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Mastering Selenium

Mastering Selenium

Selenium is a naturally occurring metalloid element that is essential to both humans and animal in trace amounts. Of all the elements, selenium has one of the narrowest ranges between dietary deficiency and toxic levels.  Selenium status of populations, animals and crops varies markedly around the world.17

Selenium is a trace element that until 1957 was thought to be only toxic. Gradually, it became clear that selenium plays an important role in normal inflammation and immune response, thyroid and reproductive function, liver reactions, protection against certain types of cancer, and cardiovascular health. It has a role in blood sugar regulation, and a deficiency has been implicated in the susceptibility to depression. Selenium is central to pathways that curb oxidative stress and regulate endocrine physiology, as well as having a critical role in neuronal function and male fertility.1

 
Physiologically, selenium and selenium compounds are not effective by themselves, but must be incorporated into proteins.2 There are over 30 selenoproteins that have been identified, many of which have vital enzymatic functions3 with their main action to reduce oxidative stress.4 Decreased expression of selenoproteins promotes cellular oxidative stress and apoptosis, which inhibits cells differentiation and development.

Selenium is the most important component in the function of one of our body’s master antioxidants, glutathione peroxidase. It is a part of the glutathione cycle. Selenocysteine is present at the catalytic site of glutathione peroxidase and selenium availability regulates glutathione peroxidase enzyme activity. Even a moderate deficiency of selenium can have long term consequences since it may increase the risk of diseases associated with aging.5


Selenium absorption

Selenium in the form of selenoproteins, is absorbed through active amino acid transport mechanisms and is more bioavailable than selenite or selenate.1

Selenium is ingested from food sources and absorbed in the gut. It is then carried to the liver to be metabolized, and transported and distributed to the tissues of the body. Selenium compounds are mostly metabolized to selenocysteine, an amino acid that is incorporated into peptide chains to form selenoproteins which are then secreted into plasma to serve as a source of selenium to other tissues of the body.1

Following ingestion, organic forms of selenium such as selenomethionine and selenocysteine are absorbed in the small intestine.1 Selenium in the form of selenoproteins, is absorbed through active amino acid transport mechanisms and is more bioavailable than selenite or selenate.3

Selenomethionine absorption in the gut occurs through the same active sodium dependent transport system as its sulfur-containing counterpart, methionine. Selenocysteine may also be absorbed similarly to cysteine1and it can compete with these proteins for absorption.3

Selenium is differentially distributed in the body, with some tissues, such as the brain and the testes, acquiring a higher percentage of the total selenium content than others, particularly in times of selenium deficiency. These two organs preferentially sequester selenium as both depend on a steady selenium supply to function.1


Selenium and glutathione peroxidase

Glutathione peroxidase is selenium dependent, and part of an elaborate system that maintains redox balance in the cell. This is essential for the maintenance of cellular homeostasis. Cells maintain homeostasis through the generation and elimination of reactive oxygen/nitrogen species.5

Glutathione peroxidase plays an important role in protecting membrane lipids (cell membranes) from oxidative disintegration. Failure to prevent oxidative breakdown can explain the oxidative damage to haemoglobin and possibly the wide variety of degenerative conditions that occur in selenium deficiency.6


Selenium and inflammatory diseases

Patients with chronic inflammation typically have lower selenium status than those who are healthy. In a recent study, selenium was measured in patients suffering from IBD revealing that levels were significantly lower than in controls. The lower the selenium status the more severe the disease.

Further studies have shown the benefit of selenium in minimizing the risk of inflammatory diseases such as cardiovascular disease and asthma.2

Glutathione peroxidase can dampen inflammatory pathways by inhibiting TNF alpha, an inflammatory cytokine produced during acute inflammation, and TLR4, which when activated leads to NF-κB and inflammatory cytokine production.2


Selenium and blood sugar regulation

High levels of oxidative stress are known to cause insulin resistance. In one study, mice fed on a selenium deficient diet developed hyperinsulinaemia and had decreased insulin sensitivity. This was caused by reduced synthesis of selenoproteins which promoted glucose intolerance and lead to a diabetes-like phenotype.7 Although the full molecular mechanisms are not understood, it is evident that modest selenium deficiency in humans is prospectively associated with dysglycaemia.5


Selenium and reproduction

Selenium’s role in glutathione peroxidase makes it an essential nutrient in reproduction. Due to its functions of protecting against damage from peroxidation and participating in critical lipid peroxide signaling pathways selenium is essential for embryonic development and fertility including an important role in spermatozoa.5


Selenium and the thyroid

It is well known that the thyroid has the highest selenium content of all body tissues. Selenium is incorporated into several selenoproteins which contribute to antioxidative defence and thyroid hormone metabolism.8

