Public Health Nutrition: 4(2B), 593±599 DOI: 10.1079/PHN2001143 Selenium, selenoproteins and human health: a review KM Brown1* and JR Arthur2 1University of Aberdeen, Scotland: 2Rowett Research Institute, Aberdeen Abstract Selenium is of fundamental importance to human health. It is an essential component of several major metabolic pathways, including thyroid hormone metabolism, antioxidant defence systems, and immune function. The decline in blood selenium concentration in the UK and other European Union countries has therefore several potential public health implications, particularly in relation to the chronic disease prevalence of the Western world such as cancer and cardiovascular disease. Ten years have elapsed since recommended dietary intakes of selenium were introduced on the basis of blood glutathione peroxidase activity. Since then 30 new selenoproteins have been identified, of which 15 have been purified to allow characterisation of their biological function. The long term health implications in relation to declining selenium intakes have not yet been thoroughly examined, yet the implicit importance of selenium to human health is recognised universally. Selenium is incorporated as selenocysteine at the active site of a wide range of selenoproteins. The four glutathione peroxidase enzymes (classical GPx1, gastro- intestinal GPx2, plasma GPx3, phospholipid hydroperoxide GPx4)) which represent a major class of functionally important selenoproteins, were the first to be characterised. Thioredoxin reductase (TR) is a recently identified seleno-cysteine containing enzyme which catalyzes the NADPH dependent reduction of thioredoxin and therefore plays a regulatory role in its metabolic activity. Approximately 60% of Se in plasma is incorporated in selenoprotein P which contains 10 Se atoms per molecule as selenocysteine, and may serve as a transport protein for Se. However, selenoprotein-P is also expressed in many tissues which suggests that although it may facilitate whole body Se distribution, this may not be its sole function. A second major class of selenoproteins are the iodothyronine deiodinase enzymes which catalyse the 505-mono-deiodination of the prohormone thyroxine (T4) to the active thyroid hormone 3,305-triiodothyronine (T3). Sperm capsule selenoprotein is localised in the mid-peice portion of spermatozoa where it stabilises the integrity of the sperm flagella. Se intake effects tissue concentrations of selenoprotein W which is reported to be necessary for muscle metabolism. It is of great concern that the health implications of the decline in Se status in the UK over the past two decades have not been systematically investigated. It is well recognised that dietary selenium is important for a healthy immune response. There is also evidence that Se has a protective effect against some forms of cancer; that it Keywords may enhance male fertility; decrease cardiovascular disease mortality, and regulate Selenium the inflammatory mediators in asthma. The potential influence of Se on these chronic Selenoprotein diseases within the European population are important considerations when Glutathione peroxidase assessing Se requirement. Human health Introduction essential to animal health when they discovered that trace amounts protected against liver necrosis in vitamin E In 1818 the Swedish chemist Jons Jacob Berzelius deficient rats1. Interest in the role of selenium in human discovered selenium. He named it Selene after the health gathered momentum in the late 1960's, and Greek goddess of the moon. One hundred and forty investigations looked for human diseases similar to years later, Schwarz and Foltz identified selenium as those of Se-responsive animal disorders2. Although *Corresponding author: Email [email protected] q The Authors 2001 Downloaded from https://www.cambridge.org/core. 23 Sep 2021 at 21:38:40, subject to the Cambridge Core terms of use. 594 KM Brown and JR Arthur selenium was identified as essential to human nutrition its activity is preserved in preference to GPx1 when 42 years ago, a universal marker of daily requirement dietary Se supply is low10. GPx4 reacts with phospholid remains elusive. Research has extended our knowledge hydroperoxides as well as small soluble hydroper- of the essential functional roles attributed to selenium, oxides11, and is also capable of metabolising cholesterol which have both short-, and long-term public health and cholesterol ester hydroperoxides in oxidised low implications. density lipoprotein. Consequently it is well recognised as essential to destruction of fatty acid hydroperoxides, Selenoproteins which if not reduced to hydroxy fatty acids, will lead to Selenium is an essential micronutrient of major metabolic uncontrolled free radical chain