Zinc is a chemical element bearing the element symbol Zn. Along with iron, copper, manganese, etc., zinc belongs to the group of transition metals, in which it occupies a special position due to properties similar to alkaline earth metals, such as calcium and magnesium (→ relatively stable electron configuration). In the periodic table, zinc has the atomic number 30 and is in the 4th period and – according to the outdated counting – in the 2nd subgroup (zinc group) – analogous to the alkaline earth metals as the 2nd main group. According to the current IUPAC (International Union of Pure and Applied Chemistry) nomenclature, zinc is in group 12 with cadmium and mercury. Because of its electron configuration, zinc easily forms coordinative bonds in plant and animal organisms, preferentially with amino acids and proteins, respectively, in which it is primarily present as a divalent cation (Zn2+). For this reason, unlike iron or copper, zinc is not directly involved in redox reactions (reduction/oxidation reactions). Similar physicochemical properties, such as isoelectricity, coordination number, and sp3 configuration, are the reason why antagonistic (opposite) interactions occur between zinc and copper. In the mammalian organism, zinc is one of the quantitatively important trace elements, along with iron. Its almost all-encompassing participation in the most diverse biological reactions makes zinc one of the most important trace elements. Its essentiality (vitality) for biological processes was proven over 100 years ago with the help of studies on plants. The zinc content of foodstuffs, which usually varies between 1 and 100 mg per kg fresh weight or edible portion, varies greatly depending on growth and production conditions. Foods of animal origin, such as lean red muscle meat, poultry, offal, crustaceans and shellfish, such as oysters and crabs, some types of fish, such as herring and haddock, eggs, and dairy products, such as hard cheeses, are good sources of zinc due to the preferential binding of the trace element to proteins. Protein-rich foods of plant origin, such as whole grains, legumes, nuts and seeds, also have high zinc levels. However, if protein components are removed from raw plant products, such as cereals, by milling or peeling during food production, the zinc content is usually also reduced. For example, white flour products have low zinc concentrations [2, 5, 6-9, 12, 18, 19, 23]. The contribution of a food to zinc supply is determined less by the absolute zinc content than by the ratio of absorption-inhibiting to -promoting food constituents. The factors that inhibit or promote zinc absorption are discussed below.
Resorption
Absorption (uptake via the intestine) of zinc occurs throughout the small intestine, predominantly in the duodenum (duodenum) and jejunum (jejunum), by both an active and passive mechanism. At low luminal (in the intestinal tract) concentrations, zinc is taken up into enterocytes (cells of the small intestinal epithelium) in the form of Zn2+ by means of the divalent metal transporter-1 (DMT-1), which transports divalent transition metals together with protons (H+), or peptide-bound, presumably as a glycine-glycine-histidine-zinc complex, by means of zinc-specific carriers, so-called Zip proteins. This process is energy-dependent and saturates at high intraluminal zinc concentrations. The saturation kinetics of the active transport mechanism causes zinc to be additionally absorbed (taken up) paracellularly (mass transfer through intercellular spaces) by passive diffusion at high doses, but this is of no consequence in normal diets. In enterocytes, zinc is bound to specific proteins, of which two have been identified so far – metallothionein (MT, heavy metal-binding cytosolic protein high in the sulfur (S)-containing amino acid cysteine (circa 30 mol%), which can bind 7 mol of zinc per mol) and the cysteine-rich intestinal (affecting the dram) protein (CRIP). Both proteins are responsible for zinc transport through the cytosol (liquid components of the cell) to the basolateral membrane (facing away from the intestine) on the one hand, and for intracellular (inside the cell) zinc storage on the other.The expression of MT and CRIP in enterocytes correlates (is interrelated) with the zinc content of the diet. While the synthesis of MT is induced (triggered) by an increased zinc intake, the expression of CRIP, which has a pronounced zinc binding affinity (binding strength), occurs predominantly at low alimentary (dietary) zinc supply. By storing excess zinc in the form of zinc thionein and releasing it to the blood only when needed, metallothionein acts as an intracellular zinc pool or buffer to control the