June 22, 2015

22/06/2015: An update on the nutritional biochemistry of Selenium and recent developments in Se bioavailability

by WL Bryden, DD Moore and S Shini, School of Agriculture and Food Sciences, University of Queensland, Australia
First published in Milling and Grain, April 2015

Selenium exists in four oxidation states: elemental Se (Se0), selenide (Se−2), selenite (Se+4), and selenate (Se+6) in a variety of inorganic and organic matrices. The natural inorganic forms, selenite and selenate, account for the majority of total global selenium.

Organically bound selenide compounds are predominantly seleno-amino acids; the principle chemical form of Se in animal tissues is selenocysteine, while selenomethionine predominates in plants.
The chemistry of selenium resembles that of sulphur in several respects but these elements are not completely interchangeable in animal systems.

Both, sulphur and Se occur in proteins as constituents of amino acids. Sulphur is one of the most prevalent elements in the body and is present in the sulphur-containing amino acids: methionine, cysteine, homocysteine and taurine. Selenium is a trace element and a component of the amino acids selenocysteine and selenomethionine. Selenocysteine is considered the 21st amino acid in terms of ribosome-mediated protein synthesis.

Selenocysteine is identical to cysteine except that sulphur is replaced by a Se atom, which is typically ionized at physiological pH.

The presence of selenocysteine in the catalytic site of Se-dependent antioxidant enzymes enhances their kinetic properties and broadens the catalytic activity of the enzymes against biological oxidants when compared with sulphur-containing species. Selenocysteine (from animal tissues) and selenomethionine (from plants) are both sources of selenium for synthesis of SePs.

Replacement of selenocysteine by cysteine in a selenoprotein usually results in a dramatic decrease of enzymatic activity, confirming that the ionized selenium atom is critical for optimum protein function.

Biosynthesis pathway
Significantly, within all cell types there is a specific biosynthesis pathway that facilitates selenocysteine synthesis and its subsequent incorporation into SePs Cellular Se concentrations are therefore tightly regulated. The regulation of selenoprotein synthesis is central to understanding Se homeostasis and disorders following the failure of homeostasis.

Cellular Se concentration is a key regulator of its incorporation into SePs and acts mainly at the post-transcriptional level in response to alterations in Se bioavailability. Selenocysteine biosynthesis represents the main regulatory point for selenoprotein synthesis and not absorption as occurs with many nutrients.
The biochemistry of Se is different from most other trace elements as it is incorporated in proteins (SePs) at their highest level of complexity and function. Selenoproteins incorporate selenium only in the form of selenocysteine and this occurs during translation in the ribosome using a transfer RNA specific for selenocysteine.

Seleno-amino acids (selenocysteine or selenocystine and selenomethionine) are required for the synthesis of selenium-containing peptides and proteins.

Importantly, selenomethionine (the major dietary organic form of Se) that is biochemically equivalent to methionine, is not incorporated into selenoproteins and therefore, is not a participant in the regulation of selenium homeostasis. There are no known human or animal functionally active SePs that contain selenomethionine.

Only proteins that are genetically programmed and perform essential biological functions are classified as SePs. Some of these SePs are enzymes such as the six antioxidant glutathione peroxidases and the three thioredoxin reductases; the three deiodinases are involved in thyroid function by catalysing the activation and deactivation of the thyroid hormones.

Some SePs have direct roles in modulating immunity and reproductive function, while other SePs facilitate tissue distribution and transfer of Se.

Selenoprotein P, for example, functions as a transporter of selenium between the liver and other organs. The functional characterisation of many SePs remains to be delineated.

Absorption, distribution and metabolic rate
An overview of the metabolism of Se is shown in Figure 1.


Figure 1: General pathways (A) of selenium absorption, hepatic 
synthesis of selenoprotein P and distribution to various organs. 
Graphical representation (B) of the optimal range of selenium 
required to avoid various human clinical conditions 
(Adapted from Kumar and Priyadarsini, 2014)
Absorption of selenium occurs in the small intestine, where both inorganic and organic forms of Se are readily absorbed.
Selenite is passively absorbed across the gut wall, while selenate appears to be transported by a sodium-mediated carrier mechanism shared with sulphur.

Organic forms of Se are actively transported. The absorption of selenomethionine is via the same carrier transport protein as methionine, with competition taking place between methionine and its seleno analog. Selenium is distributed throughout the body from the liver to the brain, pancreas and kidneys.

The highest Se concentrations are found in the liver and kidneys but the greatest total concentration occurs in muscle because of their proportion of body weight. Selenium is transported by two SePs; selenoprotein P and extracellular glutathione peroxidase (GSH-Px).

