Mechanism of Action
General: Selenium is a metallic substance that is available in a variety of chemical compounds. Often selenium is attached to an organic molecule as in selenocysteine, selenomethionine, and kappa-selenocarrageenan. In broccoli, garlic, onions, and other selenium-accumulating plants it is found as Se-methylselenocysteine or selenocystathionine. In dietary supplements selenium is commonly provided as selenomethionine or in a selenite or selenate salt form. Often selenium is given as selenized yeast, which is common brewer’s yeast that has been grown in selenium-rich media. After ingestion as a selenate salt, selenite salt, or as one of the organic forms, selenium must be reduced or metabolized to form hydrogen selenide, an important intermediary form. Selenide is essential for the activity of selenoproteins, such as the glutathione peroxidase enzyme (GSH-Px). The primary organic forms of selenium are the amino acid-based selenocysteine and selenomethionine. Selenomethionine is incorporated directly into proteins, because RNA does not differentiate it from methionine. Selenomethionine serves as a storage form, releasing selenium as the proteins containing it are catabolized.
Antiaging effects: In vitro and in vivo research show that zinc is important for immune efficiency (both innate and adaptive), metabolic homeostasis (energy utilization and hormone turnover), and antioxidant activity (SOD enzyme). Selenium provokes zinc release by metallothioneins (MT), via reduction of glutathione peroxidase. Selenium in combination with other antioxidant micronutrients (lycopene, lutein, beta-carotene, alpha-tocopherol) has been shown to increase skin density and thickness in humans; however, the mechanism of action for this effect is unclear.
Anti-inflammatory effects: Both n vitro and in vivo experiments have shown that inhibition of the complement-neutrophil-reactive oxygen (ROS) activation feedback (CNAF) mechanism with sodium selenite and vitamin E could decrease reduced reactive oxygen (ROS) production and complement activation. This mechanism may modulate the inflammatory response in a variety of diseases, including vasculitis of the skin, lung, and liver.
Antineoplastic effects: Dietary selenium may be associated with lower rates of some forms of cancer. Selenocysteine is an essential component of thioredoxin reductase, the flavoenzyme that is responsible for the reduction of thioredoxin, a protein highly expressed in some human tumors. Selenium added to the culture medium increases thioredoxin reductase activity, due to an increase in thioredoxin reductase protein, but mostly due to an increase in the specific activity of the enzyme. Recent studies in a variety of model systems have increased the understanding of the anticarcinogenic mechanisms of selenium compounds. These include effects on gene expression, DNA damage and repair, signaling pathways, regulation of cell cycle and apoptosis, metastasis, and angiogenesis. These effects would appear to be related to the production of reactive oxygen species produced by the redox cycling, modification of protein-thiols, and methionine mimicry. Selenium may stimulate autophagy vacuolization, which may be either protumorigenic or antitumorigenic. Three principal selenium metabolites appear to execute these effects: hydrogen selenide, methylselenol, and selenomethionine.
Possible mechanisms of chemopreventive activity of selenium include a restoration of immune response. The results from studies in mice inoculated with SQCC cells expressing the receptor for interleukin-2 (IL-2) and supplemented with Se (2.00ppm) indicated that Se significantly retards the clinical appearance of tumors.
The group of genes significantly altered by selenium administration for potential chemopreventive effects includes cyclin D1, cdk5, cdk4, cdk2, cdc25A, and GADD 153. Selenium induces apoptosis by producing superoxide that activates p53.
Selenium may have effects on DNA methylation, resulting in chemoprotective effects,
Most potent chemopreventive effects have been attributed to compounds in which the Se moiety is methylated. These compounds are able to induce phase 2 enzymes, which are involved in the cellular defense system that is regulated by the Nrf2 transcription factor. Selenoproteins best studied in cancer development are members of the glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) family. In various cancer cells and tissues, GPx2, and/or TrxR1 are upregulated. Interestingly, both enzymes are targets of Nrf2. An enhanced expression of these enzymes may represent a mechanism to counteract carcinogenic pathways. They may, however, also provide a selective advantage for pre-existing tumor cells in guaranteeing survival and continuous proliferation.
