Se is the 34th element in the periodic table, and it was discovered in the early 19th century by the Swedish chemist Jöns Jakob Berzelius (1779-1848). This element was investigated for a long time because of its toxic effects and possible carcinogenic properties. Hitherto only one chemical form of Se, selenium sulphide, has been recognized as a carcinogen [8]. In the middle of the 20th century it was discovered that Se is an essential micronutrient for mammals, microorganisms and other eukaryotes [9, 10]. In the 1970‘s Se was identified as an essential micronutrient for humans, and it was shown that Se has to be included in the human diet. Selenium participates in some of the key metabolic pathways, such as thyroid hormone metabolism [11 – 13], oxidative stress defense [14 – 16], and immune system [17], as it is present in the active site of the selenoenzymes that control these pathways. The effect of Se in mammals‘ health is exerted mainly through its incorporation into selenoproteins (i.e. proteins that contain Se as an integral part of the active site) as the amino acid selenocysteine, the 21st amino acid.
In humans, there have been identified 25 genes that encode selenoproteins [18], which were broadly classified as antioxidant enzymes, despite their exact function is not known for all of them [16]. The most studied selenoproteins in mammals are glutathione peroxidases (GPx), thioredoxin reductases (TR), and iodothyronin deiodinases (ITD). Additionally, other mammalian selenoproteins have been identified, such as selenoproteins H, M, T, V, W, K, S, O, and I [19], whose function has not been established so far.
Glutathione peroxidase (GPx) was the first human selenoezyme discovered [20]. This enzyme is responsible for oxygen metabolism and detoxification at cellular level. The GPx isoforms are well known to be the major components of the antioxidant defense [15], as they catalyze the destruction of hydrogen peroxide and lipoperoxides [10]. They can be found mainly in the cytosol (GPx1), gastro-intestinal mucosa (GPx2), plasma (GPx3), liver and kidney (GPx4), and olfactory epithelium and embryonic tissues (GPx6). This enzyme was the first functional biomarker of Se in mammal organisms, and it is still considered as a reliable index of Se status in humans and animals [21, 22]. Thioredoxin reductase is able to reduce oxidized thioredoxin. It is involved in the repair of methionine sulfoxide oxidized proteins, and also in redox signaling via hydrogen peroxide [15]. Additionally, TR participates in several cell signaling pathways through controlling the activity of transcription factors such as
Selenium and Health: Discovering Nutritional Biomarkers 93 NF-k and p53 [23]. Therefore, TR plays a crucial role in the control of cell proliferation, viability and apoptosis [15], and thus, it would be implicated in cancer prevention and cure. This group of selenoproteins can be found in cytosol and in nucleus (TR1), mitochondria (TR2) and testis (TR3).
Iodothyronine deiodinases (ITD1 and ITD2) catalyze the deiodination of thyroxine (T4, the major thyroid hormone) into its active form (T3), while IDT3 catalyzes the conversion of T4 into reverse-T3, thus maintaining the homeostasis of the thyroid hormones [14].
There is another group of selenoproteins whose biological roles have not been established yet. Selenoprotein P (SelP) is the most abundant selenoprotein in the blood plasma. SelP has 10 selenocysteine residues per molecule, and its main function would be the transport and delivery of Se to the tissues, and also to act as heavy metal chelator [15]. It is believed that its function is related to selenium homeostasis and oxidant defense [24]. Selenoprotein 15 (Sep15) belongs to the thioredoxin-like fold superfamily of proteins, and it is believed to be involved in glycoprotein folding in endoplasmic reticulum [25].
Selenoprotein R (SelR) reduces methionine-R-sulfoxides [15]. Selenoprotein W (SelW) is expressed in the nervous system, heart and muscles, and its functions would be related to muscle growth and differentiation by protecting the cells from oxidative stress [26].
In summary, Se plays crucial roles in different cellular metabolic processes such as oxidative stress defense, cell growth and proliferation, by means of selenoproteins.
3.S
ELENIUMM
ETABOLISMSe metabolism depends on the chemical form in which it has been incorporated in the organism. Plants can take up Se from soil, mainly as selenite or selenate salts, depending on the redox equilibrium in the soil, and also on other factors [27], and convert it to organic selenium compounds, such as seleno-amino-acids. Despite Se is not recognized as essential for plants, it has been demonstrated that Se fertilization produces antioxidant effects [28 – 30]. Selenium is metabolized by the incorporation pathway of sulfate, through the action of sulfate permease found in roots. Se (IV) is accumulated without suffering any transformation, while Se (VI) is transformed into seleno-amino-acids through the non-enzymatic reduction by glutathione. The seleno-amino-acids are finally incorporated in proteins [30], which contributes to Se toxicity in non-accumulator plants.
Some plants have the capacity to accumulate Se, thus representing an important source of Se through the mammalian diet. Some of these plants belong to Brassicae, which are recognized as Se hyper-accumulators [8]. In these plants, selenocysteine is transformed into non-proteinogenic amino acids, such as Se-methylselenocysteine (SMSeC), by the action of the enzyme selenocysteine methyltransferase [31]. These forms are accumulated without producing toxic effects for the plant [32]. The accumulation of Se in the form of non toxic compounds has been postulated as the basis of Se tolerance in Se-accumulator plants, as a protection mechanism [33]. Brassicae can accumulate SMSeC up to a concentration of 2.8 mmol /g dry weight, when grown in Se enriched medium [34, 35].
In mammals, inorganic forms of Se may produce toxic effects, unlike some organic Se compounds, which can be excreted thus minimizing toxicity. Some forms of Se are preferably incorporated specifically in selenoproteins; other forms are incorporated in common proteins
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in a non-specific way, whereas other Se compounds are preferentially excreted [36, 37]. Selenocysteine is preferentially used in the synthesis of selenoproteins, as it is encoded as amino acid in the genetic code. Selenomethionine is incorporated in Se-containing proteins (i.e. proteins that have Se in their primary structure but not in the active site) by randomly replacing the amino acid methionine in a non-specific way. This non-specific incorporation of selenomethionine produces a great Se accumulation [35]. Inorganic forms of Se can be methylated to give low toxicity compounds [38] such as methylselenol, dimethylselenide, and trimethylselenonium ion. These Se compounds are excreted in urine and breathe [20, 39]. Seleno-amino-acids can also be methylated. SMSeC, a non-proteinogenic amino acid, serves as a precursor of methylselenol or methylseleninic acid [40], and then it exhibits a low body accumulation [41]. Some of these monomethylated forms of Se have proven anticarcinogenic effects, especially SMSeC and methylselenol [42 – 44].