Selenium in Human Health and Disease: A Review

REVIEW ARTICLE SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW Munaza Riaz1, Khawaja Tahir Mehmood2 ABSTRACT Selenium is an essential trace element for humans and animals, and selenium deficiency is associated with several disease conditions such as immune impairment. Free radicals are produced in the body as a result of many biochemical processes in the body. All aerobic organisms possess antioxidant defense system to combat oxidative stress. Selenium is an important 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 by modulating the cell response. However, their exact role is still unknown. Moreover, many human diseases are related to the cell cycle regulation. Selenium intakes, greater than the recommended daily allowance (RDA), appear to protect against certain types of cancers by finding its role in regulation of cell proliferation and apoptosis. The role of selenium has been explored in normal thyroid functioning, enhancing immune function, carcinogenesis, cardiovascular diseases, in the prevention of pre-eclampsia, diabetes mellitus and male reproduction etc. This article reviews introductory aspects of selenium as an essential micronutrient, different sources of selenium, Pharmacokinetics and its role in various pathologies and aims to provide an update on selenium profile. Key Words: Selenium, Selenoprotein, Glutathione peroxidase, Free Radicals, Antioxidant, Apoptosis This article may be cited as: Riaz M, Mehmood KT. Selenium in Human Health and Disease: A Review. J Postgrad Med Inst 2012; 26(2): 120-33. INTRODUCTION Selenium (Se), a trace mineral, is the 34 element in the periodic table. It is a non metal and its properties are intermediate between adjacent sulfur and tellurium. It was originally discovered by a German chemist Martin Heinric Klaproth, but misidentified as tellurium. Later, in 1818 a Swedish chemist Jons Jacob Berzelius discovered selenium. He named it selenium from Selene, the 1 Greek goddess for moon . Interest in selenium and health was focused primarily on the potentially toxic effects of high intakes in humans, stimulated by reports of alkali disease in livestock raised in 2 seleniferous areas, in the last century . The th Lahore College For Women University Lahore - Pakistan 1 2 Health Department Punjab, Lahore - Pakistan Address for Correspondence: Dr. Munaza Riaz Lahore College For Women University Lahore - Pakistan E-mail: [email protected] Date Received: November 12, 2011 Date Revised: November 22, 2011 Date Accepted: February 10, 2012 JPMI 2012 Vol. 26 No. 02 : 120 - 133 Nutritional significance of Se was established in 1957, when Schwarz and Foltz identified Se as essential for animal health as they discovered that trace amounts of selenium protected against liver necrosis in vitamin E deficient rats and established 3 its nutrient significance . Since its discovery, Se has been a substrate for extensive research. In humans, it is well established that Se plays an important role in different physiological processes and its altered levels have direct impact on health 4 leading to development of diseases . SOURCES Selenium occurs in both organic and inorganic forms. Selenide is found frequently in the food supply among the inorganic forms (selenite, selenate or selenide) and these selenates and selenites are reduced to selenide in the liver with end products as dimethyl and trimethyl selenide5. The organic form includes selenomethionine and selenocystein which are found predominantly in plants and animals respectively. Plant foods are the major sources of selenium in most countries throughout the world. The selenium (Se) content of plants varies tremendously according to its concentration in soil which varies regionally. Plants convert Se mainly into Semethionine (Se-Met) and incorporate it into protein in place of methionine (Met). Se-Met can account for >50% of the total Se content of the plant whereas, selenocystine(Se-Cys), methyl-Se-Cys 120 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW and c-glutamyl-Se-methyl- Cys are not significantly incorporated into plant protein and are at relatively low levels irrespective of soil Se content. Higher animals are unable to synthesize Se-Met and only Se-Cys was detected in rats 6 supplemented with Se as selenite . Animals that eat grains or plants that were grown in selenium rich soil have higher levels of selenium in their muscle. It is widely distributed in all the tissues; highest concentrations are found in the liver, kidney, heart, spleen and fingernails whereas dairy products, fruits and vegetables are relatively poor sources of selenium (Figure 1). Se is present in foods like butter, eggs, brewer's yeast, wheat germ, garlic, grains, sunflower seeds, Brazil nuts, walnuts, raisins, liver, shellfish, fresh-water and salt-water fish, Broccoli, fennel seed, ginseng, raspberry leaf, radish, 6 horseradish, onion and shiitake mushrooms . ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION Selenium compounds are generally very efficiently absorbed by humans, and selenium absorption does not appear to be under 6 homeostatic control . For example, absorption of the selenite form of selenium is greater than 80% whereas that of selenium as selenomethionine or as 6,7 selenate may be greater than 90% . In mammals, ingested Se-Met is absorbed in the small intestine via the Na+-dependent neutral amino acid transport 8 system . Data on the nutritional bioavailability of selenium to humans are sparse. Although the proportion of the nutrient absorbed from the gastrointestinal tract is a major determinant (for calcium and zinc), tissue utilization of the absorbed nutrient and renal conservation (Se) are also important factors influencing bioavailability. Se bioavailability depends on the conversion of absorbed Se into a biologically active form and 9 tissue retention . However, because tRNAMet does not discriminate between Met and Se-Met, a greater percentage of Se-Met is incorporated nonspecifically into body proteins in place of Met in 10 low Met diet . Selenium levels in blood and tissues are very much influenced by dietary selenium intake. Normal blood level varies from 0.05 to 0.34 μg/ml. In selenium deficient areas of China, blood levels are as low as 0.009 μg/ml. Total body selenium has been estimated to be approximately 4 to 10 mg. Selenium is assimilated more effectively from plant food than animal products but some dietary constituents (vitamin C and vitamin E) generally affect its absorption. Selenium is absorbed mainly from duodenum and is transported actively across the intestinal brush 11 border . Selenomethionine and selenocysteine, as obtained from their dietary sources, are probably catabolised to release Se for incorporation into selenoproteins. Selenomethionine can be deposited in tissues and be taken up also by myoglobin, cytochrome C, myosin, aldolase and nucleoproteins. The main route of selenium excretion is urine and very small amount is excreted through 12 feces and expired air (Figure 1). Chronic feeding of inorganic Se compounds (>5 ppm) can be Figure 1: A scheme for selenium Absorption, Metabolism, Distribution and Excretion14 B0, amino acid transport system B0; GPx3, glutathione peroxidase 3; GS-Se-GS, selenodiglutathione; GS-SeH, glutathioselenol; GSSG, glutathione disulfide; SeCys, selenocysteine; SeMet, selenomethionine; SePP, selenoprotein P; ?, mechanism not known JPMI 2012 Vol. 26 No. 02 : 120 - 133 121 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW Figure 2: Human Selenoproteome Antioxidant Enzyme s GPx1 GPx2 GPx3 GPx4 GPx6 Sel K Sel R Sel W Redox Signalling Thyroid Hormone Metabolism Selenocystei ne Synthesis DIO1 DIO2 DIO3 SPS 2 Trx R 1 Trx R2 Trx R3 hepatotoxic and teratogenic in animals and humans. Intake of dietary Se-Met is reflected in the Se-content of human skeletal muscle which may vary according to the population; the highest in Japanese adults (1700 ng/g) and the lowest in New Zealand adults (61 ng/g) and in the populations of Se poor regions. In plasma, Se is mainly found in the albumin fraction and in erythrocytes, mainly incorporated into 11 hemoglobin . Se in the form of Se-Met is also 13 significantly retained in proteins in the brain . SELENOPROTEINS In molecular biology a selenoprotein is any protein that includes a selenocysteine (Se-Cys) 11 amino acid residue . About 25 different selenocysteine-containing selenoproteins have so far been observed in human cells and tissues. Since lack of selenium deprives the cell of its ability to synthesize selenoproteins, many health effects of low selenium intake are believed to be caused by the lack of one or more specific 13 selenoproteins . Papp et al 2007 classified the selenoproteins on the basis of their determined or potential function (Figure 2). The first identified selenoprotein was glutathione peroxidase 1 (GPx1) and the GPx family subsequently became one of the more fully characterized groups of selenoproteins. In Humans GPx1 through GPx4 and GPx6 are selenocysteine containing enzymes. Iodothyronine deiodinase (DIO) have three subtypes, DIO 1, 2, and 3. The selenoenzyme thioredoxin reductase (TrxR) is involved in disposal of the products of oxidative metabolism 14 and also has