Critical Review Biological Activity of Selenium: Revisited Jagoda K. Wrobel 1 Ronan Power 2 Michal Toborek 1,3 *

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1 Critical Review Biological Activity of Selenium: Revisited Jagoda K. Wrobel 1 Ronan Power 2 Michal Toborek 1,3 * 1 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA 2 Nutrigenomics Research Center, Alltech, Nicholasville, KY, USA 3 Jerzy Kukuczka Academy of Physical Education, Katowice, Poland Abstract Selenium (Se) is an essential micronutrient that exerts multiple and complex effects on human health. Se is essential for human well-being largely due to its potent antioxidant, antiinflammatory, and antiviral properties. The physiological functions of Se are carried out by selenoproteins, in which Se is specifically incorporated as the amino acid, selenocysteine. Importantly, both beneficial and toxic effects of Se have been reported suggesting that the mode of action of Se is strictly chemical form and concentration dependent. Additionally, there is a relatively narrow window between Se deficiency and toxicity and growing evidence suggests that Se health effects depend greatly on the baseline level of this micronutrient. Thus, Se supplementation is not an easy task and requires an individualized approach. It is essential that we continue to explore and better characterize Se containing compounds and mechanisms of action, which could be crucial for disease prevention and treatment. VC 2015 IUBMB Life, 68(2):97 105, 2016 Keywords: selenium; selenoproteins; cancer; brain; human nutrition Introduction Selenium (Se) was first identified as a by-product of sulfuric acid production by a Swedish chemist J ons Jacob Berzelius in For many years, Se was recognized as an environmental toxicant of livestock, with potential harmful effects on humans (1). In 1957, pioneering work by Schwarz and coworkers, demonstrated that liver necrosis in rats could be prevented by supplementation with low concentrations of Se, shedding new light on this microelement and leading to the recognition of Se as an essential micronutrient (2 4). In 1973, it was discovered that Se is an integral component required for glutathione peroxidase (GPx) activity, an enzyme, which plays a major role in the protection against oxidative injury (5,6). Since then Se has VC 2015 International Union of Biochemistry and Molecular Biology Volume 68, Number 2, February 2016, Pages *Address correspondence to: Michal Toborek, Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg. Room 528, 1011 NW 15th Street, Miami, FL 33136, USA. Tel: Fax: mtoborek@med.miami.edu Received 21 October 2015; Accepted 5 December 2015 DOI /iub.1466 Published online 30 December 2015 in Wiley Online Library (wileyonlinelibrary.com) been the subject of numerous scientific investigations demonstrating its substantial role in human health and disease (5). Particular interest has been given to Se anticancer properties that have been demonstrated in a number of studies. Inconsistent results from several clinical trials carried out in the past three decades serve as a reminder of the complexity of Se biology and an indication that further research is required to optimize the benefits and reduce risks associated with Se supplementation. In this review, we summarize the current knowledge regarding Se effects on human health and tissue accumulation, with particular focus on anticancer properties of this trace element. Selenium and Human Health Se is widely distributed in body tissues, has been implicated in many physiological processes, and its too low or too high concentration leads to serious health consequences (7 10). For example, Se is known to modulate the function of the thyroid glad. Se-dependent iodothyronine deiodinases (DIOs) are involved in the synthesis of active thyroid hormone, triiodothyronine (T3), while GPx3 protects thyroid cells from the hydrogen peroxide (8). In addition, several studies reported that Se supplementation is effective against Hashimoto s thyroiditis, common autoimmune thyroid disease (11). Se has been also shown to play an important role in male and female fertility and low Se plasma level in the early stage of IUBMB Life 97

