Selenium is a chemical element that bears the element symbol Se. In the periodic table, it has atomic number 34 and is in the 4th period and 6th main group. Thus, selenium belongs to the chalcogens (“ore formers”). In the earth’s crust, selenium occurs in oxidized and mineralized forms in very different concentrations, with high amounts usually found in rocks of volcanic origin. Because of the geographically varying selenium content of soils, the selenium concentration of plant foods is also subject to large regional variations. In large parts of central and northern Europe and many other regions of the world, soils are markedly poor in selenium, which is why in Germany plant sources of selenium contribute only slightly to selenium supply. Heavy metals, such as cadmium, mercury, lead and arsenic, and soil acidification by ammonium sulfate-containing fertilizers or sulfurous acid rain can further reduce the proportion of available selenium compounds in the soil substance and thus the selenium content in plants by forming poorly soluble complexes – selenides. In contrast, selenium concentration in foods of animal origin is sometimes very high and not subject to large fluctuations, which is due to the widespread feeding of selenium-rich mineral mixtures – up to 500 µg selenium/kg body weight/day – in EU countries, especially for pigs and poultry for reasons of better growth, health and reproductive performance (reproductive potential). The selenium concentration of food depends not only on its origin (plant, animal) and geographical origin, but also on its protein content, since selenium in biological material is mostly present in the protein fraction – bound to certain amino acids. Accordingly, selenium-rich foods include, in particular, protein-rich animal products, such as fish, meat, offal, and eggs. Likewise, legumes (pulses), nuts, for example Brazil nuts, seeds, such as sesame, and mushrooms, for example porcini mushrooms, can be a good source of selenium because of their sometimes high protein content. Grains imported from North America are also a good source of selenium due to selenium-rich soils. As an essential trace element, selenium is chemically related to the mineral sulfur. In plants and animals, selenium is incorporated into the amino acid methionine (Met) or cysteine (Cys) instead of sulfur. For this reason, selenium is found in food preferably in organic form as selenium-containing amino acids – in plant foods and selenium-rich yeasts as selenomethionine (SeMet) and in animal foods as selenocysteine (SeCys). As proteinogenic amino acids, SeMet and SeCys are used in the human organism for protein biosynthesis, with SeMet being incorporated into proteins instead of methionine and SeCys as the 21st proteinogenic amino acid. Inorganic selenium compounds, such as sodium selenite (Na2SeO3) and sodium selenate (Na2SeO4), play less of a role in conventional foods of general consumption and more of a role in dietary supplements and medications to which they are added for supplementation (nutritional supplementation) and therapy.
Absorption
Absorption (uptake via the intestine) of selenium occurs predominantly in the upper small intestine–duodenum (duodenum) and proximal jejunum (jejunum), depending on the mode of binding. Dietary selenium is supplied mainly in organic form as selenomethionine and selenocysteine. Since selenomethionine follows the metabolic pathway of methionine, it is actively taken up in the duodenum (small intestine) by a sodium-dependent neutral amino acid transporter into the enterocytes (cells of the small intestinal epithelium). Little is known to date about the molecular mechanism of intestinal absorption (uptake) of selenocysteine. However, there is evidence that selenocysteine is not absorbed like the amino acid cysteine, but follows the active sodium gradient-dependent transport mechanism for basic amino acids such as lysine and arginine.Inorganic selenate (SeO42-) supplied via dietary supplements or drugs uses the same transport pathway as sulfate (SO42-) due to chemical similarities and is thus actively absorbed by a sodium-dependent carrier-mediated mechanism. In contrast, intestinal absorption of inorganic selenite (SeO32-) occurs by passive diffusion. The absorption rate of selenium depends on the type (organic, inorganic), amount, and source (food, beverage, supplement) of selenium compounds supplied and on the interaction (interaction) with food ingredients. Individual selenium status does not influence the absorption rate. In principle, the bioavailability of organic forms of selenium is higher than that of inorganic forms. While selenomethionine and selenocysteine have an absorption rate of 80% to almost 100%, the inorganic selenium compounds selenate and selenite are absorbed only 50-60%. Selenium from plant foods is more bioavailable (85-100%) than from animal foods (~15%). Although fish is exceedingly rich in selenium, only 50% of the trace element is absorbed from tuna, for example. In most cases, however, the absorption rate from fish is < 25%. Overall, a bioavailability of selenium between 60-80 % can be expected from a mixed diet. Compared to the diet, selenium absorption from water is low. Interactions (interactions) with other food components or drugs occur less with the amino acid-bound selenium forms than with the inorganic selenite and selenate. Thus, a high content of sulfur (sulfate, thiosulfate, etc.) and heavy metals, such as molybdenum, cadmium, mercury, lead and arsenic, in the diet, for example, through contamination (pollution) of crops by acid rain, etc., can reduce the bioavailability of selenium, reduce the bioavailability of selenate (SeO42-) by forming insoluble complexes – selenides – or by blocking the transport proteins of the brush border membrane of enterocytes (cells of the small intestinal epithelium). Intestinal absorption of selenite (SeO32-) is promoted by cysteine (sulfur-containing amino acid), glutathione (GSH, antioxidant composed of the three amino acids glutamate, cysteine, and glycine), and physiological (normal for metabolism) amounts of vitamin C (ascorbic acid), and inhibited by high-dose vitamin C administration (≥ 1 g/day) due to a reduction of selenite. Finally, therapeutic agents containing selenite should not be taken together with high-dose ascorbic acid preparations.