reactions that are deleter- significance. It is incorporated as selenocysteine at the ious to the integrity of membranes. In animal models, the active site of a wide range of proteins. Under physiolo- amount of the protein GPx4 present in tissues does not gical conditions the Se in selenocysteine is almost fully exactly reflect the activity distribution. This may be a ionised and consequently is an extremely efficient reflection of site specific Se dependent cell function, or biological catalyst3. It has been suggested that up to 100 differences in the level of factors which activate GPx4. selenoproteins may exist in mammalian systems4 of which The mechanism for the activation-inactivation of the up to 30 have been identified by 75Se labelling in vivo5. enzyme is unknown, but the evidence of high activity in To date 15 selenoproteins have been purified or cloned membranes of differentiating spermatogenic cells sug- allowing further characterisation of their biological func- gests a possible relationship between cell differentiation tion. These include four glutathione peroxidase enzymes and peroxide levels12. (classical GPx1, gastrointestinal GPx2, plasma GPx3, phospholipid hydroperoxide GPx4) which represent a Extracellular glutathione peroxidase major class of functionally important selenoproteins. The Extracellular GSHPx (GPx3) is another selenoprotein with Se peroxidases are genetically, structurally and kineti- antioxidant potential, but this may not be its main cally different yet have both common and individual function in plasma. Hybridization studies show that functions3. GPx3 mRNA occurs in the renal proximal tubular epithelial cells13, and since the concentrations of GSH Glutathione peroxidase are high in the kidney, GPx3 may have a specific Classical glutathione peroxidase (GPx1) was the first antioxidant function in renal tubules or extracellular selenoprotein, identified, and the strong linear relation- spaces. However, other thiols such as thioredoxin can ship demonstrated between erythrocyte Se concentration act as electron donor and support an antioxidant role for and GSHPx activity provided us with the first functional GPx3 in plasma14. Thioredoxin is a protein disulphide biochemical marker of Se status6. GSHPx is present in the important to antioxidant defences and the regulation of cell cytosol where it functions as an antioxidant by cell growth. directly reducing H2O2, and phospholipase A2 cleaved lipid hydroperoxides6. It may also act as a storage vehicle Thioredoxin reductase for Se7 containing 4 selenocysteine residues in a Thioredoxin reductase is a recently identified seleno- tetrameric structure. cysteine containing enzyme which catalyzes the NADPH dependent reduction of thioredoxin and therefore plays a Gastrointestinal glutathione peroxidase regulatory role in its metabolic activity15. This discovery Gastrointestinal glutathione peroxidase (GPx2) protects extends the role of Se to redox regulation. Since mammals from the toxicity of ingested lipid hydro- thioredoxin stimulates proliferation of normal and tumour peroxides8. In animal studies, Se deficiency decreases cells, and is present in high concentrations in tumour the enzyme activity, but any effect on human GPx2 cells16, an enhanced TR activity may play an important activity has not been reported. Gastrointestinal glu- role in the prevention of some forms of cancer. tathione peroxidase is the most important selenoprotein antioxidant in the colon. Oxidative stress is a critical event Selenoprotein P in tumourogenesis. It is therefore likely that the anti- Approximately 60% of Se in plasma is incorporated in oxidant function of GPx2 will provide an early defence selenoprotein P which contains 10 Se atoms per molecule against colon cancer. as selenocysteine4. Extracellular GSHPx, and selenopro- tein-P account for over 90% of plasma selenium and both Phospholipid hydroperoxide glutathione may serve as a transport protein for Se17. However, peroxidase selenoprotein-P is also expressed in many tissues and has A membrane associated phospholipid hydroperoxide been associated with cell membranes18 which suggests glutathione peroxidase (GPx4) has been identified that although it may facilitate whole body Se distribution, which is directly responsible for the reductive destruction this may not be its sole function, and it may serve as an of lipid hydroperoxides9. The enzyme is a monomer and antioxidant. Downloaded from https://www.cambridge.org/core. 23 Sep 2021 at 21:38:40, subject to the Cambridge Core terms of use. Selenium, selenoproteins and human health 595 Iodothyronine deiodinases fluid Se concentration and improve sperm motility22. The A second major class of selenoproteins are the iodo- potential influence of Se on the increasing