2 IUBMB LIFE pregnancy has been proved to be a reliable predictor of low birth weight of a newborn (12). In addition, Se deficiency has been reported to cause cardiac and skeletal muscle disorders, characterized by changes in muscle fibers that lead to contraction impairment and muscle atrophy (13). Se has also been shown to be important for the brain physiology and abnormal levels of Se were found in the plasma of patients with impaired cognitive functions and neurological disorders (14). Epidemiological studies conducted across the past decades reported that low Se status correlates with increased incidence of several human diseases. For example, an inverse association between Se concentration and the incidence of coronary heart disease and certain types of cancers has been reported in numerous studies (3,15 18). Several studies have investigated potential antiviral effects of Se and it has been observed that Se deficiency was associated with higher mortality among human immunodeficiency virus (HIV)-infected patients. Additionally, it has been reported that in HIV-positive adults Se supplementation have markedly reduced hospital admission due to the infection (19). Se enters the food chain through plants and the soil content of an area determines the amount of Se available in the food supply (20). Therefore, Se intake varies greatly worldwide, ranging from deficient to toxic concentrations (8). High intakes of Se have been reported in Canada, U.S.A., Japan and some parts of South America, whereas much more moderate intakes were observed in Europe, particularly in Eastern Europe. China has areas of both Se deficiency and excess. Several diseases, including Keshan disease, Kashin-Beck disease, and Myxedematous endemic cretinism, have been associated with severe Se deficiency, due to their occurrence in areas characterized by Se poor soils (3). Although Se may be only a cofactor in these diseases, with other factors contributing to their incidence or severity, Se supplementation provides significant therapeutic benefit in all of these conditions (3,21). Keshan disease is an endemic cardiomyopathy characterized by acute or chronic episodes of a heart disfunction, including cardiogenic shock and congestive heart failure (3). Kashin- Beck disease is a degenerative osteoarthropathy commonly observed in Se deficient regions, while Myxedematous endemic cretinism is induced by thyroid atrophy and results in mental retardation (21). On the other hand, exposure to unusually high concentrations of dietary Se leads to selenosis, a condition that is observed when Se levels reach toxic concentrations. The symptoms vary depending on the severity of the poisoning and include garlic breath, poor dental health, brittle hair and nails, nausea, and even pulmonary oedema (3). While there is a relatively narrow window between Se intakes that result in deficiency or toxicity, the recommended dietary intake of Se for healthy adults is 60 lg per day for men and 53 lg per day for women (1,3,8). According to the World Health Organization (WHO), 19 lg of Se per day is the minimal requirement to prevent the diseases associated with Se deficiency (22). The main sources of Se in human diet are cereal grains, soybeans, meat, seafood, eggs, and dairy products (3,23,24). While there are various formulations of supplements available with varying doses and species of Se, the current knowledge advises that people whose serum or plasma Se concentration is 122 lg L 21 or higher should not supplement with Se (3,8). This applies mainly to the western populations, where great part of the societies takes dietary supplements on daily basis (8). Selenium Containing Proteins Mammalian Se-containing proteins can currently be divided into three categories: specific enzymatic proteins with selenocysteine (Sec) incorporated into their active center, proteins containing nonspecifically incorporated Se and Se-binding proteins (SBPs) (4,8,25). Dietary Se acts principally though selenoproteins, which are proteins with enzymatic activity that incorporate Se in the form of Sec, Se-containing homolog of cysteine (Cys). The biosynthesis of the selenoproteins is a complex process, consisting of many steps and involving a cadre of specialized reactions leading to insertion of Sec by the ribosome. The insertion of Sec is specified by the UGA codon in mrna (3,26). Since UGA serves also as a stop codon the presence of a stemloop structure, a Sec insertion sequence (SECIS), downstream from UGA in the 3 0 -untranslated region (3 0 UTR) of mrna is required for UGA to be read as Sec (3,27). So far, 25 selenoproteins have been identified in humans (Table 1) (4,29). The synthesis of selenoproteins has been demonstrated to be sensitive to the supply of Se, but not all selenoproteins are affected in the same way (30,31). mrna levels of several selenoproteins, including type I iodothyronine deiodinase (DIO1) and selenoprotein P (SelP) have been found to remain relatively high even during prolonged Se deficiency, whereas the expression of other selenoproteins, for example, GPx1, rapidly decreases when the supply of Se is low (30). The hierarchy of selenoprotein mrna expression was postulated to correlate with the relative importance of the specific selenoproteins in cellular homeostasis (31,32). Selenoproteins exhibit varied subcellular locations, which may offer insights into their functions and regulation (31). Although all of the functionally characterized selenoproteins have been shown to possess redox-active properties, it has become evident that selenoproteins do not simply function as antioxidant enzymes. For example, MsrB1 (also known as SelR or SelX), present in the cytosol and nucleus, is the only selenoprotein among the mammalian MsrB enzyme family (33,34). MsrBs belong to methionine sulfoxide reductases (Msrs), thiol-dependent enzymes that catalyze the reduction of free and protein-based methionine sulfoxides to methionine and modulate protein function (33,35). Indeed, regulation of protein function based on oxidation of sulfur-containing residues emerged as a key mechanism of redox control (36). MsrB1 was found to control, in conjunction with Mical proteins, the assembly and disassembly of actin in mammals in a reversible, site-specific manner (36,37). Importantly, the catalytic activities of two other 98 BIOLOGICAL ACTIVITY OF SELENIUM

3 TABLE 1 Selected biological functions of mammalian selenoproteins (4,28) Selenoprotein Function 15 kda selenoprotein (Sep15) Quality control of protein folding Type I iodothyronine deiodinase (DIO1) Type II iodothyronine deiodinase (DIO2) Type III iodothyronine deiodinase (DIO3) Glutathione peroxidase 1 (GPx1) Glutathione peroxidase 2 (GPx2) Glutathione peroxidase 3 (GPx3) Glutathione peroxidase 4 (GPx4) Glutathione peroxidase 6 (GPx6) Selenoprotein H (SelH) Selenoprotein I (SelI) Selenoprotein K (SelK) Selenoprotein M (SelM) Selenoprotein N (SelN) Selenoprotein O (SelO) Selenoprotein P (SelP) Selenoprotein R (SelR, MsrB1) Selenoprotein S (SelS) Selenophosphate Synthetase (SPS2) Selenoprotein T (SelT) Regulation of thyroid hormone activity by reductive deodination Regulation of thyroid hormone activity by reductive deodination Regulation of thyroid hormone activity by reductive deodination Glutathione (GSH)-dependent detoxification of hydrogen peroxide GSH-dependent detoxification of hydrogen peroxide GSH-dependent detoxification of hydrogen peroxide Inhibition of lipid peroxidation GSH-dependent detoxification of hydrogen peroxide Regulation of GSH synthesis and phase II detoxification enzymes Unknown function ER-associated degradation of misfolded proteins Rearrangement of disulfide bonds in the ER-localized proteins Regulation of intracellular calcium mobilization Unknown function Se transport to peripheral tissues and antioxidant function Repair of oxidized methionines in proteins ER-associated degradation of misfolded proteins Synthesis of selenophosphate Regulation of pancreatic b-cell function and glucose homeostasis Thioredoxin reductase 1 (TXNRD1) Reduction of the oxidized form of cytosolic thioredoxin Thioredoxin reductase 2 (TXNRD2) Formation/isomerization of disulfide bonds during sperm maturation Thioredoxin reductase 3 (TXNRD3) Reduction of mitochondrial thioredoxin and glutaredoxin 2 Selenoprotein V (SelV) Selenoprotein W (SelW) Unknown function Redox regulation of protein members of MsrB family, MsrB2 and MsrB3 that are Cyscontaining isozymes, were reported be markedly lower as compared to MsrB1 (33,38). The other specific functions of selenoproteins include glutathione-dependent hydroperoxide removal, reduction of thioredoxins, selenophosphate synthesis, activation and inactivation of thyroid hormones, control of cytoskeleton assembly, systemic transport of Se, and endoplasmic reticulum (ER)-associated protein degradation (4,6). The role of Se in human health and development seems to be mediated by the combined action of all the proteins constituting human selenoproteome (8). In addition to incorporation as Sec, Se can replace sulfur in methionine (Met), forming selenomethionine (Se-Met). Since cells do not distinguish between Met and Se-Met during protein synthesis, Se-Met that is not immediately metabolized, is randomly incorporated into proteins in place of Met (39). When needed, Se-Met is reversibly released and via the transselenation pathway may be converted to Sec, which is then used for selenoprotein synthesis (1,20,40). This nonspecific incorporation of Se-Met into the general body proteins, allows Se to be stored in the organism; offering therefore Se-Met an advantage over other Se compounds used for dietary WROBEL ET AL. 99

