1. Eukaryotic selenoproteins and selenoproteomes

Department of Biochemistry and Redox Biology Center , University of Nebraska , Lincoln , NE 68588 , USA .

Biochim Biophys Acta. 2009

Selenium is an essential trace element for which both beneficial and toxic effects in human health have been described. It is now clear that the importance of having adequate amounts of this micronutrient in the diet is primarily due to the fact that selenium is required for biosynthesis of selenocysteine, the twenty first naturally occurring amino acid in protein. In this review, we provide an overview of eukaryotic selenoproteins and selenoproteomes, which are sets of selenoproteins in these organisms. In eukaryotes, selenoproteins show a mosaic occurrence, with some organisms, such as vertebrates and algae, having dozens of these proteins, while other organisms, such as higher plants and fungi, having lost all selenoproteins during evolution. We also discuss selenoprotein functions and evolutionary trends in the use of these proteins in eukaryotes. Functional analysis of selenoproteins is critical for better understanding of the role of selenium in human health and disease.

2.Selenium and thyroidal function; the role of immunoassays

Kaprara A , Krassas GE .

Department of Endocrinology, Diabetes and Metabolism, Panagia General Hospital , N Plastora 22, 551 32 Kalamaria, Thessaloniki , Macedonia , Greece .

Hell J Nucl Med. 2006

It is well known that selenium plays a fundamental role in regulating thyroid and other functions of the human body like reproduction, autoimmunity, glucose metabolism or bone metabolism. While for thyroid function investigation, radioimmunoassays and radioimmunometric assays both key techniques of nuclear medicine are used, for selenium measurements atomic absorption spectrometry is the method of choice. Normal thyroid gland retains high selenium concentrations even under conditions of inadequate selenium supply and expresses many of the known selenocysteine-containing proteins. Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland damage by excessive iodide exposure. In regions where a combined severe iodine and selenium deficiency exist, normalization of iodine supply is mandatory before initiation of selenium supplementation in order to prevent hypothyroidism. Selenium deficiency and disturbed thyroid function may develop under conditions of special dietary regimens, such as long-term total parenteral nutrition or after inadequate nutrition in children. Some investigators suggest that selenium may be a useful adjunctive treatment for autoimmune thyroid diseases, such as Hashimoto and Graves' disease. Low serum selenium levels have been associated with higher incidence of thyroid cancer, as well as with chronic illness or lomicronw triiodothyronine syndrome. These biological actions are mediated through the expression of selenoproteins, the most important being the glutathione peroxidases, the iodothyronine deiodinases, the thioredoxine reductase and the selenoprotein P. Selenium is also associated with animal proteins. Subsequently meats and seafood are dietary sources of selenium. The ingestion of large quantities of selenium may have adverse effects. It has been shown that dietary intake of about 300 micro g of selenium daily may have a toxic effect on growth hormone and insulin like growth factor-1 metabolism, as well as in the synthesis of thyroid hormones. Main adverse effects may be anorexia, diarrhea, depression, hemorrhage, liver and kidney necrosis, blindness, ataxia and respiratory disturbances. Dermatitis and CNS deficiency have also been described. It is concluded that selenium plays an important role in regulating thyroid function, as well as in the homeostasis of thyroid hormones through the action of selenoproteins, in which it incorporates as selenocystein.

3. Selenium, selenoproteins and human health: a review

Brown KM , Arthur JR .

University of Aberdeen , Scotland .

Public Health Nutr. 2001

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, gastrointestinal 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 5'5-mono-deiodination of the prohormone thyroxine (T4) to the active thyroid hormone 3,3'5-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 may enhance male fertility; decrease cardiovascular disease mortality, and regulate the inflammatory mediators in asthma. The potential influence of Se on these chronic diseases within the European population is important considerations when assessing Se requirement.

4 . The role of selenium in epilepsy and other neurological disorders

Faik Atroshi, Erkki Antila, Tuomas Westermarck

Pharmacology & Toxicology, ELTDK, University of Helsinki , Helsinki

Rinnekoti Research Centre

• Introduction.
  
  Ever since oxidative stress has been implicated in epilepsy and various neurodegenerative disorders there has been considerable interest in drugs that prevent oxidative stress including antioxidants, modifiers of the enzymes involved in ROS generation and metabolism, metal chelating agents and agents that can remove the stimulus for ROS generation.

• Objective.
  
  In this review, we elaborate oxidative stress-mediated neuronal loss and asses the role of selenium in several neurological disorders including epilepsy.

• Discussion.
  