concentration of free Zn2+. MT is considered the most important sensor for the regulation of zinc homeostasis. The transport of Zn2+ across the basolateral membrane of enterocytes into the bloodstream is mediated by specific transport systems, for example, by zinc transporter-1 (ZnT-1). In breast milk, specific low-molecular-weight zinc-binding ligands or proteins could be discovered, which, due to their good digestibility and their specific absorption process, increase intestinal zinc uptake in the newborn even before other absorption mechanisms are formed. In contrast, zinc in cow’s milk is bound to casein, a mixture of several proteins, some of which are difficult to digest. Accordingly, zinc from women’s milk exhibits significantly higher bioavailability than from cow’s milk. The absorption rate of zinc is on average between 15-40% and depends on the preceding state of supply – nutritional status – or physiological requirement and on the presence of certain dietary components. Increased zinc requirement, for example during growth, pregnancy and deficiency state, leads to increased absorption from food (30-100%) as a result of increased expression of DMT-1, Zip proteins and CRIP in enterocytes. In contrast, when the body is well supplied with zinc, the absorption rate from food is low because, on the one hand, the active transport mechanism – DMT-1, Zip proteins – is downregulated (downregulated) and, on the other hand, the trace element is increasingly bound by MT and remains as zinc thionein in the mucosa cells (mucosal cells of the small intestine). Intestinal absorption of zinc is promoted by the following dietary components:
- Low-molecular-weight ligands that bind zinc and are absorbed as a complex.
- Vitamin C (ascorbic acid), citrate (citric acid), and picolinic acid (pyridine-2-carboxylic acid, intermediate in the metabolism of the amino acid tryptophan) promote zinc absorption at physiological concentrations, whereas this is inhibited when high doses are ingested
- Amino acids, such as cysteine, methionine, glutamine and histidine, for example, from meat and cereals, whose zinc content has a high bioavailability.
- Proteins from foods of animal origin, such as meat, eggs and cheese, are easily digestible and are characterized by high bioavailability of the zinc portion of their amino acid complexes
- Natural or synthetic chelators (compounds that can fix free divalent or polyvalent cations in stable, ring-shaped complexes), such as citrate (citric acid) from fruits and EDTA (ethylenediaminetetraacetic acid), which is used, among other things, as a preservative and drug, for example, in metal poisoning, stimulate zinc absorption in physiological amounts by binding the zinc from other complexes, while this is inhibited when high doses are ingested
The following dietary ingredients inhibit zinc absorption at higher doses [1-3, 5, 8, 12, 14-16, 18, 19, 22, 23, 25]:
- Minerals, such as calcium – intake of high amounts of calcium, for example, through supplements (dietary supplements).
- Calcium forms insoluble zinc-calcium phytate complexes with zinc and phytic acid (myo-inositol hexaphosphate from cereals and legumes), which decrease intestinal zinc absorption and increase enteric zinc losses
- Divalent calcium (Ca2+) competes with Zn2+ at the apical (intestine-facing) enterocyte membrane for DMT-1 binding sites and displaces zinc from this transport mechanism
- Trace elements, such as iron and copper – supply of high doses of iron (II) and copper (II) preparations, respectively.
- Trivalent iron (Fe3+) has a less inhibitory effect than bivalent iron (Fe2+), which impairs zinc absorption already at a ratio Fe: Zn of 2: 1 to 3: 1
- Inhibition of Zn2+ uptake into enterocytes (cells of the small intestinal epithelium) by Fe2+ and Cu2+, respectively, occurs by displacement from DMT-1
- Hemiron (Fe2+ bound in a porphyrin molecule as a component of proteins, such as hemoglobin) has no effect on zinc absorption
- In iron deficiency, zinc absorption is increased
- Heavy metals, such as cadmium
- Cadmium-rich foods include flaxseed, liver, mushrooms, mollusks and other shellfish, as well as cocoa powder and dried seaweed
- Artificial fertilizers sometimes contain high levels of cadmium, which leads to the enrichment of agricultural land and thus almost all foods with the heavy metal
- Cadmium inhibits zinc absorption in high concentrations on the one hand by forming poorly soluble complexes, especially tetravalent cadmium, on the other hand by displacement from DMT-1, if cadmium is present in divalent form (Cd2+)
- Dietary fiber, such as hemicellulose and lignin from wheat bran, complex zinc and thus deprive the trace element of intestinal absorption.