In human research, selenium supplementation increased thrombocyte glutathione peroxidase (GPX) in women only, whereas no effects on phase 1 genes in leukocytes (GPX1), NAD(P)H:quinone oxidoreductase (NQO1), or aryl hydrocarbon receptor repressor (AhRR) gene expression were found. Furthermore, a significant downregulation of the expression of some phase 2 genes (GCLC, Fra1) was observed following Se supplementation, which may increase the risk of cancer.
Antioxidant effects: Selenium serves as a cofactor for glutathione peroxidase, an enzyme of the antioxidant defense system. Glutathione peroxidases (EC 1.11.1.9 and EC 1.11.1.12) catalyze the reduction of H(2)O(2) or organic hydroperoxides to water or corresponding alcohols using reduced glutathione. Selenium-containing glutathione peroxidase has been shown to catalyze peroxynitrite reduction, which may play a role in decreasing the incidence of disease, but its role in vivo is still a matter of debate.
Redox-protective peroxidases in the thyroid are peroxiredoxins, glutathione peroxidases, and catalase. Glutathione peroxidases are selenoenzymes, whereas selenium-independent peroxiredoxins are functionally linked to the selenoenzymes of the thioredoxin reductase family through their thioredoxin cofactors. Thus, selenium directly and indirectly affects protective enzymes in the thyroid, a link that has been supported by animal experiments and clinical observations.
Studies have shown that selenium supplementation for four weeks (150 mcg daily) did not have an effect on body antioxidative status (plasma alpha-tocopherol, retinol, uric acid, and whole blood glutathione). Selenium, when taken in combination with zinc, vitamin A, beta-carotene, vitamin E, and L-cysteine, did not show any pro-oxidant activity, although selenium may play an important role in the balance of antioxidant-pro-oxidant levels of cells.
The kidney accumulates the highest level of selenium (Se) in the organism and is the major source of plasma glutathione peroxidase (GSH-Px). Decreased blood Se levels and GSH-Px activity are common in chronic renal failure (CRF) patients. Erythropoietin (EPO) therapy with Se supplementation, but not EPO alone, has been shown to increase whole blood and plasma Se in hemodialysis (HD) patients, and to raise red cell GSH-Px activity, but not plasma GSH-Px activity, plasma superoxide dismutase, and plasma and red cell TBARS.
In human research, Se supplementation induced a 32% increase in blood glutathione (GSH) levels, which coincided with a 26% decrease in protein-bound GSH (bGSH) and a 44% decrease in bGSH:GSH ratios. These changes in GSH and bGSH were highly correlated with changes in plasma selenium concentrations and may reflect a decrease in oxidative stress.
Selenium, in combination with vitamin C, vitamin E, and beta-carotene, significantly diminishes oxidative damage to lipids when it is high initially and is effective in decreasing chromosomal instability in lymphocytes of middle-aged men. There was a significant decrease of malondialdehyde concentration in nonsmokers, while in smokers, the decrease of malondialdehyde concentration was not significant. Antioxidant supplementation did not affect the proportion of lymphocytes with micronuclei or the total number of micronuclei; however, there was a significant positive correlation between the malondialdehyde concentration at the beginning of the supplementation trial and the difference in the number of cells with micronuclei before and after the supplementation. Antioxidant supplementation (selenium, in combination with alpha-lipoic acid, coenzyme Q10, manganese, vitamin C, N-acetyl cysteine, and 400 IU of alpha-tocopherol) did not protect against exercise-induced DNA damage.
In studies in humans, selenium has been shown to inhibit oxidative stress during a second exposure to ultraviolet light .
Animal studies have shown that endotoxin injection results in lipid peroxide formation and membrane injury, causing decreased levels of free radical scavengers or quenchers, and that intracellular selenium levels may participate in the oxidative stress during endotoxemia.