  Selenium as an essential trace element has attracted the attention of many researchers because of its potential for human health. It plays an important role in the immune response, defence against tissue damage and thyroid function. Selenium forms part of the active site of the peroxide-destroying enzyme glutathione peroxidase (GSHPx) and it also has other functions, for example in biotransformation and detoxification. Functional and clinical consequences of selenium deficiency states in neurological diseases are described and the selenium requirement, which is influenced by the usual selenium exposure, is discussed. Wide variations have been found in selenium status in different parts of the world and populations or groups of patients exposed to marginal deficiency are more numerous than was previously thought. Chronic diseases, such as neurological disorders, heart disease, diabetes, cancer, ageing and others, are reportedly associated with markers of oxidative damage. It is therefore not unreasonable to suggest that antioxidants may alleviate oxidative damage and thus prevent disease and delay ageing. In recent years, laboratory experiments, clinical trials and epidemiological data have all established the role of selenium in a number of the above mentioned conditions. Most of these effects are related to the function of selenium in antioxidant enzyme systems

• Conclusion.
  
  Current research activities in the field of human medicine and nutrition are devoted to the possibilities of using selenium as an adjuvant for the treatment of degenerative or free radical diseases such as neurological disorders, inflammatory diseases or cancer.

5. Selenium and Its Role in Health and Disease

Rahul Saxena, Geeta Jaiswal

Department of Biochemistry, MLN Medical College , Allahabad , India

Kuwait Medical Journal 2007

Selenium, an essential trace element, has been known for its toxicity in most of the livestock over past several decades but later research on selenium explored the hidden facts about its role in health and disease. Selenium is an essential constituent of antioxidant enzymes especially glutathione peroxidase and some other selenoproteins that participate in various physiological activities and protects the cell against the deleterious effects of free radicals. However, their exact role is still unknown. Current evidence indicates that selenium is involved in a wide array of physiological functions and pathological conditions which include normal thyroid functioning, enhancing immune function, c a rcinogenesis, cardiovascular diseases, male re production and in the prevention of pre-eclampsia etc . However, the exact mechanism behind its involvement in such events is not yet fully elucidated and needs further investigation. This article reviews an introductory overview covering the current concepts related to selenium balance, its metabolic and physiologic functions with special reference to human health and disease

6. From selenium to selenoproteins: synthesis, identity, and their role in human health.

Papp LV , Lu J , Holmgren A , Khanna KK .

Queensland Institute of Medical Research, Cancer and Cell Biology Division, Herston, QLD, Australia

Antioxid Redox Signal. 2007

The requirement of the trace element selenium for life and its beneficial role in human health has been known for several decades. This is attributed to low molecular weight selenium compounds, as well as to its presence within at least 25 proteins, named selenoproteins, in the form of the amino acid selenocysteine (Sec). Incorporation of Sec into selenoproteins employs a unique mechanism that involves decoding of the UGA codon. This process requires multiple features such as the selenocysteine insertion sequence (SECIS) element and several protein factors including a specific elongation factor EFSec and the SECIS binding protein 2, SBP2. The function of most selenoproteins is currently unknown; however, thioredoxin reductases (TrxR), glutathione peroxidases (GPx) and thyroid hormone deiodinases (DIO) are well characterised selenoproteins involved in redox regulation of intracellular signalling, redox homeostasis and thyroid hormone metabolism. Recent evidence points to a role for selenium compounds as well as selenoproteins in the prevention of some forms of cancer. A number of clinical trials are either underway or being planned to examine the effects of selenium on cancer incidence. In this review we describe some of the recent progress in our understanding of the mechanism of selenoprotein synthesis, the role of selenoproteins in human health and disease and the therapeutic potential of some of these proteins.

7. The role of selenium in thyroid autoimmunity and cancer

Duntas LH .

Endocrine Unit, Evgenidion Hospital , University of Athens , Medical School , Athens , Greece .

Thyroid. 200 6

The essential micronutrient selenium (Se) occurs in the form of the amino acid selenocysteine in selenoproteins which exert various effects, while maintaining the cell reduction-oxidation balance. The discovery that all three deiodinases that convert thyroxine (T4) into triiodothyronine (T3) contain selenocysteine illustrates how the production of the active thyroid hormone is dependent on Se status. The selenoenzyme families of glutathione peroxidases (GPx) and thioredoxin reductases (TRx) possess powerful antioxidant properties and form a complex defense system that protects thyrocytes from oxidative damage. Se supplementation in patients with autoimmune thyroiditis seems to modify the immune response, probably by enhancing plasma GPx activity and decreasing excess levels of hydrogen peroxide. However, the enhancement of immunocompetence may also be the result of the synergistic action of various selenoproteins and not exclusively of GPx. There is evidence supporting considerable oxidative stress in Graves' disease where Se supplementation, because of its free radical scavenging properties, may increase the enzymatic antioxidant activity. TRx has been found significantly elevated in GD revealing its involvement in the pathogenesis of this condition and representing a potential future target for therapeutical intervention. Low Se serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis. It is noteworthy, that the Food and Drug Administration has recently determined that there is sufficient evidence to warrant a qualified health claim for Se and cancer. Furthermore, the recent discovery that defects in the SECIS-binding protein 2 (SBP2), which is an indispensable protein for the incorporation of Se into the selenoproteins, result in thyroid dysfunction, together with the recognition of the many roles of selenoprotein P in Se distribution and storage in the human body, reveal not only the indispensability of Se and the selenoproteins as essential factors in thyroid metabolism and pathogenesis, but open up new prospects for enhanced treatment.

