Selenium is a trace element that is the essential cofactor of the glutathione peroxidase (GPx) family of antioxidant enzymes — the enzymes that are the primary defence against hydrogen peroxide (H2O2) and organic hydroperoxides in virtually every cell in the body. Selenium is incorporated into the GPx enzymes as the amino acid selenocysteine (the 21st genetically encoded amino acid, which is encoded by the codon UGA in a context-specific manner that allows the ribosome to distinguish between a stop codon and a selenocysteine insertion signal). There are at least 25 selenoproteins in the human body, including the GPx enzymes (GPx1-4 and GPx6), the thioredoxin reductases (TrxR1-3), the iodothyronine deiodinases (D1, D2, D3), and the selenoprotein P (SelP), all of which require selenium for their activity and all of which are functionally impaired when selenium status is marginal or deficient. Selenium deficiency is therefore associated with a broad range of clinical manifestations — including the Keshan disease (a cardiomyopathy that is endemic to the selenium-deficient regions of China), the Kashin-Beck disease (an osteoarthropathy that is also endemic to selenium-deficient regions of China), impaired thyroid function, and reduced immune function.
Glutathione Peroxidase and Oxidative Stress
The glutathione peroxidase (GPx) enzymes are the primary defence against the hydrogen peroxide and the organic hydroperoxides that are generated as byproducts of normal cellular metabolism and as products of the inflammatory response. GPx1 is the most abundant GPx isoform — it is expressed in virtually every cell in the body and is particularly concentrated in the erythrocytes, the liver, and the kidney, where it is the primary defence against the H2O2 that is generated by the electron transport chain and by the oxidases of the cellular metabolism. When GPx1 activity is adequate, the H2O2 that is generated by cellular metabolism is rapidly reduced to water before it can accumulate to levels that would damage the cell. When GPx1 activity is low (as in selenium deficiency), H2O2 accumulates, the Fenton reaction generates the hydroxyl radical, and the oxidative damage that results from hydroxyl radical accumulation produces the cellular dysfunction that is the hallmark of oxidative stress. The GPx enzymes work alongside catalase and the other antioxidant enzymes to maintain the H2O2 concentration at levels that are safe for the cell.
The clinical importance of selenium for GPx activity is most clearly demonstrated by the effect of selenium deficiency on GPx activity in humans. In selenium deficiency, the GPx activity in erythrocytes, plasma, and tissues falls to very low levels (by approximately 90% in severe deficiency), and the oxidative damage that results from impaired GPx activity produces the clinical manifestations that are characteristic of selenium deficiency. In the Keshan disease (the cardiomyopathy that is associated with severe selenium deficiency in the endemic regions of China), the impaired GPx activity in the myocardium allows the oxidative damage to accumulate to levels that damage the myocardial cells, producing the myocardial necrosis and the cardiac dysfunction that characterise this condition. Selenium supplementation in these endemic regions has virtually eliminated the Keshan disease, demonstrating the power of targeted selenium replacement for this selenium-specific cardiomyopathy.
Selenium and Thyroid Function
Selenium is also the essential cofactor of the iodothyronine deiodinases (D1, D2, D3) — the enzymes that convert the thyroid hormone T4 (thyroxine) to T3 (triiodothyronine, the active form) and that degrade T4 and T3 to the inactive metabolites rT3 and T2. The deiodinases are selenoproteins (they contain selenocysteine at their active site), and their activity is impaired when selenium status is marginal. This selenium-thyroid connection is clinically important because the conversion of T4 to T3 is impaired in selenium deficiency, leading to the low T3 levels, the elevated rT3 levels, and the impaired thermogenesis that characterise the selenium-deficient state. In the developed world, where selenium deficiency is less common than in the endemic regions of China, marginal selenium deficiency may still impair thyroid function and contribute to the hypothyroidism that is characterised by fatigue, weight gain, cold intolerance, and the slowing of metabolism.
Practical Application
For general selenium supplementation, the evidence-based dose is 100-200mcg of selenium daily (as selenomethionine or selenomethylcysteine, the organic forms that are better absorbed and retained than the inorganic selenite and selenate forms). The RDA for selenium is 55mcg daily for adults, and most people in the developed world achieve this from a varied diet that includes Brazil nuts (which are the richest dietary source of selenium, with approximately 68-91mcg per nut), seafood (shrimp, tuna, sardines), meat, and poultry. One Brazil nut daily is sufficient to maintain adequate selenium status in most people. Selenium is generally well-tolerated with no significant adverse effects at therapeutic doses, though chronic supplementation above 400mcg daily should be avoided because selenium is a trace element that can accumulate to toxic levels with chronic oversupplementation (producing the selenosis that is characterised by GI upset, hair loss, nail changes, and in severe cases, neurological symptoms). For comprehensive antioxidant and thyroid support, selenium pairs well with the other antioxidant nutrients (including vitamin E, which regenerates the GPx substrate glutathione, and vitamin C, which supports the general antioxidant defence system), with iodine (which is the raw material for thyroid hormone synthesis), with the omega-3 fatty acids (which have anti-inflammatory effects that reduce the demand for GPx activity in the inflammatory response), and with the Mediterranean dietary pattern (which is associated with better selenium status and with reduced risk of the chronic diseases that are associated with oxidative stress).
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