Cardiovascular effects: Selenium is a central determinant of antioxidative glutathione peroxidase 1 (GPx-1) expression and activity. Sodium selenite and Se-methyl-selenocysteine hydrochloride increased GPx-1 protein and activity in coronary artery endothelial cells. Sodium selenite supplementation has been shown to increase glutathione peroxidase 1 (GPx-1) activity in endothelial cells and in coronary artery disease (CAD) patients. In type 2 diabetic patients, activation of NF-kappaB measured in peripheral blood monocytes can be reduced by selenium supplementation, confirming its importance in the prevention of cardiovascular diseases. In studies in animals, a supplement containing taurine, coenzyme Q10, carnitine, thiamine, creatine, vitamin E, vitamin C, and selenium given to cardiomyopathic hamsters during the late stages of the disease markedly improved myocyte sarcomeric structure, developed pressure, +dp/dt, and -dp/dt.
Keshan disease is a cardiomyopathy restricted to the endemic areas of China and seen in residents having an extremely low selenium (Se) status. Prophylactic administration of sodium selenite has been shown to decrease significantly the incidence of acute and subacute cases. In human research, both forms of Se (selenite and organic Se-yeast) were equally effective in raising GSHPx activity, although Se-yeast provided a longer-lasting body pool of Se.
Fertility effects: In human research, dietary selenium supplementation resulted in changes in selenium concentrations in seminal plasma, but not in sperm; furthermore, serum androgen concentrations were unchanged. Serum triiodothyronine decreased and thyroid-stimulating hormone increased in the high-selenium group, suggesting that altered thyroid hormone metabolism may have affected sperm motility.
Hematological effects: In human research, although a diet rich in fish increased bleeding time and reduced serum triglyceride levels, selenium had no such effects. In children with thalassemic disease, selenium levels in red blood cells (RBC) appeared normal; however, GSH-Px activity was increased, and after vitamin E supplementation, these levels decreased. The authors noted that vitamin E and selenium have related functions in the prevention of RBC oxidation.
Hormonal effects: Higher levels of estrogens in females are protective against aging, by upregulating the expression of antioxidant, longevity-related genes, such as that of selenium-dependent glutathione peroxidase (GPx). Selenium is often combined with other macronutrients, and in one study, supplementation of a combination of vitamin E, selenium, vitamin C, and coenzyme-Q10 did not affect serum levels of PSA or hormone levels in patients with hormonally untreated carcinoma of the prostate.
Immune system effects: As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes, and other immune mechanisms. Selenomethionine supplementation has been shown to produce transient and acute changes in lymphocyte, granulocyte, and platelet phospholipid-hydroperoxide glutathione peroxidase (GPx4) activity, possibly affecting the normal function of the cell.
Selenium may improve T lymphocyte responsiveness and thereby enhance primary immunity. Selenium may exert modulatory effects on keratinocyte-derived inflammatory cytokines. In human research, selenium supplementation has been shown to increase cytotoxic lymphocyte-mediated tumor cytotoxicity and natural killer cell activity. The authors speculated that these increased activities may have been related to the ability of selenium to enhance the expression of receptors for the growth regulatory lymphokine interleukin-2, and consequently, the rate of cell proliferation and differentiation into cytotoxic cells.
Correlations between plasma selenium concentrations and the numbers of CD4 lymphocytes have been observed in healthy elderly subjects. Also, selenium supplementation can increase proliferative responses to pokeweed mitogens in elderly subjects . An in vitro study has shown that selenium supplementation can influence both cellular and humoral immunity as measured by decreases in EG1 and EG2 epitopes on intracellular eosinophil cationic protein and eosinophil peroxidase, increases in relative numbers of CD3 HLADR+ T lymphocytes, decreases in responses of T lymphocytes to mitogenes PHA and ConcA in a lymphocyte blastogenesis test, decreases in activation of complement via complementary pathways (CP50) and alternate pathway (AP50), and finally, increases in IgG and IgA and decreases in IgE.
Selenium supplementation in corticoid-dependent asthmatics has been shown to affect the expression of adhesion molecules that are crucial in the inflammatory process, including decreases in adhesion molecules on peripheral blood mononuclear cells (PBMCs) (CD11a, CD11b, and CD62L), and decreases in those on cultured human umbilical vein endothelial cells (HUVEC) (VCAM-1, and P- and E-selectins).