One of these is iodothyronine deiodinase 2, a selenoprotein that converts T4 into T3. 5 Selenium deprivation impaires the expression of this selenoprotein.9 An adequate supply of the essential trace element selenium is beneficial for thyroid function and can prevent the negative impact of excessive iodide load.8


Selenium and the liver

Selenium deficiency can cause liver function disorder, resulting in peroxidative damage and oxidative necrosis. Selenium can protect liver cells from oxidative damage and enhance the antiviral activity of liver cells and resistance to alcohol-induced lipid peroxidation and liver cell damage. Selenium can scavenge free radicals, inhibit collagen synthesis and guard against fibrosis of the liver.

A study conducted in China compared the hair selenium levels of patients with non alcoholic steatohepatitis (NASH) with that of healthy subjects. It found that selenium levels were significantly lower in those with NASH. When liver selenium reserves decrease it leads to peroxide scavenging decline, leading to liver cell membrane lipid oxidative damage, and ultimately liver cell necrosis.10

Selenium and depression

Depression has increasingly become recognized as an inflammatory disorder. Selenium inhibits the activation of NF-kappaB by modulating the expression of selenoprotein genes and suppressing C-reactive protein production which helps to reduce inflammation.11

During times of selenium deficiency there is preferential storage of selenium in the brain. It has significant modulatory effects on dopamine, which plays an important role in the pathophysiology of depression and other psychiatric disorders. Selenium supplementation has been linked with improvements in mood and protection against post partum depression.11

The glutathione antioxidant system is implicated in the pathophysiology of mood disorders. Selenium is a crucial cofactor for the enzyme, glutathione peroxidase. There is support for its role from clinical trials involving treatment with N-acetyl cysteine, a precursor of cysteine and glutathione.12


Selenium and cardiovascular health

It is well known from the example of Keshan disease, that the cardiovascular system can be affected by selenium deficiency. In selenium deficiency, lipid peroxides may accumulate in the blood and induce vascular and tissue damage. Many selenoproteins are considered to reduce oxidative stress, prevent oxidative modification of lipids, inhibit platelet aggregation and reduce inflammation.2

Destruction of oxidants by glutathione peroxidase 3 may protect against cardiovascular disease by preserving nitric oxide, which plays an important role in cardiovascular function, and also by preventing the oxidation of fibrinogen, known to promote fibrin thrombus formation.5


Selenium and obesity

Morbidly obese patients display significantly reduced serum selenium concentrations. Significantly reduced selenium status in obesity appears to result from obesity-related oxidative stress. Obesity is moreover associated with a state of chronic inflammation, which also contributes to the pro-oxidant environment of the condition.4


Selenium and immunity

From the moment of birth our bodies are bombarded by pathogens whose sole purpose is to live and replicate in a warm, moist, nutrient rich environment.13 Even marginal selenium deficiency is associated with an impaired immune function. Selenium deficiency negatively affects immune cells during activation, differentiation and proliferation.4

Selenium deficiency not only influences the expression of selenoportines in immune cells, but is also associated with immune response and the development of immune cells. Selenium and selenoproteins pay an important role in immune regulation. Selenium deficiency reduces resistance to infection through modulation of interleukin production and subsequently the Th1/Th2 response.14

One study has suggested that selenium deficiency induced a polarization in the immune response from Th2 to Th1, by reducing the production of IL-10 and increasing the production of IL-12p40. IL-12p40 has the ability to stably induce the differentiation of naive T cells to Th1. This excessive drift to Th1 may induce inflammation and increase the incidence of autoimmune diseases.14


Selenium intake

Important sources of selenium in our diet are whole grain, cereals, wheat, sunflower seeds, Brazil nuts, eggs, organ meats, garlic, mushrooms, and seafood. However, there is much variation in the selenium content of foods. Geographical differences, environmental conditions and agricultural practices have a profound influence on how much selenium is present. Selenium enters the food chain through plants15 and the selenium content of plants varies depending on the selenium content in the soil.2 This is also true of the selenium content of foods of animal origin.15


Determining selenium status

To get an idea of the selenium status of individuals, plasma selenium levels are often used, however the different forms of selenium found in plasma are not functionally equal. Some forms of selenium are not active but still contribute to plasma selenium status.2

Measurement of selenium in serum can be subjective since serum measurements fluctuate due to their sensitivity to daily intake from dietary sources. In a deficient person a single 200 ug dose of selenium can immediately produce a reading of adequate serum levels. In a study on patients with autoimmune thyroiditis with selenium deficiency, serum selenium levels were within normal range. To accurately measure selenium stores, it is important to measure tissue status. 16


InterClinical Comment

Measuring selenium through hair tissue mineral analysis (HTMA) is a reliable and non-invasive test and can quickly establish the tissue content. In clinic it is very important to obtain selenium levels since deficiency or excess can be damaging. HTMA also provides the opportunity to examine toxic elements that may have a detrimental effect on selenium status, since it is one of the key minerals that enable to us to resist oxidative damage. 