Other transport mechanisms have been postulated but not delineated. Only insignificant transitory amounts of free selenomethionine are found in blood. Following protein turnover, the released Se, can be recycled via enterohepatic circulation or excreted. Selenium is eliminated primarily in urine and faeces.

The distribution between the two routes varies with the level of exposure and time after exposure.

In ruminants, selenite is the primary compound available for absorption because the reducing conditions within the rumen convert the majority of selenate to selenite.

In the rumen, about a third of selenite is converted to insoluble forms that are passed into manure. Of the soluble selenite that reaches the intestine, some 40 percent will be absorbed, compared to about 80 percent of selenomthionine. As a consequence of these differences, in cows, the digestibility of Se from selenite is around 50 percent compared to about 66 percent for selenium-yeast. There is no information on the impact of the gut microbiota on the Se requirements of monogastric animals.

Inorganic Se is recognised by the digestive tissues and is absorbed and converted into SePs.

In contrast, organic Se (selenomethionine) is not recognized as Se-containing by mammalian cells. As a consequence, selenomethionine is absorbed and metabolized relative to methionine needs.

If selenomethionine is broken down within the cell, Se is released and recognized by the cell as a mineral. It is then processed according to the need for Se.

However, if the cell does not break down selenomethionine, it may be inadvertently incorporated into a wide variety of proteins that are not genetically programmed to contain selenium.

The functionality of these proteins will be compromised. As a metabolic safeguard, neither dietary selenocysteine nor selenomethionine is directly incorporated into selenoproteins. All dietary forms of selenium must be metabolised and converted to selenocysteine and selenoproteins under the genetically controlled mechanism within the cell.

Much of the absorbed organic Se is transferred into the amino acid pool, where together with the existing intracellular pool, it is metabolised by different pathways (see Figure 1). From there, it is enzymatically converted in the liver to selenide, which serves as the Se source for selenocysteine synthesis.

Deficiency and requirements
Selenium acts biochemically in the animal or bird in a complimentary manner to vitamin E. Both nutrients prevent peroxidation of unsaturated fatty acids in cell membranes.

Most of the deficiency signs of these nutrients can be explained by their antioxidant properties. The requirement for each is therefore influenced by the dietary concentration of the other.

For example, the Se requirement of the chick is inversely proportional to dietary vitamin E intake. Thus Se has sparing effect on the requirement for vitamin E and vice versa.

Manifestation of Se deficiency can take many forms and varies between species. Muscular degeneration or white muscle disease occurs to varying degrees in all species. In birds, pancreatic fibrosis is an uncomplicated Se deficiency, whereas exudative diathesis (generalised oedema visible under the skin) is responsive to both Se and vitamin E.

Pigs with hepatosis diatetica (severe necrotic liver lesions) are responsive to Se supplements, while both Se and vitamin E are effective in treating mulberry heart disease (a dietetic microangiopathy). Reproductive disorders, including retained placenta in dairy cows, and lowered disease resistance are observed in all Se deficient species. Some species, such as rabbits and horses, seem to be more dependent on vitamin E than Se for their antioxidant protection.

This may reflect species differences in dependence on non-selenium containing GSH-Px.

Selenium presents a nutritional conundrum because it is both essential and highly toxic. There are several approaches to measuring Se status. These include the measurement of changes in plasma Se concentration, measurement of GSH-Px enzyme activity, and absorption/retention studies.

The use of stable isotopes of Se have been used in human studies and to determine endogenous forms of selenium in foods. All of these biomarkers are useful indicators of Se status but because of the role of Se in many biochemical pathways, a single indicator may not be an appropriate index of Se status.

Dietary supplementation
Selenium is routinely added to animal diets to ensure that requirements are met.

There has been increased interest recently in Se dietary supplementation to enrich animal products. The production of selenium-enriched meat, milk and eggs is viewed as an effective and safe way of improving the selenium status of humans.

There are a range of products available for dietary Se supplementation (see Table 1).

Selenium is commonly added to diets as sodium selenite.

However, there has been growing interest in dietary addition of organic Se. Organic sources are assimilated more efficiently than inorganic Se and considered to be less toxic and therefore more appropriate as a feed supplement.

Yeast has become the most popular vehicle for the addition of organic Se because of its rapid growth, ease of culture and high capacity to accumulate Se. The major product in selenized yeast is selenomethionine.

Selenomethionine was found to be four times more effective than selenite in preventing the characteristic pancreatic degeneration caused by selenium deficiency in chicks.

Selenium yeast (selenomethionine) was found to be much more effective than inorganic Se in increasing the Se concentration of cow’s milk. This is in accord with many animal studies and human clinical trials that have demonstrated the superior efficacy of L-selenomethionine, in increasing Se muscle content compared to inorganic Se. 