- Phytic acid (hexaphosphoric ester of myo-inositol with complexing properties) from cereals and legumes – formation of insoluble zinc-calcium phytate complexes, reducing both intestinal absorption of zinc from food and reabsorption of endogenous zinc
- Mustard oil glycosides and glucosinolates, respectively (sulfur (S)- and nitrogen (N)-containing chemical compounds formed from amino acids), which are found in vegetables such as radish, mustard, cress, and cabbage, tend to form complexes in high concentrations
- Tannins (vegetable tannins), for example, from green and black tea and wine, are able to bind zinc and reduce its bioavailability
- Chelators, such as EDTA (ethylenediaminetetraacetic acid, six-dentate complexing agent that forms particularly stable chelate complexes with free divalent or polyvalent cations).
- Chronic alcoholism, laxative abuse (abuse of laxatives) – alcohol and laxatives stimulate intestinal transit, whereby orally supplied zinc can not be sufficiently absorbed by the intestinal mucosa (intestinal mucosa) and is predominantly excreted in the stool
The absence of absorption-inhibiting substances, such as phytic acid, and the binding of zinc to easily digestible proteins or amino acids, such as cysteine, methionine, glutamine and histidine, are the reason that zinc is more bioavailable from foods of animal origin, such as meat, eggs, fish and seafood, than from foods of plant origin, such as cereal products and legumes [1, 2, 6-8, 16, 18, 23]. In strict vegetarians who consume predominantly cereals and legumes and whose diets thus have a high phytate-to-zinc ratio (> 15: 1), intestinal zinc absorption is decreased, which may increase their zinc requirements by up to 50%. However, some studies have shown that when phytate-rich foods are consumed over a longer period of time, the intestinal absorption capacity of the organism adapts to the more difficult conditions, so that sufficient absorption of zinc can be ensured. In contrast to adults, children are not yet able to adapt intestinal absorption to specific conditions, so vegetarian-fed children are more sensitive to insufficient zinc intake. The increased zinc requirement during growth further increases the risk of zinc deficiency in young vegetarians. The bioavailability of zinc from phytate-rich foods can be increased by activation or addition of the enzyme phytase. Phytase occurs naturally in plants, including the germ and bran of cereal grains, and in microorganisms and leads to hydrolysis after activation by physical effects, such as grain milling and swelling, or as a component of microorganisms, such as lactic acid bacteria and yeasts, which serve the process of fermentation (microbial degradation of organic substances for the purpose of preservation, dough loosening, improvement of taste, digestibility, etc.). ), to hydrolytic cleavage (degradation by reaction with water) of phytic acid in food. Consequently, zinc from acidified wholemeal bread has a higher bioavailability than from unacidified wholemeal bread.Zinc absorption from phytate-rich foods can also be increased by a high proportion of animal proteins in the diet, such as by eating wholemeal bread and cottage cheese together. The amino acids released during intestinal protein digestion bind zinc and thus prevent the formation of non-absorbable zinc-phytate complexes. In addition to the listed dietary components, luminal conditions such as pH and digestive intensity, liver, pancreas (pancreas) and kidney function, parasitic diseases, infections, surgical procedures, stress, and hormones such as series-2 prostaglandins (tissue hormones derived from arachidonic acid (omega-6 fatty acid)) can also affect intestinal zinc absorption. While prostaglandin-E2 (PGE2) promotes zinc transport through the intestinal wall into the bloodstream, prostaglandin-F2 (PGF2) leads to the reduction of zinc absorption.