Nutritional support effects: In humans with low selenium intake, selenium supplementation significantly altered the retention of radiolabeled Se in the plasma, but not in the erythrocytes or platelets. Supplementation resulted in relatively more isotope being retained in a medium molecular mass protein considered to be albumin, and relatively less in another fraction considered to be selenoprotein P. The authors suggest that supplemental Se was not being used to replete critical pools of Se, and this may have been due to an adaptation to low Se intake.
In patients with end-stage renal disease on hemodialysis, selenium supplementation has been shown to maintain selenium concentrations within normal range and, in fact, could increase plasma selenium levels. Supplementation with a preparation containing selenium and vitamins with antioxidant properties (Protecton Zellaktiv from Smith Kline Naturarznei-Germany) has been shown to increase glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) activities .
Physical endurance effects: The link between selenium supplementation and endurance training adaptations at the mitochondrial level appear to be contradictory. One study has shown that selenium supplementation failed to show any effects on endurance training adaptations, as indicated by a lack of effect on total oxygen uptake during a running test, mitochondrial activity of succinate dehydrogenase (SDH) and cytochrome c oxidase (Cyt Ox), and myosin heavy-chain (MHC) expression in muscle fibers. However, another study suggests that selenium supplementation may dampen mitochondria changes during both chronic and acute exercise, although the mechanism behind this action in unclear.
Platelet aggregation effects: In human research, selenium supplementation increased platelet GSH-Px activity; however, no effects were observed on platelet aggregation.
Protection against toxicity: Zinc and selenium have been shown to exert protective effects against mercury toxicity, most likely mediated by induction of the metal-binding proteins metallothionein and selenoprotein P. Selenium also alters carcinogen metabolism, resulting in the production of inactive compounds.
Skin effects: Selenium supplementation increased C-reactive protein (CRP) and soluble tumor necrosis factor-alpha receptor type 1 (sTNF-R1) in patients with psoriasis receiving narrow-band ultraviolet B therapy and selenomethionine supplementation. The authors concluded that supplementation with selenomethionine is inefficacious as adjuvant therapy in patients with psoriasis.
Thyroid effects: Thyroid function depends on the essential trace mineral selenium, which is at the active center of the iodothyronine deiodinase enzymes that catalyze the conversion of the prohormone thyroxine (T(4)) to the active form of thyroid hormone, triiodothyronine (T(3)). However, no evidence of any effect of selenium supplementation on thyroid hormone function (T(4)-to-T(3) conversion) was observed in elderly volunteers or in healthy men.
Vascular effects: In animal research, selenoprotein P binds to endothelial cells in the rat, and plasma levels of the protein correlate with prevention of diquat-induced lipid peroxidation and hepatic endothelial cell injury.
PharmacokineticsAbsorption: Diet is the major source of selenium, and approximately 80% of dietary Se is absorbed, depending on the type of food consumed. Selenium compounds in yeast are available for absorption and further metabolism . L-selenomethionine has been shown to be absorbed more efficiently than parselenium. One pharmacokinetic study suggests that selenomethionine is rapidly absorbed. Volunteers taking one dose of selenomethionine 200 mcg showed increased serum selenium levels at 2 hours, peak serum selenium levels at 4 hours, and abundant amounts of selenium in the serum 24-hours post consumption.
Bioavailability: Selenium bioavailability varies according to the Se source and nutritional status of the subject, being significantly higher for organic forms of Se. Different forms of organic selenium elicit widely different responses when administered to a relatively selenium-replete population, and the explanation for this must be sought at the metabolic level. Se-yeast is capable of increasing the activity of the selenoenzymes, and its bioavailability has been found to be higher than that of inorganic Se sources. Seleno-methionine (SeMet) is a naturally occurring toxic amino acid, but at the same time represents the major nutritional source of selenium for higher animals and humans and had nearly twice the bioavailability of selenium as selenite. The ability of selenomethionine (SeMet) to be incorporated into the body proteins in place of methionine furthermore provides a means of reversible Se storage in organs and tissues. This property is not shared by any other naturally occurring selenoamino acids and thus could be associated with a specific physiological function of SeMet.