Figure 2. Proposed metabolic pathways for SeHLan and SeMet in

animal cells (Source: Tsuji et al. 2010)
Selenohomoalanthionine (SeHLan; 2 hydroxy-4-methylselenobutanoic acid) was recently identified in Japanese pungent radish and has generated much interest as it was less toxic in human cell culture than selenomethionine.
As shown in Figure 2, differences in metabolism between SeHLan and selenomethionine may, in-part, explain the apparent difference in toxicity. 
Selenomethionie mimics methionine by sharing the same metabolic pathways and can replace methionine in peptide synthesis, as noted above, and thus disrupt protein synthesis.

As shown in Figure 2, the proposed metabolic pathway for SeHLan appears to be much less complex; SeHLan is only utilised in the trans-selenation pathway for selenoprotein synthesis and therefore is not expected to interfere with the methionine metabolic pathways. The tissue distribution of these two selenoamino acids may also contribute to differences in toxicity.

Both are distributed throughout the body with higher liver and pancreas accumulation of selenomethionine in contrast to SeHLan which preferentially accumulates in the liver and kidneys.

At higher doses, selenomethionine has been shown to induce pancreas damage whereas SeHLan is excreted by the kidneys without inducing pancreatic damage.

Selenomethionine enriched yeast has been available commercially for many years.

Recently, a yeast product enriched with SeHLan has become available and a number of efficacy studies with growing pigs and broiler chickens have been conducted in Australia with these selenoamino acid sources.

In the studies both selenomethionine (Sel Plex) and SeHLan (AB Tor-Sel) were compared to sodium selenite. In the clean experimental conditions, as demonstrated on many occasions, dietary supplementation with both the inorganic and organic selenium resulted in similar animal and bird performance.

However, tissue accumulation was significantly greater when the organic forms of Se were fed, which is in accord with the literature. Interestingly, the yeast enriched with SeHLan generated significantly higher Se concentrations in muscle tissue than the selenomethionine enriched product.

The implication of this finding in both pigs and broilers may imply a greater efficacy of SeHLan in stressful commercial environments.

Selenium’s nutritional essentiality was discovered in the 1950s.

It is now clear that the importance of having adequate amounts of Se in the diet is primarily due to the fact that this micronutrient is required for the biosynthesis of selenocysteine as a part of functional selenoproteins.

Although animals, and presumably humans, are able to efficiently utilise nutritionally adequate levels of Se in both organic and inorganic forms for selenoprotein synthesis, it is clear that the bioavailability of Se varies, depending on the source and chemical form of the Se supplement.

Tissue enrichment with Se is greater when organic forms of the micronutrient are fed.

Organic selenium, in the form of yeast enriched with selenomethionine, is widely used in animal nutrition.

Recently, yeast enriched with SeHLan became commercially available and initial research suggests that it may be more efficacious than selenomethionine for tissue accumulation of Se.

This has obvious implications for the production of Se enriched animal products but may also be important in commercial production units. Greater tissue reserves of Se may enhance an animals’ resilience to stress and disease challenge.

A brief history of Selenium
Selenium (Se) is an essential trace element for animals and humans. It was discovered in 1818 and named Selene after the Greek goddess of the moon.

Selenium exerts its biological effects as an integral component of selenoproteins (SePs) that contain selenocysteine at their active site. Some 30 SePs, mostly enzymes, have been identified, including a series of glutathione peroxidases, thioredoxin reductases and iodothyronine deiodinases.

The majority play important roles in redox regulation, detoxification, immunity and viral suppression. Deficiency or low selenium status leads to marked changes in many biochemical pathways and a range of pathologies associated with defects of selenoprotein function may occur.

Selenium content of soils can vary widely.

In areas where soils are low in bioavailable Se, deficiencies can occur in humans and animals consuming plant-based foods grown in those soils.

Selenium deficiency have been reported in many countries including China, Japan, Korea, and Siberia, Northern Europe, USA, Canada, New Zealand and Australia. Within each country there are large regional differences in soil Se status and in some localities there are plants that accumulate Se resulting in selenosis or Se toxicity to grazing animals.

Dietary Se supplementation was first permitted some 40 years ago.

Since then, there has significant advances in our knowledge of Se metabolism and the important role that Se plays in animal productivity and health.

During this period, Se has become an important addition to dietary supplements for animals.

Further reading
Bellinger FP, Raman AV, Reeves MA, Berry MJ. 2009. Regulation and function of selenoproteins in human disease. Biochemical Journal, 422:11-22.

Brennan,KM, Crowdus, CA, Cantor, AH. et al 2011 Effects of organic and inorganic dietary selenium supplementation on gene expression profiles in oviduct tissue from broiler-breeder hens Animal Reproduction Science 125: 180– 188

Celi P, Selle PH, