for Zinc or a reduced ability to regulate the amount of Zinc retained with aging.
Rates of Zinc absorption and retention have been ascertained in preterm infants. Because the infants were growing during the study, it was necessary to model both tracer and tracee (total Zinc). In addition, it was necessary to model clinical interventions, such as blood transfusions, because the administration of adult blood cells provided a significant source of Zinc to the infants. The results from a population of infants who were healthy and growing at expected rates can be used to evaluate Zinc metabolism and requirements in infants who are sick or growing slowly.
Dunn and Cousins (Dunn 1991 , Dunn and Cousins 1989 ) studied the effect of metallothionein induction on Zinc kinetics in vivo in rats. They found that induction caused increased redistribution of Zinc among body tissues; there was a fourfold increase in Zinc uptake by liver metallothionein and a 85% decrease in release of Zinc from hepatic metallothionein. The kinetics provided an understanding of the mechanisms involved in Zinc redistribution between tissues and between pools within liver after metallothionein induction.
Kinetic studies in animals will provide information on the overexpression of and deletion of genes coding for specific proteins involved in Zinc transport and metabolism. By comparing kinetics in wild types with those in mutants, the role of specific proteins can be determined in vivo. Studies are in progress to describe the role of metallothionein on Zinc kinetics in knockout mice.
Zinc is widely distributed among both plants and animals. Galtsoff found it in many marine invertebrates. It has also been reported for the silkworm and for vertebrates generally. Gettler and Bastian 9 describe a simple method of detecting Zinc in tissues and they find rather high amounts (50 mg. per kilo) in human liver and kidney. Keilin and Mann showed that Zinc is a constituent of the important enzyme carbonic anhydrase and Smirnov finds that the Zinc content of the red blood cells of various vertebrates runs parallel to their carbonic anhydrase content. Zinc is also present in blood plasma.
The retina, iris, and choroid of vertebrate eyes and especially the eyes of fish are rich in Zinc and this is also to be correlated with a high carbonic anhydrase content of these tissues. In view of the fact that the insulin molecule is thought to contain Zinc, it is not surprising that the pancreas should be rich in this element.
Manganese is also an important element. It is essential for the growth of rats and chickens, and also for the growth of various types of plants. Webb found manganese generally present in invertebrates; according to Vinogradoff, ants have an especially high content. Human blood contains only a small amount of it. In almost all plant and animal tissues, it is possible to detect cobalt and nickel by means of extremely delicate tests. The quantities found range from 0.002 to 2 mg. per kilo. All types of animals that have been tested contain molybdenum; tunicates are especially rich in it. 16 Marston (loc. cit.) believes that molybdenum is probably always present in living matter.
Some metallic elements are of rather sporadic occurrence. Small amounts of arsenic and of silicon have been found in various tissues of man and higher animals. Ohlmeyer and Olpp
found quite appreciable amounts of silicon in the blood, lung and pancreas of the calf. It had previously been found in connective tissue, hair and feathers. Some plants seem to have a definite need for silicon. Webb found tin in the starfish, the sea urchin, and in a gastropod mollusk. There is a literature on the presence of vanadium in the blood cells of ascidians. 18 The element is also present in other tissues of ascidians but not in detectible amounts in rat tissues.
Vanadium occurs in a wide variety of plants. Traces of uranium have been found in the fungi Aspergillus niger and Ustilago carbo; also in human kidney, brain, thyroid and blood. The rare element gallium is apparently essential for Aspergillus. Many human organs contain mercury in small amounts. In some parts of the world gold is found in the soil and is taken up by plants. Deer eating such plants accumulate gold in their horns, hoofs and hair.
There is a large body of evidence to show that metallic elements present in traces have a profound effect on the life of various types of plants. The subject is of great practical importance. It is discussed briefly in Chapter 15; see also Stiles’ book on Trace Elements in Plants and Animals.
According to Gavino et al (2007) when the small intestine is impaired, also caecum and colon can participate in zinc uptake. ZnT1, the first mammalian zinc transporter discovered, is expressed at the basolateral membrane of villus enterocytes of the small intestine, where it probably participates in zinc transfer to the circulation. ZnT1 is probably also involved in cadmium transport. ZnT2 is localized to vesicles (late endosomes) at the apical surface of enterocytes ; its putative function is to sequester zinc ions into vesicles and to down-regulate zinc absorption. ZnT4, whose mutation is responsible for the lethal milk mouse disorder in mice, is localized to enterocytes of the small intestine.
ZTL1, a zinc transporter which belongs to the cation diffusion facilitator family, is localized to the enterocyte apical membrane and putatively plays a role in the absorption of dietary zinc across the enterocyte membrane. The divalent cation transporter 1 (DTC-1), also called Nramp2, is a zinc transporter which also shows iron transport capabilities. DTC-1 is located at the basolateral membrane of enterocytes. It has been suggested that a zinc–protein, cystein-rich intestinal protein (CRIP), which plays an important role in the regulation of the gut-associated lymphoid tissue, also may facilitate zinc transport across the enterocyte and its transfer across the basolateral membrane into the blood.