three subtypes . A summary of some of the selenoproteins is given in the Table 1. SELENIUM BIOMARKERS There is heterogeneity in the response of biomarkers towards selenium intake. Plasma, JPMI 2012 Vol. 26 No. 02 : 120 - 133 Transport & Storage of Se Sel P Protein Folding (Potential) Sel 15 Sel N Sel M Sel S Unknown Function Sel H Sel I Sel O Sel T Sel V erythrocyte and whole blood selenium, plasma selenoproteins P, and plasma, platelet and whole blood glutathione activity are good biomarkers of selenium status in the body. The usefulness of other potential biomarkers including urinary selenium, plasma T3/T4 ratio, plasma thyroxine, plasma total homocysteine, hair and toenail selenium and muscle glutathione peroxidase activity has not been established. For these potentially useful biomarkers, more information, in terms of effects of varying intakes, duration of intervention, baseline selenium status and effects of genotype, is needed to evaluate their strengths 39 and limitations in different populations . SELENIUM AND HEALTH Today, Selenium deficiency is suggested to implicate in the pathogenesis of wide variety of processes that affect our state of health and longevity. The list of clinical disorders expected to be influenced by Se deficiency is rapidly growing with time. Se deficiency has also been observed 112 during total parentral nutrition (TPN) . Some selected issues regarding the role of Se in health and disease have been briefly outlined as follows: AGING In humans, some controversy exists concerning the effects of Se levels on aging. Circulating Se concentrations either fall slightly or remain stable with age. However, the tissue distribution may be altered. The free radical theory 40 of aging states that aging is the result of cumulative damage incurred by free radical reactions as well as progressive defects in protection against free radical reactions with the passage of time. Free radical mediated lipid peroxidation in lysosome membrane leak out lysosomal hygrolases which cause dystrophic changes in muscle fibers. As a result, muscles 41 become weak with growing age . Lipid 122 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW Table 1: A Summary of Selenoproteins Name S. No. Tissue Distribution Function An antioxidant enzyme, decomposes H2O2 and other hydroperoxides Protection against certain cancers17 Protection against neurodegenerative diseases18,19 Cytosolic GPx (GPx1) All, including thyroid16 Phospholipid hydroperoxide / Sperm capsule selenoprotein (GPx4) All, including thyroid, sperm tail16 Metabolism of lipids20 Protective role in cardiovascular diseases Structural protein in spermatozoa and shields developing sperm cells21 Gastrointestinal GPx (GPx2) Gastrointestinal tract16 Antioxidant Extracellular GPx (GPx3) Plasma, thyroid16 Regulating the bioavailability of nitric acid produced from platelet and vascular cells22 Mediator of effects of estrogen in terms of fat mass23 GPx6 Embryo, olfactory epithelium in adults24 Thioredoxin reductase(TrxR) All, including thyroid16 Iodothyronine-deiodinase (DIO1) Liver, kidneys, and thyroid16 Iodothyronine-deiodinase (DIO 2) Central nervous system, and pituitary16 Iodothyronine-deiodinase (DIO 3) Brown adipose tissue, central nervous system, and placenta16 4 Selenoprotein P Plasma16 5 Selenoprotein W Muscle, heart, brain, and tongue16 Antioxidant 6 Selenoprotein K Heart, skeletal muscles31 Antioxidant 7 Selenoprotein V Testes Unknown(Suggested redox function)30 8 Selenoprotein S All Regulation of cellular redox balance3 9 Selenoprotein R Liver and kidney32 Antioxidant 10 Selenoprotein M Brain, thyroid33 Redox function23 11 Selenoprotein 15 Brain, lung, testis, liver, thyroid, and Kidney34 Regulation of apoptosis38 12 Selenoprotein N Skeletal Muscles, brain, lung and placenta35 Presumably regulates calcium channels in redox balance37 13 Selenophosphate Synthetase 2(SPS2) All23 Biosynthesis of selenocysteine36 1 2 3 JPMI 2012 Vol. 26 No. 02 : 120 - 133 Provides protection to skin from free radicals25 Protein thiol redox regulation Vitamin C recycling and DNasynthesis26 Synthesis of active thyroid hormone27 Functions as an antioxidant In the transport of selenium28 Protection against Hepatitis B virus X protein induced lipid peroxidation29 24 peroxidation and accumulation of carbonyl moieties on protein are produced by oxidative stress. Mitochondria accumulate age-related damage, releasing more reactive oxygen species. Thus, GPx and other selenoproteins may play a role in slowing cellular damage and the aging 42 process by scavenging free radicals . GPx, a selenium containing antioxidant enzyme which scavenges