4 IUBMB LIFE supplementation (1,39). For example, it has been demonstrated that Se-Met supplemented animals maintained higher activities of selenoenzymes during Se depletion for longer periods than previously selenite-supplemented animals (39). Organs with high rates of protein synthesis such as the skeletal muscles, pancreas, liver, or kidney, have been found to serve as a rich source of Se-Met (39,40). The replacement of Met by Se-Met usually does not alter significantly protein structure and it has been suggested that the random incorporation of SeMet in place of Met in proteins may provide protection against radical species within susceptible nearby amino acid residues (1,38). Additionally, substitution of Met with Se-Met in amyloid proteins has been reported to modulate their aggregation and neurotoxicity, suggesting potential implications of Se- Met supplements for amyloid diseases (41). Another group of Se containing proteins are Se-binding proteins that covalently bind Se and whose functions have not been characterized well so far (24,26). SBPs are much smaller family of proteins and the best studied of them is SBP1. The exact physiological function of SBP1 is unknown, although it was suggested to be involved in intra-golgi transport and in ubiquitination-mediated protein degradation pathways (42,43). Additionally, SBP1 has been proposed to play a role in malignant transformation and cancer progression, as markedly reduced SBP1 levels have been detected in multiple epithelial tumors and low SBP1 expression has been found to correlate with poor prognosis in various human cancers (44,45). Overview of Selenium Metabolism The majority of Se compounds, organic and inorganic, are easily absorbed from the diet and then transported to the liver (46). The absorption of Se-species occurs mainly in the small intestine and involves various mechanisms, often shared with their sulfur analogues, although the identity of specific transporters responsible for the absorption of dietary Se remains uncertain (3,47). Selenate is absorbed paracellularly through a passive diffusional process. Following absorption, it is reduced to selenite by ATP sulfurylase via uncharacterized Se-isologue of 3-phosphoadenosine 5-phosphosulfate (47). Seamino acids, SeMet and Sec, are absorbed through transcellular mechanisms, but the identity and affinity of the transporter proteins is still to be determined (47,48). Liver is the key organ for Se metabolism, where most of the Se-containing proteins are being synthesized (3). While our understanding regarding the assimilation process of dietary Se into proteins is incomplete, hydrogen selenide (H 2 Se) is known to act as precursor for Se containing protein synthesis for both, organic and inorganic Se compounds (Fig. 1) (1,3,28). Hydrogen selenide is formed from sodium selenite (Na 2 SeO 3 ) via selenodiglutathione (GS-Se-SG), through reduction by thiols and NADPH-dependent reductases. It can also be formed through demethylation of methylselenol (CH 3 SeH) via methyltransferases or be released from Sec through the trans-selenation pathway, analogous to the trans-sulfuration pathway (28,47). Hydrogen selenide is also involved as a key metabolite in Se excretion, when methylation by thiol S-methyltransferases generates different methylated metabolic forms of Se that are exhaled in the breath or excreted in urine contributing to Se homeostasis (Fig. 1) (1,3,20,29). Selenium Supplementation and Cancer Of all the health benefits attributed to Se, the one that has received the most attention is its role as a cancer prevention agent. Epidemiological studies conducted over the past four decades have shown lower death rates for cancer in regions with high soil levels of Se, as well as a correlation between the occurrence of certain types of cancers and Se plasma level in the population (8,15,18,49). Anticancer properties of Se, mostly at supranutritional levels of supplementation, have been demonstrated in a number of animal and in vitro studies (5,8,49 51). In addition, it has been reported that Se has the potential to be used not only in cancer prevention but also in cancer treatment. Se supplementation along with conventional anticancer therapies was shown to enhance the efficacy of standard chemotherapeutic drugs, limit side effects and improve general condition of the patients, without reducing effectiveness of the treatment (52 54). These encouraging reports, resulted in several large clinical trials examining anticancer effects of Se supplementation, however the conclusions have been inconsistent. For example, the nutritional prevention of cancer (NPC) trial performed by Clark et al. in the mid- 1990s demonstrated that the supplementation with 200 lg of Se in the form of selenized yeast for 4.5 years reduced significantly the incidence of several common cancers, including prostate cancer, along with an overall decrease in cancer mortality (55). The study was a randomized, double blind, placebo-controlled and involved over 1,000 participants who had a history of nonmelanoma skin cancer. However, recent Selenium and Vitamin E Cancer Prevention Trail (SELECT) that was carried out on a large, heterogeneous population of healthy men, was terminated early concluding that neither Se, in the form of selenomethionine the major component of selenized yeast, nor vitamin E prevent prostate cancer (56). The early termination was due to the nonsignificantly increased risk in type 2 diabetes that was observed in the Se supplemented group. Contradictory results of the trials, suggested that additional genetic factors could influence the relationship between Se and human health. Nutritional genomic studies validated this hypothesis, as risk of several diseases, including cancer, was linked to a number of single nucleotide polymorphisms (SNP) altering Se metabolism, as well as selenoprotein synthesis and activity (27,57). For example, since Sec incorporation involves the 3 0 -untranslated region (3 0 UTR) of the mrna, it was proposed that SNPs within the region of the gene coding the 3 0 UTR, could affect selenoprotein synthesis 100 BIOLOGICAL ACTIVITY OF SELENIUM

5 FIG 1 Se metabolism. The diagram illustrates the main metabolic pathways by which dietary Se can nonspecifically incorporate into body proteins, contribute to selenoprotein synthesis or be excreted from the body. and response to dietary Se (58). Indeed, SNPs were found in the 3 0 UTR of GPx4 and the 15-kDa selenoprotein (Sep15) (59,60). In addition, it has been suggested that the confusing findings of the studies might be due to the insufficient understanding of Se biology at the molecular level, and too little consideration that was given to the basal Se status of the participants as the risk-benefit window for Se supplementation is very narrow and the cancer preventive effects are strictly concentration dependent (6,27,49,61). Emerging evidence suggests that the relationship between Se status and the incidence of specific cancers is U-shaped, rather than linear and while additional Se intake may benefit people with low Se status, individuals of adequate or high plasma Se levels may be affected adversely (1,8). Indeed, the mean baseline plasma Se level in the NPC trial was 114 ng ml 21 versus 135 ng ml 21 in SELECT (1). Moreover, it has been demonstrated that the biological activity of Se depends upon its chemical speciation (1). Se exists in organic (e.g., Se-Met) and inorganic (e.g., sodium selenide, Na 2 Se) forms (42). Se-Met is the main source of Se in human diet and usually the major component of various Se supplemental formulas, including selenized yeast (1). Although both, organic and inorganic Se compounds can be used as nutritional and supplemental Se sources, they differ in their absorption, tissue accumulation, metabolism, mechanism of action and therefore biological activity (1,62 64). Se-enriched yeast is the most common source of Se available commercially and is also the most widely used Se supplementation method in clinical trials (65). In the recent years it has been reported that microalgae, for example, Chlorella vulgaris, accumulate Se with high efficiency and effectively transform inorganic Se species into organic forms, therefore microalgae may constitute a potential promising alternative for Se supplementation (64,66,67). The exact mechanism explaining the cancer preventive effects of Se is not known (1). While mutagenic oxidative stress is known to be one of the major factors in the initiation of cancer process, protection against oxidative injury is often suggested to be involved in the anti-cancer effects of Se. Se antioxidative properties, especially the effects mediated by the GPxs and thioredoxin reductases (TXNRDs), have been a subject of extensive investigations, but the fact that the anticarcinogenic activity is usually observed at supranutritional levels of Se supplementation, that greatly exceed doses needed for maximal selenoprotein expression, indicates that the antioxidative properties are not the major, or at least not the only factors contributing to Se anti-cancer activity (25,62,68). It has WROBEL ET AL. 101

6 IUBMB LIFE FIG 2 Mechanisms involved in Se anti-cancer activity. The exact molecular mechanisms by which Se compounds mediate anti-tumor activity remain unclear; however, several pathways have been implicated through experimental studies. It is likely that Se acts through multiple pathways. been suggested that cancer preventive effects of Se might be mediated by specific Se metabolite(s), likely a monomethylated Se species, which concentrations are increased at supranutritional levels of supplementation. The chemopreventive efficacy of a given Se compound would then depend on a rate of its metabolic conversion to that active Se form (25,62). The proposed mechanisms potentially involved in the anticarcinogenic activity of Se include alterations of carcinogen metabolism, stimulation of DNA repair, modulation of inflammatory and immune responses, regulation of cell cycle and attenuation of cell proliferation, inhibition of cell motility and angiogenesis, and stimulation of apoptosis (Fig. 2) (24,26,29). It is possible that Se acts via multiple pathways and all of these mechanisms contribute to Se anti-cancer properties. Better understanding of Se biology is a crucial requirement to effectively target Se supplementation in cancer prevention and treatment. Selenium in the Brain At normal dietary levels, the highest Se concentration was found in kidney, followed by liver, spleen, pancreas, heart, brain, lung, bone, and skeletal muscle (14). However, as compared to the other body tissues, the brain is a privileged organ with respect to Se accumulation and metabolism. Experimental studies showed that animals fed Se-deficient diets retained relatively high levels of Se in their brains, whereas Se 102 BIOLOGICAL ACTIVITY OF SELENIUM

7 concentration in other organs, including liver and kidney, was severely depleted (14,69,70). Moreover, when Se was administered to Se-deficient animals, a large portion of the available Se was rapidly impounded by the brain (71). These and other reports suggested that Se plays an important role in physiological functions of the brain. Indeed, some functionally characterized selenoproteins have been demonstrated to protect against neurodegeneration by eliminating reactive oxygen species (ROS) and promoting antioxidant defense. In addition, changes in Se concentrations in plasma and brain have been reported in patients suffering from brain diseases, including brain tumors, multiple sclerosis, and Alzheimer disease (14,42,54). Studies on Se retention in the brain suggest existence of a specific mechanism that maintains baseline brain Se levels at the expense of other tissues. Experimental investigations have suggested SelP to be involved in supplying Se to the brain, as mice with deletion of SelP gene expressed severe neurological dysfunctions and markedly decreased brain Se levels under suboptimal Se supply (72,73). SelP is produced primarily in the liver and is involved in maintaining Se homeostasis by distributing Se to the peripheral tissues (4,69). It has also been reported that approximately 75% of the Se in mouse plasma is present in the form of SelP (14,74). SelP has been also found to be present in the brain, mainly in grey and white matter, as well as in cerebrospinal fluid (75). Astrocytes have been reported to synthesize and secrete SelP. Studies on Se and spermatogenesis have led to the discovery that apolipoprotein E receptor-2 (apoer2), a member of the low-density lipoprotein receptor family, facilitates endocytosis of SelP and is involved in supplying Se to the testis (76). Further research demonstrated that apoer2 is also involved in supplying Se to the brain, as Se status in apoer2 2/2 mice was dramatically reduced (74). It has been proposed that the remarkable ability of the brain to maintain high levels of Se is attributed to a unique two-tier mechanism of SelP-apoER2 interactions (77). The first interplay takes place at the blood-brain barrier (BBB) level where SelP is taken up from the circulation by brain capillary cells. The immediate fate of SelP after being picked up by brain capillary cells in unknown. It is hypothesized that vascular endothelial cells release Se into the brain in a form that has not been characterized so far (77). The second interaction has been postulated to occur within the brain, where astrocytes and perhaps other brain cells, take up the Se and secrete it into brain interstitial fluid as SelP, which is then picked up by cells expressing apoer2 (77). Importantly, astrocytes have been shown to produce and secrete SelP (78). Within the brain apoer2 has been found to be expressed primarily by neurons and it has been postulated that SelPapoER2 interaction within the brain serves mostly to maintain neuron Se levels at the expense of other brain cells (77). Conclusions The effects of Se on human health are complex and at the same time there are many aspects of Se biology and metabolism that remain uncharacterized. A better understanding of these biological processes and characterization of Se containing compounds that are effective in experimental studies, will eventually lead to human trials and better strategies for therapeutic as well as preventive interventions. The brain is a privileged organ with respect to Se accumulation and metabolism. Therefore, further research is required to optimize the benefits and reduce potential risks associated with Se supplementation in the context of brain disorders. 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