CRIP could also compete with metallothionein, inhibiting zinc absorption. While in physiological conditions the jejunum and ileum play a key role in zinc absorption, during zinc deficiency the colon and caecum can participate in zinc absorption ZnT4 and ZnT2 are the major Zn transporters subtypes expressed in the colon, which is considered a very sensitive organ for Zn homeostasis
Albumin is the principal zinc carrier in plasma. Zinc may also form complexes with cysteine or histidine. Zinc concentration in plasma is about 15 mol/l, 84% of which is bound to albumin, 15% is tightly bound to an alpha-2-macroglobulin and 1% to amino acids. Albumin is also involved in zinc transport across the endothelial membrane, with a mechanism of vesicular cotransport. Vesicular sequestration of zinc is facilitated by ZnT2.
Since a great portion of plasma zinc is bound to alpha-2-macroglobulin, this protein has been suggested to be a plasmatic carrier of the metal. Recently, however, it has been shown that the macroglobulin fraction does not function in zinc transport and distribution. It has been suggested that transferring may also play a role as a carrier of zinc ions in plasma. Zinc plasma levels have been proved to be modulated by different hormones: growth hormone (GH) increases zinc plasma level, whereas prolactin decreases it. Zinc might also be transported into erythrocytes as a zinc–histidine complex.
Zinc movement in the cell is tightly regulated and intracellular free zinc is very limited. Trafficking of zinc in the hepatocyte is complex and involves several transport proteins. Two mechanisms have been suggested for Zn uptake in cultured liver cells: a high affinity saturable pathway and a low affinity linear pathway. Within the hepatocytes, within the enterocytes as well as within other cells, zinc is mainly stored bound to metalloproteins, which include metalloenzymes, gene regulatory molecules, storage proteins and zinc carriers.
Within the hepatocytes zinc is mainly bound to metallothioneins. These are ubiquitous proteins characterized by low molecular weight and high cysteine content. Human MTs are encoded by a multigene family located on chromosome 16 ; they are a family of at least 17 closely related gene products. EachMTcontains 60–68 amino acids, 20 of which are cysteines, and binds seven zinc atoms. MTs bind to zinc, cadmium and copper.
The advances that have been made in our understanding of the role of Zinc in metabolism have been aided by the development of techniques for the accurate determination of isotopes in biological materials. New developments will allow more detailed kinetics to be described in at least three ways. First, increased levels of stable isotope detection will allow smaller doses to be administered, reducing the risk of the dose perturbing the system and reducing cost.
Second, methods are being developed to measure isotope enrichment in various Zinc-binding species (e.g., metalloproteins and metalloenzymes) within blood and other tissues. Measurement of the kinetics of Zinc bound to different species may provide insight into the forms of Zinc that are the most active physiologically. Third, multielement studies will be possible in which the kinetics of several elements will be determined simultaneously on the same subject. This will allow interactions to be studied more extensively and sites, as well as the degree of interaction, to be determined.
Abnormal Zinc metabolism occurs in a number of disorders, and kinetic studies can be used to identify the site or sites with altered Zinc metabolism. This information can be used to determine the mechanisms by which Zinc metabolism is involved in the disease as a basis for suggesting therapeutic approaches. By comparing kinetics in healthy subjects versus that in patients, the sites of abnormal Zinc metabolism in diabetes, Crohn’s disease, sickle cell anemia and many other disorders could be identified.
For example, patients with adrenal corticosteroid insufficiency have increased serum Zinc and decreased urine Zinc levels, and kinetic studies showed that Zinc uptake by erythrocytes and liver was low in these patients. Rates of Zinc uptake were restored by steroid treatment, and the increase in uptake is considered to occur through metallothionein induction in these tissues.
To understand the roles of Zinc in metabolism, kinetic studies are needed in both healthy and disease states. For example, Zinc kinetics in healthy preterm infants could be used to assess whether Zinc metabolism is perturbed in infants who are growing at suboptimal rates and, if so, at which sites. By knowing whether Zinc absorption, endogenous excretion or uptake by tissues is perturbed, rather than whether serum levels are altered, it may be possible to more fully understand the role of Zinc in human health and to devise therapeutic strategies and dietary recommendations.
We have reviewed kinetic studies only at the whole body level here. Many in vitro studies have addressed tissue and cellular uptake and the metabolism of Zinc. Models will be increasingly used to integrate information from the cellular to the whole body level. They will be refined to account for changes in metabolism in different physiological and clinical conditions. Most current models are based on kinetic studies in the steady state, but they will be increasingly used to understand the dynamics of Zinc metabolism, when Zinc levels change such as after a meal, during dietary perturbations or during growth.