H2O2 and prevents the initiation of free radical chain reaction, has been theorized to extend Antioxidant life span and prevent age related functional disorders. Selenium deficiency plays a crucial role in causing or aggravating anemia and cell destruction as glutathione peroxidase protects red blood cells from free radical damage and destruction. Ji et al also observed the age related decline in GPx activity and its impact on the 43 genesis of various diseases . Moreover, the efficiency of the immune system declines with age. In humans, low Se status in the elderly was 123 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW Figure 3: adapted from H. Tapeiro et al . (a) Selenium compounds in cancer prevention. (b) Methylated selenium compounds. Methylated selenium compounds have been shown to modify various biological processes including suppression of angiogenesis and cancer prevention. Se ingested as Se-Met may follow the transsulfuration pathway, converted to Se-Cys and then cleaved to produce selenide. In contrast, Se-methyl selenocysteine (SeMSC) may be converted to methyl selenol by cleavage of the Se-methyl group. The chemical form of Se found in broccoli is similar to that found in Se garlic and the inhibition of carcinogenesis seems to be a consequence of the uniqueness of Se in those plants and not a consequence of the total intake of Se, garlic or broccoli. 104 correlated with lower triiodothyrinine to thyroxine ratios due to the raised thyroxine concentrations. Se supplementation decreased the serum thyroxine 44 concentration . A deficiency in thyroxine to triiodothyrinine conversion will affect general 45-48 metabolism including immunity . Finally, telomere length decreases with age in peripheral leukocytes and is accelerated by oxidative stress in fibroblasts. The rate of telomere shortening and carbonyl group accumulation was inversely 49 correlated with GPx activity in fibroblasts . Serum selenium concentration is associated with 50 metabolic factors in the elderly . IMMUNE FUNCTION Although the mechanisms involved have yet to be fully elucidated, significant amounts of Se present in lymph nodes, liver and spleen signify 51 its role in immunity . The effects of Se deficiency can include reduced T-cell counts, impaired 52 lymphocyte proliferation and responsiveness . Dietary supplementation of humans with 200 mg of sodium selenite enhances T-lymphocyte immune 53 responses . A progressive decline in plasma Se has JPMI 2012 Vol. 26 No. 02 : 120 - 133 been widely reported in adult respiratory distress syndrome (ARDS) and AIDS patients, and approximately parallels T-cell loss or stage of HIV infection. Chronic oxidative stress has been reported during the early and advanced stages of HIV-1 infection. It is particularly noticeable at the terminal stages of disease where Se deficiency is now considered a classical symptom/sign of end stage. There is an extremely high turnover of CD4 T-cells in AIDS, with billions of new cells lost and replaced daily. The constant formation of new cells to replace those lost requires an extremely efficient and effective Se supply to keep up with the high demand in active lymphocytes. Sub-clinical requirement for Se by lymphocytes and granulocytes will clearly not be as great when the immune system is not overly stressed. After selenium supplementation, the range of variation in % change in selenoenzyme activity between individuals may reflect the tocopherol status of the blood cells. Lymphocytes and granulocytes can contain up to 35 times more alpha-tocopherol than red blood cells or platelets, probably reflecting preferential mobilization to cells with different metabolic need. All of these cells are capable of 124 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW increasing their metabolic activity as a function of their immunosuppressive role. In doing so, membrane sensitive oxidases are generated which oxidise NADH and NADPH thereby increasing O2 utilization and its subsequent reduction to reactive oxygen species (ROS). Tocopherol and Se supply to these cells is therefore essential to provide control over their functional generation of 54 excessive ROS . ASTHMA Evidence of an extended role of GPx4 beyond that of an antioxidant comes from the work 55 of Weitzel and Wendel (1993) , who have demonstrated that GPx4 regulates the activity of lymphocyte 5-lipoxygenase, and Steinhilber D et 56 al , who show that GPx 4 supresses 5lypoxygenase activity in lymphocytes and granulocytes. Consequently, GPx 4 may have a regulatory role in the inflammatory response through suppression of lypoxygenase catalysed leukotriene