8. Selenium: its role as antioxidant in human health

Tinggi U .

Centre for Public Health Sciences, Queensland Health Scientific Services

Environ Health Prev Med. 2008

Selenium (Se) is an essential trace element, and its low status in humans has been linked to increased risk of various diseases, such as cancer and heart disease. In recent years, Se research has attracted tremendous interest because of its important role in antioxidant selenoproteins for protection against oxidative stress initiated by excess reactive oxygen species (ROS) and reactive nitrogen species (NOS). The synthesis of selenoproteins requires a unique incorporation of amino acid selenocysteine (Sec) into proteins directed by the UGA codon, which is also a termination codon. Interest in Se research has led to the discovery of at least 30 selenoproteins; however, the biochemical functional roles of some of these selenoproteins are still unknown. Besides in the form of selenoproteins, Se can exist in many different chemical forms in biological materials either as organic Se compounds, such as selenomethionine and dimethylselenide, and inorganic selenites and selenates. In foods, Se is predominantly present as selenomethionine, which is an important source of dietary Se in humans, and also as a chemical form that is commonly used for Se supplements in clinical trials. Concern for potential deficiency diseases associated with low Se status has led to the establishment of the recommended daily requirements for Se in many countries. However, excess Se intakes through supplementation and its potential misuse as health therapy could also pose a risk of adverse health effects if its use is not properly regulated.

9. Selenium

Alexander J .

Department of Food Safety and Nutrition, Norwegian Institute of Public Health (NIPH), Norwegian University of Science and Technology.

Novartis Found Symp. 2007

Selenium occurs as inorganic selenite or selenate and in organic forms in plants and other organisms used for food. The human selenoproteome consists of 25 selenoproteins. The main groups are glutathione peroxidases 1-5, iodothyronine deiodinases 1-3, thioredoxin reductases, selenoprotein P (SelP), and other proteins mostly with unknown function. In selenoproteins selenium occurs as selenocysteine. SelP works as a transporter of selenium between the liver and other organs. Selenium in the form of selenomethionine can also unspecifically substitute for methionine in other proteins. No specific deficiency condition has been described in humans. The aetiology of Keshan disease, a cardiomyopathy, is a combination of coxsackie virus and low selenium. Selenium status has been linked to the incidence of cancer and other diseases. Excess selenium can produce selenosis in humans affecting liver, skin, nails and hair. Recommended intake and upper tolerable level are 40-55 and 300 microg/day. A better chemical characterization of selenium compounds in foods and in particular supplements as well as knowledge on the apparent differences in biological activity between selenium compounds, both with respect to nutrition, disease protection and adverse effects, are needed. Supplementation studies should in addition to possible beneficial effects also focus on the possibility of possible adverse effects.

10. Mechanisms of mammary cancer chemoprevention by organoselenium compounds

El-Bayoumy K , Sinha R .

Institute for Cancer Prevention, American Health Foundation Cancer Center , 1 Dana Road, Valhalla , NY 10595 , USA

Mutat Res. 2004

Searching for optimal diets and for naturally occurring agents in routinely consumed foods that may inhibit cancer development, although challenging, constitutes a valuable and plausible approach to finding ways to control and prevent cancer. To date, the use of the micronutrient selenium in human clinical trials is limited but the outcome of these investigations indicates that selenium is one of the most promising agents. Data presented in this mini-review indicate that the dose and the form (structure) in which selenium is used are the most critical determinants of success in future clinical trials. The focus of this mini-review is on the mechanisms of mammary cancer chemoprevention by organoselenium compounds. Among the naturally occurring organoselenium compounds, Se-Methylselenocysteine is more efficacious than the most extensively studied forms, such as selenomethionine. However, we showed that synthetic organoselenium compounds can be tailored to achieve greater chemopreventive efficacy with minimal side effects by structural modifications; it is evident that synthetic agents are superior to the inorganic selenite, naturally occurring selenium compounds and their sulfur-containing analogs. We have demonstrated that 1,4-phenylenebis (methylene) selenocyanate (p-XSC) and its putative metabolite glutathione conjugate (p-XSeSG) are highly promising agents in the chemoprevention of mammary carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)-rat mammary tumor model system. Both compounds inhibit the initiation phase of carcinogenesis by inhibiting DMBA-DNA adduct formation in the target organ in vivo. cDNA microarray analysis indicates that both selenium compounds alter genes in a manner that leads to inhibition of cell proliferation and induction of apoptosis; modulation of apoptosis and cell proliferation can account for chemoprevention during the post-initiation phase of mammary carcinogenesis. Using a rat mammary cancer cell line, we compared p-XSC and p-XSeSG as inhibitors of cell proliferation; depending on the selenium dose and time point selected, p-XSC was comparable to or better than p-XSeSG. Collectively, the results described here, suggest that the molecular targets modulated by organoselenium compounds are highly useful indicators of success in clinical cancer chemoprevention trials.