Models can be used to represent the current understanding of a system, to identify gaps in knowledge and in experimental design to ensure that necessary and sufficient data are collected to determine parameters of interest. In the future, models will play a greater role in the design of studies as well as in the interpretation of data.
With respect to nutrition, kinetic studies can be used to determine the sites where Zinc interacts with other nutrients, including trace elements, vitamins and macrominerals; to determine the degree of interaction; and to predict how these interactions may alter Zinc requirements. With respect to physiology, kinetic studies could address how rates of Zinc metabolism and pool sizes change under different physiological and clinical conditions, such as during growth or pregnancy. By comparing kinetics in healthy and various disease states, the roles of Zinc in disease may be elucidated through the identification of differences in metabolic processes.
From an environmental perspective, it is important to know how Zinc interacts with nonessential metals, and this information can be obtained from kinetic studies. Finally, a powerful use of kinetics will be to study and define the role of gene products in vivo by comparing kinetics in the wild type versus conditions in which the genes are overexpressed or missing. In conclusion, although tissue levels provide a snapshot of the Zinc status, kinetic studies allow the exploration of mechanisms, such as the pathways of metabolism, rates of movement and sites of homeostasis, that vary with conditions such as diet, genetics and disease.
According to Gavino et al (2007) the main excretory route for zinc in humans is gastrointestinal secretion, which is calculated as 2.5–5.5 mg/day. It occurs via apoptosis of epithelial cells lining the intestinal mucosa or via salivary glands, pancreatic, biliary and intestinal cell secretion. Liver plays a pivotal role in the homeostasis of zinc, by extracting the trace metal from plasma, storing it, metabolizing zinc ions and inserting them in various proteins, and redistributing zinc in various forms into bile or back to the bloodstream.
Bidirectional transport across the sinusoidal pole of hepatocytes allows the liver to control plasma zinc concentration and, therefore, zinc availability to peripheral tissues. Zinc transport at the biliary pole of hepatocytes into bile canaliculi appears to be mainly unidirectional, and is considered the major excretory pathway for excess zinc in the human body.
Fecal loss may range from less than 1 mg/day with a zinc-poor diet, up to 5 mg/day with a zinc-rich diet. Renal zinc secretion, which accounts for about 0.3–0.7 mg/day, is considered of lower relevance. Zinc loss from the body is also attributed to epithelial cell desquamation, sweat, semen, hair and to the menstrual cycle reduction. Due to its antioxidant capabilities, zinc may inhibit lipid peroxidation, which can result in the loss of membrane fluidity, receptor alignment and cell necrosis. It may also minimize the toxic effects of free radicals and of reactive oxygen species, producing SOD enzymes and reduced glutathione (GSH), which are pivotal in antioxidant defence in humans.
The liver contains high concentrations of Cu/Zn SOD, present in the cytosol, in the hepatocytic nucleus and in peroxisomes, where it catalyses superoxide anions to oxygen and hydrogen peroxide. Multiple zinc enzymes contribute through GSH synthesis or the GSH redox cycle to regenerate GSH from its oxidized form GSSG. Catalase and GSHPx utilize GSH as a sacrificial reducing agent to reduce hydrogen peroxide and alkyl hydroperoxides into water and alcohol, respectively.
Reduced glutathione (GSH2), synthesized in hepatocytes, is considered the main intracellular defence against damage from free radicals, reactive oxygen species and xenobiotics. The role of GSH in protecting liver cells against xenobiotics has been demonstrated, in clinical practice, by the observation of fulminant hepatitis in patients assuming high doses of paracetamol, an antipyretic drug. Paracetamol is metabolized, in the hepatocytes, by the drug
Asc Gavino et al (2007) concludes Zinc research may be considered still at an early stage of its evolution. There is a need for accelerate its progress, which could be relevant in human health and disease and, in particular, to better understand the pathogenesis and progression of liver and gastrointestinal disease. The correlation of zinc status in liver and gut in patients affected by chronic hepatitis or inflammatory bowel disease respectively could help to better analyze the role played by pro-inflammatory factors and by anti-inflammatory components in the evolution of these diseases.
An in deep study of the tissue expression of zinc carriers in the epithelial cells covering the various sections of the intestinal tract, both in physiology and in disease, will allow us to improve our knowledge of the molecular basis of the disarrangement in zinc metabolism in human disease. Consequently, there may be promising possibilities for in the introduction of zinc in the treatment of acute and/or chronic gastrointestinal disorders. The study of zinc carrier expression in the liver of subjects affected by acute or chronic hepatitis could lead to the introduction of zinc, as a powerful antioxidant, even in the therapy of liver disease.
The ability of zinc to halt hepatic fibrosis and to favour regression of liver fibrosis, well accepted in patients affected by Wilson’s disease, could be the basis of its introduction in clinical practice with beneficial effects in cirrhosis of different aetiology.
Gavino et al (2007) Department of Pathology, K.U. Leuven, Leuven, Belgium.
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