biosynthesis from arachidonic acid. Moreover, it has been hypothesised that vitamin E may have a regulatory influence over leukotriene biosynthesis as a substrate for both n-6 and n-3 57 unsaturated fatty acid desaturase enzymes . This indication, that functional selenium and vitamin E status may influence leucotriene metabolism, has important implications in relation to chronic inflammatory disease, particularly asthma which is now the most prevalent chronic inflammatory condition in childhood, and has doubled over the last 20 years in the UK. There is a dramatic rise in the prevalence of asthma in the UK which mirrors the dramatic decline in blood Se concentration. This situation has the potential to exacerbate the imbalance in n6/n3 fatty acid status already recognized as involved in the pathogenesis of the disease. Moreover, Se status is decreased in patients with asthma, as is activity of glutathione peroxidase in platelets and erythrocytes. There is an associated marked oxidant/antioxidant imbalance in the blood of asthmatics, which reflects poor antioxidant status and enhanced 58 inflammatory mediated oxidative stress . According to the University of Maryland Medical Center, a 2004 study of 24 asthmatics that were given selenium supplements for 14 weeks had significant improvement in their symptoms when compared to a control group given a placebo. Although this is a small study done over a short 59 amount of time, it's encouraging . DIABETES MELLITUS The evidence supporting an effect of selenium on the risk of diabetes is variable, occasionally conflicting, and limited to very few human studies. Following a trial investigating the effect of selenium supplementation (200 μg/day) on skin cancer, subsequent analysis showed that there was an increased risk of developing type 2 60 diabetes in the supplemented group . Evidence JPMI 2012 Vol. 26 No. 02 : 120 - 133 from analysis of NHANES III supports these findings; the adjusted mean serum selenium concentrations were slightly, but significantly, higher in diabetics compared with those without the disease. This study, conducted in an elderly French population, found a sex-specific protective effect of higher selenium status at baseline on later occurrence of dysglycemia; that is, risk of dysglycemia was significantly lower in men with plasma selenium in the highest tertile compared with those in the lowest tertile (14.21–78.96 ng/ml) (HR: 0.48, 95% CI: 0.25–0.92), but no significant relationship was 62 observed in women . Cross-sectional case–control analyses have also given mixed results. A number of studies have found a lower selenium status in diabetic patients 63,64 compared with controls , which is in contrast to 61-65 the findings from the NHANES III analysis . Analysis of the Health Professionals Follow-up Study found the prevalence of diabetes to be greater in men with the lowest tertile of toenail selenium (OR: 0.43, 95% CI: 0.28–0.64) compared 66 with the highest tertile . The study also analyzed men with both diabetes and CVD compared with controls, but no association was found. Due to the global variations in selenium status these studies may not be directly comparable, and the results may in fact indicate a U-shaped risk curve, which could be further complicated by other diseases associated with diabetes. The mechanisms behind this potential Ushaped risk association have not yet been clearly defined. In its role as an antioxidant, particularly within the GPxs, selenium is likely to be important in reducing oxidative stress, an important risk factor for developing diabetes. There are also plausible suggestions that selenium can influence glucose metabolism. However, at high intakes it is also conceivable that reactive oxygen species could be generated or selenium may accumulate in the 69 organs associated with glucose metabolism . In patients with diabetes, selenium supplementation (960 μg/day) reduced NF-κB levels to those 67 comparable with nondiabetic controls . Animal model work has also suggested a role for selenium supplementation in reducing some biochemical effects of diabetes. The study also suggested that treatment with selenium may influence aspects of other chronic diseases associated with diabetes, for example, by decreasing the levels of serum markers of liver damage. Expression of SelS was found to be significantly lower in diabetic rats in a fed state compared with normal control animals and appears to be regulated by glucose. Whatever the mechanisms responsible, current evidence implies that both low and high selenium intakes could influence the risk of diabetes, and this relationship requires further investigation through 68 good quality human studies . 