REFERENCES

1 Ha, H. Y., Alfulaij, N., Berry, M. J., & Seale, L. A. (2019). From Selenium Absorption to Selenoprotein Degradation. Biological Trace Element Research. doi:10.1007/s12011-019-01771-x 
2 Brigelius-Flohé, R. (2018). Selenium in Human Health and Disease: An Overview. Selenium, 3–26. doi:10.1007/978-3-319-95390-8_1 

3 Davis, T. Z., & Hall, J. O. (2017). Selenium. Reproductive and Developmental Toxicology, 595–605. doi:10.1016/b978-0-12-804239-7.00034-2 
4 Pfister, C., Dawczynski, H., & Schingale, F. J. (2020). Selenium Deficiency in Lymphedema and Lipedema—A Retrospective Cross-Sectional Study from a Specialized Clinic. Nutrients, 12(5), 1211. doi:10.3390/nu12051211
5 McCann, J. C., & Ames, B. N. (2011). Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. The FASEB Journal, 25(6), 1793–1814. doi:10.1096/fj.11-180885 
6 Mills, G. C. (1960). Glutathione peroxidase and the destruction of hydrogen peroxide in animal tissues. Archives of Biochemistry and Biophysics, 86(1), 1–5. doi:10.1016/0003-9861(60)90357-x
7 Labunskyy, V. M., Lee, B. C., Handy, D. E., Loscalzo, J., Hatfield, D. L., & Gladyshev, V. N. (2011). Both Maximal Expression of Selenoproteins and Selenoprotein Deficiency Can Promote Development of Type 2 Diabetes-Like Phenotype in Mice. Antioxidants & Redox Signaling, 14(12), 2327–2336. doi:10.1089/ars.2010.3526 
8 Köhrle, J., & Gärtner, R. (2009). Selenium and thyroid. Best Practice & Research Clinical Endocrinology & Metabolism, 23(6), 815–827. doi:10.1016/j.beem.2009.08.002 
9 Pallud, S., Lennon, A.-M., Ramauge, M., Gavaret, J.-M., Croteau, W., Pierre, M. Germain, D. L. S. (1997). Expression of the Type II Iodothyronine Deiodinase in Cultured Rat Astrocytes Is Selenium-dependent. Journal of Biological Chemistry, 272(29), 18104–18110. doi:10.1074/jbc.272.29.18104 
10 Pan, D., & Huang, H. (2013). Hair Selenium Levels in Hepatic Steatosis Patients. Biological Trace Element Research, 152(3), 305–309. doi:10.1007/s12011-013-9624-9 
11 Pasco, J. A., Jacka, F. N., Williams, L. J., Evans-Cleverdon, M., Brennan, S. L., Kotowicz, M. A., … Berk, M. (2012). Dietary selenium and major depression: a nested case-control study. Complementary Therapies in Medicine, 20(3), 119–123. doi:10.1016/j.ctim.2011.12.008 
12 Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I. Bush, A. I. (2008). N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial. Biological Psychiatry, 64(5), 361–368. doi:10.1016/j.biopsych.2008.03.004 
13 Gombart, A. F., Pierre, A., Maggini, S. (2020). A Review of Micronutrients and the Immune System – Working in Harmony to Reduce the Risk of Infection, Nutrients, (12) 236; doi:10.3390/nu12010236
14 Sun, Z., Xu, Z., Wang, D., Yao, H., & Li, S. (2018). Selenium deficiency inhibits differentiation and immune function and imbalances the Th1/Th2 of dendritic cells. Metallomics, 10(5), 759–767. doi:10.1039/c8mt00039e 
15 Joshi, N., (2019). Selenium. Pharmacognosy & Nutrition. 1st ed. India: Virgin Sahityapeeth, ch 4, pp 38-47
16 Turker, O. (2006). Selenium treatment in autoimmune thyroiditis: 9-month follow-up with variable doses. Journal of Endocrinology, 190(1), 151–156. doi:10.1677/joe.1.06661 
17 Hác, E., Krechniak, J., & Szyszko, M. (2002). Selenium Levels in Human Plasma and Hair in Northern Poland. Biological Trace Element Research, 85(3), 277–285. doi:10.1385/bter:85:3:277 

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