Transport and distribution in the body
With an average concentration of about 20-30 mg/kg body weight, corresponding to a total adult body content of about 1.5-2.5 g, zinc represents the second most abundant essential trace element in the human organism after iron [3, 6-8, 19, 23]. In tissues and organs, most of the zinc (95-98%) is present intracellularly (within cells). Only a small proportion of body zinc is found in the extracellular space (outside the cells). Both intracellular and extracellular zinc are predominantly bound to proteins. Tissues and organs with the highest concentration of zinc include iris (aperture of the eye colored by pigments that regulates the incidence of light) and retina (retina) of the eye, testes (testicles), prostate, islets of Langerhans of the pancreas (collections of cells in the pancreas, that both register blood glucose levels and produce and secrete/secrete insulin), bone, liver, kidney, hair, skin and nails, and urinary bladder and myocardium (heart muscle). In terms of quantity, muscle (60%, ~ 1,500 mg) and bone (20-30%, ~ 500-800 mg) contain the largest amount of zinc. In the cells of the aforementioned tissues and organs, zinc is an integral component and/or cofactor of numerous enzymes, especially from the group of oxidoreductases (enzymes that catalyze oxidation and reduction reactions) and hydrolases (enzymes that cleave compounds hydrolytically (by reaction with water)). In addition, intracellular zinc is partially bound to metallothionein, whose synthesis is induced by elevated zinc concentrations. MT stores excess zinc and keeps it available for intracellular functions. Induction of MT expression also occurs by hormones, such as glucocorticoids (steroid hormones from the adrenal cortex), glucagon (peptide hormone responsible for increasing blood glucose levels), and epinephrine (stress hormone and neurotransmitter from the adrenal medulla), which plays a role especially in disease and stress and leads to zinc redistribution in the organism. For example, in insulin-dependent diabetes mellitus, a redistribution of zinc can be observed, with zinc levels in plasma and erythrocytes and leukocytes increasing in correlation with the extent of hyperglycemia (elevated blood glucose levels). Only about 0.8% (~20 mg) of the total body inventory of zinc is localized in the blood (61-114 µmol/l), of which 12-22% is in the plasma and 78-88% in the cellular blood components – erythrocytes (red blood cells), leukocytes (white blood cells), platelets. In plasma, more than half of the zinc (~ 67%) is loosely bound to albumin (globular protein) and approximately one-third is tightly bound to alpha-2-macroglobulin, such as caeruloplasmin. In addition, binding to transferrin (beta-globulin, which is mainly responsible for iron transport), gamma-globulins, such as immunoglobulin A and G (antibodies), and amino acids, such as cysteine and histidine, could be observed. Plasma zinc concentrations are 11-17 µmol/l (70-110 µg/dl) and are influenced by gender, age, circadian rhythm (internal body rhythm), food intake, protein status, hormone status, stress, and the regulatory mechanisms of absorption (uptake) and excretion (elimination), among other factors [1-3, 12, 18, 19, 23].While acute phase reactions (acute inflammatory responses to tissue damage as a non-specific immune response of the body), physical exertion, stress, infections, chronic diseases, hypalbuminemia (decreased albumin concentration in blood plasma), oral contraceptives (birth control pills), and pregnancy lead to increased uptake of zinc into the tissues and thus decrease serum zinc concentration, corticosteroids (steroid hormones from the adrenal cortex), cytokines (proteins that regulate cell growth and differentiation), such as interleukin-1 and interleukin-6, food intake, and venous congestion during blood sampling result in an increase in serum zinc concentration. There is little response of serum zinc levels to marginal (borderline) intake or malnutrition and catabolism (breakdown metabolism), because it is kept constant by release of zinc from muscle and/or bone tissue. Thus, even in a state of deficiency, the zinc serum concentration can still be within the normal range, which is why the zinc serum level is only of very limited use for determining zinc status. In adults, the zinc concentration per blood cell in leukocytes exceeds that of platelets and erythrocytes by a factor of about 25. In relation to the content in whole blood, erythrocytes contain 80-84%, platelets about 4% and leukocytes about 3% of zinc. In erythrocytes, zinc is found