61 125 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW HIV/AIDS Chronic oxidative stress has been reported during the early and advanced stages of HIV-1 70 infection . Oxidative stress has been linked to 71 HIV-induced apoptosis of T lymphocytes , to alterations in the HIV promoter that may produce 72 progression to AIDS in patients with latent HIV 73 and to the development of AIDS Kaposi sarcoma . It has also been identified as one of the 74 factors that may lead to neural damage . In addition, oxidative stress may induce alterations in the interleukin profile, contributing to immune deregulation and increased viral replication during 74 the progression of HIV-1 infection to AIDS . Selenium and its biologically active compounds play a vital role in maintaining the normal immune system and preventing the alteration in cells, thereby controlling the occurrence and progression o f v i r a l i n f e c t i o u s d i s e a s e s u c h a s H I V. Biochemical deficiency of vitamins A, B6, B12 and zinc levels has been associated with an increased rate of disease progression while normalization of these levels has been linked to 76,77 slower disease progression . In HIV-infected patients, Se deficiency has been significantly correlated with total lymphocyte counts. Plasma Se levels have been positively correlated with CD4 cell counts and CD4/CD8 ratio. Loss of CD4T cells in HIV1 infection was found to be closely associated with depletion in 78 plasma selenium level . It has been suggested that the increased oxidative stress in HIV infection is caused by elevated IL-8 levels which exhausts the available Se to protect cells against the 79 inflammatory response . Minor concentration of reactive oxygen species induces the expression and replication of HIV in human T cells. This effect is mediated by the activation of NF-KB, transcription factor via H2O2. In vitro models have shown that Se enhances interleukin-2 production in a dosedependent manner (the cytokine responsible for the earliest and most rapid expansion of T lymphocytes). This probably occurs via the 80 increased expression of high-affinity receptors . In addition, Se reduces TNF receptors and prevents the adverse effects of high circulating TNF levels including Kaposi's sarcoma. It seems also to suppress TNF induced HIV replication probably through selenoproteins synthesis particularly in the 78,81,82 GSH and Trx systems . Thus, maintaining an optimal Se status in HIV-1 infected men and women may help to increase the enzymatic defense 83,84 and improve general health in those patients . CARDIOVASCULAR DISORDERS Low blood Se concentrations have been associated with increased cardiovascular disease mortality. In an epidemiological study, an excess of incidence of mortality from ischemic heart disease in eastern Finnish men and women with low serum selenium concentrations was observed, JPMI 2012 Vol. 26 No. 02 : 120 - 133 suggesting that low selenium levels have a causal effect in development and deterioration of 85 ischemic heart disease . Free radicals are toxic to the myocardium and can cause tissue damage that leads to extensive necrosis, myocytolysis and 86 cellular edema Atherosclerotic plaque formation may be a reflection of sub-optimal GPx4 activity in the prevention of LDL oxidation, with subsequent uptake by endothelial cells and 91 macrophages in arterial blood vessels . Selenium via GPx reduces phospholipids, hydro peroxides and cholestryl esters associated with lipoproteins and may there f o re, not only reduce the accumulation of oxidized LDL in arterial wall but also reduce platelet aggregation and activation of 87 monocyte and macrophages . Selenium owing to its antithrombotic effect on the interaction between platelets and endothelial cells via GPx, also provides concrete evidence in the prevention of 88 atherosclerosis . Kharb, in her study on acute myocardial infarction (AMI) patients, observed that selenium dependent GPx level decreases significantly in AMI patients and explained it as an imperative consequent of GPx activity in annihilating oxygen toxicity by metabolizing H 2 O 2 and inhibiting further free oxygen radical production in early 89 phase of myocardial infarction . Decrease in selenium levels are also reported to produce 90 changes similar to lipid peroxidation . CANCER Among various antioxidant minerals, selenium t may prove to be of major significance as a prophylactic agent against cancer. Low blood selenium concentration and incidence of carcinognesis have been well observed in both 92 93 animals as well as in