Transport and distribution in the body
After absorption, selenium travels to the liver via the portal vein. There, selenium accumulates in proteins to form selenoproteins-P (SeP), which are secreted (secreted) into the bloodstream and transport the trace element to extrahepatic (“outside the liver“) tissues, such as the brain and kidney. SeP contains approximately 60-65% of the selenium found in blood plasma. The total body inventory of selenium in an adult is about 10-15 mg (0.15-0.2 mg/kg body weight). Selenium is found in all tissues and organs, although its distribution is uneven. The highest concentrations are found in the liver, kidneys, heart, pancreas (pancreas), spleen, brain, gonads (gonads) – especially testes (testicles), erythrocytes (red blood cells) and platelets (blood platelets) [6-8, 10, 16, 28, 30, 31]. However, the skeletal muscles have the largest proportion of selenium due to their high weight. There, 40-50% of the body’s selenium stock is stored. A high selenium content of the kidney often results from deposits of insoluble selenides (metal-selenium compounds) as a consequence of increased exposure to heavy metals, such as mercury (amalgam exposure) and cadmium. Intracellularly (inside the cell) and extracellularly (outside the cell), selenium is predominantly present in protein-bound form and hardly ever in free form.While the trace element in the cells, such as erythrocytes, neutrophil granulocytes (white blood cells, as phagocytes (“scavenger cells”) part of the innate immune defense with antimicrobial effect), lymphocytes (white blood cells of the acquired immune defense → B cells, T cells, natural killer cells that recognize foreign substances, such as bacteria and viruses, and remove them by immunological methods) and platelets, functions as an integral component of numerous enzymes and proteins, such as glutathione peroxidases (GSH-Px, antioxidant active → reduction of organic peroxides to water) and selenoproteins-W (SeW, component of muscle and other tissues), it is bound in the extracellular space to plasma proteins, such as selenoprotein-P (primary selenium transporter to target tissues), beta-globulin, and albumin. Selenium concentration in blood plasma is usually lower than in erythrocytes. Isotope distribution studies have shown that in the presence of selenium deficiency, redistribution of selenium pools occurs, so that the incorporation of selenium in some selenoproteins occurs preferentially in certain tissues and organs over others – “hierarchy of selenoproteins” [1, 7-9, 25]. In this process, selenium is rapidly mobilized from liver and muscles in favor of endocrine tissues, reproductive organs (reproductive organs), and central nervous system, for example, to increase the activity of phospholipid hydroperoxide-GSH-Px (PH-GSH-Px, antioxidant active → reduction of peroxides to water) or deiodase (activation and deactivation of thyroid hormones → conversion of prohormone thyroxine (T4) to active triiodothyronine (T3) and T3 and reverse T3 (rT3) to inactive diiodothyronine (T2)) for important body functions. Due to the redistribution of selenium between organs and cell types under marginal supply, some selenoenzymes remain preferentially active while others show a relatively rapid loss of activity. Accordingly, proteins that react late with a decrease in activity in selenium deficiency and can be reactivated more rapidly by selenium substitution (dietary supplementation with selenium) seem to be of higher relevance compared to other selenoproteins in the organism. To determine selenium status, both selenium concentration in blood plasma (normal range: 50-120 µg/l; indicator of short-term changes – acute selenium status) and selenium concentration in erythrocytes (long-term parameter) related to hemoglobin content are used. Since selenium in plasma is predominantly bound to selenoprotein-P, which is a negative acute-phase protein (proteins whose serum concentration decreases during acute inflammation), liver dysfunction, inflammatory reactions, or the release of proinflammatory (inflammation-promoting) cytokines, such as interleukin-1, interleukin-6, or tumor necrosis factor-alpha (TNF-alpha), can interfere with the determination of selenium status in blood plasma. Similarly, malnutrition, hypalbuminemia (decreased concentration of the plasma protein albumin), chronic dialysis (blood purification procedure for chronic renal failure), and blood transfusions (intravenous infusion of red blood cell concentrates), may cause false results in blood selenium status analysis.