predominantly (80-88%) at carbonic anhydrase (zinc-dependent enzyme that catalyzes the conversion of carbon dioxide and water to hydrogen carbonate and vice versa: CO2 + H2O ↔ HCO3- + H+) and approximately 5% bound to Cu/Zn superoxide dismutase (copper- and zinc-dependent antioxidant enzyme that converts superoxide anions to hydrogen peroxide: 2O2- + 2H+ → H2O2 + O2). In leukocytes, the trace element is mainly in a bond with alkaline phosphatase (zinc-dependent enzyme that removes phosphate groups from various molecules, such as proteins, by hydrolytic cleavage of phosphoric acid esters and works most effectively at an alkaline pH). In addition to the enzymes listed, zinc present in blood cells is bound to metallothionein, depending on the zinc status of the cell. By far the most zinc-rich secretion in the body is sperm, whose zinc concentration exceeds that of blood plasma by a factor of 100. In contrast to the trace element iron, the organism does not have large zinc reserves. The metabolically active or rapidly exchangeable zinc pool is relatively small and amounts to 2.4-2.8 mmol (157-183 mg). It is represented mainly by the zinc of the blood plasma, liver, pancreas, kidney and spleen, which can release the trace element relatively quickly after rapid absorption. Organs and tissues, such as bone, muscle, and erythrocytes (red blood cells), on the other hand, absorb zinc slowly and retain it for a long time, with the administration of vitamin D increasing retention. The small size of the metabolically active zinc pool is the reason why marginal intake can quickly lead to deficiency symptoms if adaptation (adjustment) to intake is disturbed. For this reason, continuous dietary intake of zinc is essential. A number of transmembrane transport carriers are involved in the distribution and regulation of zinc at the intercellular and intracellular levels. While DMT-1 transports Zn2+ into cells, specific zinc transporters (ZnT-1 to ZnT-4) are responsible for transporting Zn2+ both into and out of cells, with ZnT-1 and ZnT-2 acting only as exporters. Expression of DMT-1 and ZnT occurs in many different organs and tissues. For example, ZnT-1 is expressed primarily in the small intestine and ZnT-3 is expressed only in the brain and testes. The latter transport system leads to vesicular accumulation of zinc, suggesting involvement in spermatogenesis. Where and to what extent DMT-1 and ZnT-1 to ZnT-4, respectively, are synthesized is influenced, among other things, by hormonal factors as well as by the individual nutritional and health status – independent of the metallothionein concentration …For example, acute inflammatory reactions, infections, and stress, respectively, corticosteroids (steroid hormones from the adrenal cortex) and cytokines (proteins that regulate the growth and differentiation of cells) induce increased intracellular expression of transmembrane transport carriers and thus increased uptake of Zn2+ into tissue cells and release of Zn2+ into the bloodstream, respectively.
Excretion
Zinc is excreted primarily (~90%) through the intestine in the feces. This includes both unabsorbed zinc from food and zinc from exfoliated enterocytes (cells of the small intestinal epithelium). In addition, there is zinc contained in pancreatic (pancreas), biliary (bile), and intestinal (bowel) secretions, which release the trace element into the intestinal lumen. To a small extent (≤ 10%), zinc is excreted via the kidneys in the urine. Other losses occur via skin, hair, sweat, semen, and menstrual cycle. Similar to the trace element copper, homeostasis (maintaining a constant internal environment) of zinc is primarily regulated by enteric excretion (excretion via the intestine) in addition to intestinal absorption. As oral intake increases, fecal excretion of zinc also increases (<0.1 to several mg/d) and vice versa. In contrast, the level of renal zinc excretion (150-800 µg/d) remains unaffected by zinc supply – provided there is no marked zinc deficiency. Under various conditions, such as starvation and postoperative (after surgical procedures), as well as in diseases, such as nephrotic syndrome (disease of the renal corpuscles), diabetes mellitus, chronic alcohol consumption, alcoholic cirrhosis (end-stage chronic liver disease), and porphyria (hereditary metabolic disease characterized by a disturbance in the biosynthesis of the red blood pigment heme), renal zinc excretion may be increased. The overall turnover of zinc is relatively slow. The biological half-life of zinc is 250-500 days, probably due to zinc of the skin, bone, and skeletal muscle.