human studies . In addition, it has been demonstrated in a double blind randomized cancer prevention trial in humans that increased selenium intake has a significant role in 94 the treatment of cancer . Various investigators have reported the role of selenium as an inhibitor of carcinogenesis in various organs including liver, skin, stomach, mammary gland and oral cavity 95,96 etc . In vitro and In vivo studies on selenium supplementation also suggested that selenium inhibits cell growth and DNA synthesis in a variety of cell lines leading to the normalization of regulatory pathways that are affected in early 97,98 stages of carcinogenesis . Klein et al, on the basis of SELECT (Se and vitamin E cancer prevention trial) in humans, concluded that treatment with a high dose of Se in combination with vitamin E can prevent the incidence of prostrate cancer. This reflects the importance of Se 99 and vitamin E in the etiology of cancer . Despite numerous investigations regarding the prophylactic role of selenium against cancer, the exact mechanism behinds its role is still a matter of debate and needs further investigation. However, in 126 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW order to explore the hidden mechanism involved in chemopreventive action of selenium, it has been suggested that irrespective of its antioxidant role (as component of GPx enzyme) with optimal selenium concentration, high dose of selenium induces oxidative stress and apoptosis in cancer 102 cells . Furthermore, to emphasize its chemopreventive action, Spray et al have also reported that selenium inactivates the transcription factor NF-KB, thereby leading to inhibition of cell 100 growth . Another marked explanation for selenium activity includes its direct role in the liver mixed function oxidase system that is responsible for the 101 metabolism of chemical carcinogens . Although the mechanism for Se inhibition of carcinogenesis is still unclear, it might be associated with the monomethylated form of Se that can be metabolized to methylselenol which may provide 103 better cancer protection . Other mechanisms proposed for anticancer action of selenium include antioxidant effects, enhanced carcinogen detoxification, enhanced immune surveillance, modulation of cell proliferation, inhibition of tumour cell invasion, and inhibition of angio105 genesis . There is evidence of anticar-cinogenic activities for several intermediary metabolites of naturally occurring organic and inorganic forms of 51 selenium . MALE FERTILITY Selenoprotein P transports selenium 107 particularly to testis and brain . Inactivation of selenoprotein P gene in mice due to selenium deficiency generally effects the normal functioning 106 of testis leading to male infertility . In addition, testis has the highest selenium concentration among the reproductive organs and studies on GPx activity in humans have revealed that this enzyme is the metabolic mediator of body selenium and protects spermatozoa against pro-oxidant induced death and oxidative injury, which reflect the importance of selenium and its related enzymes 108 during spermatogenesis . Among the five enzymes of GPx, GPx1 prevents apoptosis induced by oxidative stress and GPx4 acts directly on membrane phospholipid hydroperoxides and detoxifies them. GPx polymerizes to form a structural protein into mitochondrial capsule and thereby shields the developing sperm cells from 13,108 oxidative stress . Selenium as GPx, is present in spermatids and forms the structural part in the mid piece of mature spermatozoa. Some well known effects of selenium deficiency include instability of the middle piece leading to defective sperm 109 motility , low reproductive ability and abnormal 110 development of spermatozoa . Selenium is also required for testosterone synthesis and sequential 111 development of flagella . It can restore the physiological constitution of polyunsaturated fatty 112 acid in the cell membrane . A study on infertile men with unilateral JPMI 2012 Vol. 26 No. 02 : 120 - 133 varicocele or genital tract inflammation, showed the observation that glutathione treatment has a statistically significant positive effect on sperm motility, sperm morphology and sperm quality and suggested the therapeutic importance of 113 Glutathione against male infertility . Testes are extremely resistant to Se depletion and have high Se content. Recent studies have shown that sperm and testicular Se was unaffected by the supplementation, suggesting that testes are protected from Se 114 excess as well as from Se deficiency . PRE-ECLAMPSIA Pre-eclampsia (pregnancy induced