Metabolism
Diet-derived selenomethionine, following its absorption, can be nonspecifically metabolized in place of the sulfur-containing amino acid methionine into proteins such as albumin (protein of blood plasma), selenoprotein-P and -W, and hemoglobin (iron-containing, oxygen (O2)-transporting red blood pigment of erythrocytes), especially of skeletal muscle, but also of erythrocytes, liver, pancreas, kidneys, and stomach. The exchange of methionine for SeMet in protein biosynthesis depends on the dietary selenomethionine-to-methionine ratio and does not appear to be homeostatically controlled. During protein and amino acid degradation, selenium is released from SeMet-containing proteins and selenomethionine, respectively, and used for selenocysteine biosynthesis – process of transselenation. Absorbed selenomethionine that has not been incorporated into proteins is directly converted to selenocysteine in the liver by transsulfuration. Orally supplied selenocysteine or selenocysteine formed by SeMet conversion is degraded in the liver by a specific pyridoxal phosphate (PALP, active form of pyridoxine (vitamin B6))-dependent lyase to the amino acid serine and selenide (compound of selenium and H2S).While serine is bound by a SeCys-specific transfer RNA (tRNA, short ribonucleic acid molecule that provides amino acids in protein biosynthesis), selenide undergoes a conversion to selenophosphate, which reacts with serine to form selenocysteine. The resulting SeCys-loaded tRNA makes selenocysteine available for incorporation into the peptide chain of selenium-dependent proteins and enzymes. The possibility of transferring orally ingested SeCys or SeCys resulting from the degradation of SeMet directly to corresponding tRNAs and using them for the synthesis of selenoproteins does not exist in the human organism. Passively absorbed inorganic selenite is – without intermediate storage – directly reduced to selenide in the liver by the action of glutathione reductase (enzyme that reduces glutathione disulfide to two GSH molecules) and NADPH (nicotinamide adenine dinucleotide phosphate). The inorganic selenate that enters the blood by active absorption must first be converted in the liver to the more stable oxidation form selenite before it can be reduced to selenide. Conversion of selenide to selenophosphate and its reaction with tRNA-bound serine results in the formation of selenocysteine, which is incorporated into selenium-dependent proteins and enzymes by means of the tRNA. Selenite and selenate are acutely available as precursors for the synthesis of selenocysteine and are therefore used for supplementation to compensate for acute deficiencies, for example in intensive care medicine or other clinical applications. In contrast, SeMet and SeCys are not directly acutely available due to their degradation and remodeling, respectively, required for SeCys biosynthesis. Accordingly, no acute effects are to be expected from the organic selenium forms, which is why SeMet, for example in yeast, is more suitable for preventive and long-term supplementation. All functionally significant selenium-dependent proteins of the human organism contain selenocysteine – biologically active form of selenium. In contrast, selenomethionine does not perform any known physiological function in the body. SeMet acts only as a metabolically inactive selenium pool (selenium storage), the size of which (2-10 mg) depends on the amount supplied alimentarily (through food) and is not subject to homeostatic regulation. For this reason, SeMet is retained (retained) in the organism longer than selenocysteine and inorganic selenium, as evidenced, for example, by a longer half-life – SeMet: 252 days, selenite: 102 days – and higher selenium concentrations in blood serum and erythrocytes after oral intake of SeMet compared with equal amounts of inorganic forms of selenium.
Excretion
Selenium excretion depends on both individual selenium status and orally supplied amount. Selenium is excreted mainly through the kidney in the urine as trimethylselenium ion (Se(CH3)3+), which is formed from selenide by multiple methylation (transfer of methyl (CH3) groups). In selenium-poor regions of Europe, a renal selenium excretion of 10-30 µg/l can be recorded, while in well-supplied areas, such as the USA, a urinary selenium concentration of 40-80 µg/l can be measured. In breastfeeding women, an additional selenium loss – depending on the orally ingested amount – of 5-20 µg/l can be expected via breast milk. When higher amounts of selenium are ingested, release via the lungs becomes more important, with volatile methyl selenium compounds, such as the garlic-smelling dimethyl selenide (Se(CH3)2) derived from selenide, being released via the breath (“garlic breath”) – an early sign of intoxication (poisoning). In contrast to other trace elements, such as iron, copper, and zinc, whose homeostasis is controlled mainly by intestinal absorption, the homeostatic regulation of selenium occurs mainly through renal (affecting the kidney) excretion, and in the case of selenium excess, additionally through respiration. Thus, in the case of insufficient selenium supply, renal excretion (excretion) is reduced and, in the case of increased selenium supply, elimination via the urine or respiration is increased.
