Selenium is an essential trace mineral that is the cofactor for the glutathione peroxidase (GPx) family of enzymes — the primary enzymes that detoxify the hydrogen peroxide (H2O2) and the lipid hydroperoxides (LOOH) in all cells. The GPx enzymes (particularly the cytosolic GPx1, the gastrointestinal GPx2, the plasma GPx3, and the phospholipid hydroperoxide GPx4) catalyse the reduction of the H2O2 and the LOOH to the water and the corresponding alcohol, using the reduced glutathione (GSH) as the electron donor and producing the oxidised glutathione (GSSG) as the byproduct. Without adequate selenium and functional GPx enzymes, the hydrogen peroxide and the lipid hydroperoxides accumulate in the cells, the oxidative stress increases, and the cellular macromolecules (DNA, proteins, lipids) are damaged — producing the genomic instability, the protein aggregation, and the lipid peroxidation that are the hallmarks of the oxidative stress and of the ageing process. The selenium deficiency is also associated with the Keshan disease (a cardiomyopathy that is endemic in the selenium-deficient regions of China), with the Kashin-Beck disease (an osteoarthritis that is endemic in the selenium-deficient and iodine-deficient regions of Asia), and with the male infertility (because the GPx4 is essential for the sperm structure and function). The typical dietary selenium intake is 40-120mcg daily (from the Brazil nuts, the seafood, the organ meats, and the cereals), and the RDA is 55mcg daily for adults — but the selenium deficiency is common in the soils that are low in selenium (which covers approximately 15-20% of the global land area), in people who follow the vegan diet (which is naturally low in selenium unless the Brazil nuts or the selenium supplements are included), and in people with the malabsorption syndromes.
Glutathione Peroxidase and the Antioxidant Defence
The glutathione peroxidase (GPx) enzymes are the primary defence against the hydrogen peroxide and the lipid hydroperoxides in all cells — they catalyse the reduction of these reactive oxygen species using the reduced glutathione (GSH) as the co-substrate. The H2O2 is generated as a byproduct of the normal cellular metabolism (particularly by the oxidase enzymes in the peroxisomes and by the mitochondrial electron transport chain), and it is also generated by the immune cells (by the NADPH oxidase) during the respiratory burst. If the H2O2 is not rapidly detoxified by the GPx enzymes (or by the catalase, which is the other H2O2-detoxifying enzyme in the cell), it can diffuse through the cell and generate the highly reactive hydroxyl radical (OH) through the Fenton reaction (when H2O2 reacts with the ferrous iron, Fe2+). The hydroxyl radical is the most reactive and the most damaging of all the reactive oxygen species — it attacks the DNA (causing the strand breaks and the base modifications), the proteins (causing the carbonylation and the aggregation), and the lipids (causing the lipid peroxidation chain reaction). The GPx4 is particularly important for the male fertility, because it is located in the mitochondria of the sperm cells and because it protects the sperm membrane from the lipid peroxidation — which is one of the most important causes of the sperm DNA damage and of the male factor infertility.
The clinical importance of the selenium for the GPx function is underscored by the observation that the selenium supplementation reduces the oxidative stress markers and improves the immune function in selenium-deficient individuals. A study in 60 healthy adults found that the selenium supplementation at 200mcg daily (as sodium selenite) for 8 weeks significantly increased the GPx activity in the erythrocytes (by 30%), reduced the oxidative stress markers (by 20%, as measured by the malondialdehyde in the serum), and improved the immune function (as measured by the NK cell activity and by the T cell-mediated immune response) — demonstrating the essential role of selenium in the antioxidant defence and in the immune function.
Selenium and the Keshan Disease
The Keshan disease is a cardiomyopathy (disease of the heart muscle) that is endemic in the selenium-deficient regions of China, where the soil selenium content is very low (less than 0.1mg/kg) and where the dietary selenium intake is less than 20mcg daily. The Keshan disease is characterised by the acute or the chronic heart failure, by the cardiac arrhythmias, by the cardiomegaly (enlarged heart), and by the fibrotic changes in the myocardium — and it is one of the most dramatic and most specific manifestations of any mineral deficiency in humans. The selenium supplementation (at 50-100mcg daily, as sodium selenite) has been shown to prevent the Keshan disease in the selenium-deficient populations of China, and it has been estimated that the selenium supplementation programme in China has prevented approximately 20,000 cases of the Keshan disease since its introduction in the 1970s.
Practical Application
For general selenium supplementation, the evidence-based approach is to supplement with 100-200mcg of selenium daily (as selenomethionine, selenocysteine, or sodium selenite — the forms that are well absorbed and well utilised by the GPx enzymes). The selenomethionine form is preferred because it is incorporated into the body’s protein stores (particularly in the muscle) and provides a more stable and sustained selenium status than the inorganic selenite form. The RDA of selenium is 55mcg daily for adults, and the tolerable upper intake level is 400mcg daily for adults (above which the selenium can cause the selenosis — the toxicity syndrome that includes the nausea, the diarrhoea, the hair loss, the nail changes, and the neurological symptoms). For comprehensive antioxidant and immune support, selenium pairs well with the vitamin E (which has complementary antioxidant effects in the lipid phase and which works synergistically with selenium for the prevention of the lipid peroxidation), with the vitamin C (which regenerates the reduced glutathione and which has complementary antioxidant effects in the aqueous phase), with the zinc (which is required for the Cu,ZnSOD activity and for the immune function), and with the CoQ10 (which is required for the electron transport chain and which has complementary antioxidant effects in the mitochondrial membrane).
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