hypertension; PIH), is an important cause of maternal morbidity and mortality with essentially unknown etiology (i.e., the precise factors involved 115 in the pathogenesis of PIH are still unknown) . It has been conceived that free radical mediated oxidative stress may contribute to the development of pre-eclampsia. Selenium and its related enzymes specially GPx play a crucial role in annihilating oxygen toxicity and there by controlling the 116 progression of disease . In addition, selenium deficiency in women may result in infertility, 117 miscarriages and retention of the placenta . Furthermore, Han and Zhon studied the effect of selenium supplement in 52 pregnant women with high risk factors of pregnancy induced hypertension (PIH) and concluded that selenium supplements prevent and decrease the incidence of 118 PIH and gestational edema in pregnant women . GASTROINTESTINAL PROBLEMS Selenium deficiency has been observed in patients with severe gastrointestinal disorders. James et al reported that selenium in association with other trace element (Zn, Cu and Mn) perform numerous functions indispensable to maintenance 119 of life, growth and reproduction . Gastrointestinal problems that impair selenium absorption usually affect absorption of other elements as well and thereby, impair cellular and physiological functions leading to the development of various patho120 physiological conditions . THYROID METABOLISM A selenoenzyme, Iodothyronine deiodinase, catalyzes the biotransformation of 121 thyroxine (T4) to triiodothyronine (T3) . These Deiodonases also catalyze the breakdown of T4 to reverse T3, degrade T4 to T2, inactive T3 and regulate the hypothalamic-pituitary-thyroid 122 axis(HPTA) . Selenomethionine, of which Se is the chief constituent, supplementation produced no clinically significant changes in thyroid hormone 123 concentration . KESHAN & KASCHINBECK DISEASE Previously, it has been reported that selenium deficiency is most commonly seen in the development of two diseases, both of which are 127 SELENIUM IN HUMAN HEALTH AND DISEASE: A REVIEW only seen in the People's Republic of China, where acutely low soil levels of the element are detected. Keshan disease is a cardiomyopathy of children and young women and manifests as acute or chronic cardiac enlargement and arrhythmia. Kaschinbeck disease is an osteoarthropathy that occurs mainly in young people. This disease shortens the fingers and long bones with severe enlargement and dysfunction of joints resulting in retardation of growth. Although they are multifactorial in origin, selenium deficiency is a major factor in their etiology and both the diseases are effectively prevented by therapy with selenium 16,124 supplementation . RHEUMATOID ARTHRITIS Scientific research shows that people with rheumatoid arthritis have low levels of selenium. A study suggests, it is part of the body's defense mechanism. The authors found lower selenium levels in patients with rheumatoid arthritis who were treated with arthritis medication compared 125 with people without the condition . In people without rheumatoid arthritis or a family history of the condition, low levels of the mineral may increase the risk of developing rheumatoid 126 arthritis . However, scientific findings supporting the link are conflicting. Further research is n ec e s s a r y t o s u p p o r t th e u s e o f s ele n iu m supplements. SELENIUM TOXICITY High Se levels in blood can result in a toxic condition called “selenosis”. Symptoms of Se toxicity include gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, irritability, 127 fatigue and mild nerve damage . National Academy of Sciences has set a tolerable upper intake level of selenium at 400 micrograms per day for adults to prevent the risk of developing 128 toxicity . CONCLUSION Selenium has long been a source of concern as a toxic element but research over time has shown that it is vital for human health. Selenium is the chief component of the selenoproteins which exert their major role as antioxidants. An adequate level of body Se status is essential for exerting its beneficial effects. Different biomarkers have been evaluated for the measurement of selenium in the body. Population S e l e n i u m l e v e l s a r e d i ff e r e n t i n d i ff e r e n t geographic areas of the world because of variability in selenium content of soil. Individuals may have differing metabolic needs for selenium, regulated at the level of Se dependent cell function, for example in relation to immunoresponsive roles, depicting pharmacogenetic variability among individuals. 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