Distribution: The kidney accumulates the highest level of selenium (Se) in the organism and is the major source of plasma glutathione peroxidase (GSH-Px). It has been proposed that dietary bioactive compounds, such as selenium, must pass down the gastrointestinal tract, cross the intestinal barrier, reach the blood circulation, and then be distributed to the different tissues of the body, including the skin, which allows for selenium to be metabolized and presented to the entire tissue, potentially in an active form.
These observations and those of gel filtration studies of erythrocytes and plasma proteins reported elsewhere are consistent with the incorporation of Se from selenomethionine into a general tissue protein pool while selenate is directly available for GSHPx synthesis, and explain the poorer correlation between Se and GSHPx in individuals with higher Se status. However, selenate raised platelet GSHPx activities to a greater extent than did selenomethionine suggesting some other effect of selenate on platelets that needs further investigation. A response of GSHPx activity in New Zealand subjects indicates that their dietary Se intake is insufficient to meet recommended intakes based on the criterion of saturation of GSHPx activity, and could reflect a marginal Se status. The level of blood Se necessary for saturation of GSHPx of about 100ng of Se/mL of whole blood confirms observations in earlier studies.
Metabolism: The metabolism of selenium by the brain differs from other organs in that at times of deficiency, the brain retains selenium to a greater extent.
Excretion: Plasma and urinary Se have been shown to be the most sensitive indices to Se exposure. In human research, Se in plasma has been shown to increase steadily, whereas urinary Se reached a plateau between 30 and 60 days following exposure. By contrast, erythrocyte Se only changed after 45 days. Enzyme in plasma and erythrocytes did not respond, whereas platelet GSH Px did. The plateau of activity that was observed after 15 days for plasma Se in the range 1.40-1.50mcM/L could mean that the Se status is insufficient for an optimal function of GSH Px, and implies that dietary intake in Belgium (less than 50-60 mcg of Se daily) is not adequate. Organic Se forms (Se-yeast, selenomethionine, and food Se) increased blood Se more concentration rapidly and to a greater extent than inorganic forms (selenite and selenate). However, no significant difference in the response of both plasma and erythrocyte GSH-Px activity could be observed.
In human research, supplementation with high-selenium yeast, the form used in most supplements (300 mcg daily, 3.8mcM daily) for 48 weeks more than doubled urinary selenium excretion, from 69 to 160 mcg daily (876 to 2,032nM daily). Urinary excretion was correlated with recent selenium intake. After 48 weeks of supplementation, plasma selenium was increased 60%, from 142 to 228 mcg/L (1.8 to 2.9mcM/L) and erythrocyte selenium was approximately doubled, from 261 to 524 mcg/L (3.3 to 6.6mcM/L). Selenium concentrations increased more modestly in hair (56%) and platelets (42%). Platelets were the only blood component in which glutathione peroxidase activity was significantly related to selenium content. Selenium levels decreased rapidly after the end of supplementation, and there were no significant differences in selenium status indicators between groups by week 96. The absorption, distribution, and excretion of selenium from high-Se yeast were similar to selenium in foods.
Urinary selenium excretion has been shown to be greater after selenomethionine than after selenite, with excretion after yeast being intermediate and not significantly different from either of the other two. Selenoprotein P turns over rapidly in rat plasma, with the consequence that approximately 25% of the amount of whole-body selenium passes through it each day. In human research, following supplementation with Se-rich bread (providing 100, 200, and 300 mcg of Se daily) for six weeks, about 50% of the Se intake was excreted in the urine by week 6, compared with 67% before the intervention started.
Clinical research shows that taking selenium 200 mcg daily in combination with levothyroxine significantly reduces thyroid peroxidase antibodies by about 6% to 30% more than placebo in adult patients with thyroiditis after 3-12 months of treatment. Selenium also seems to improve measures of quality of life such as feelings of well-being and mood.
References
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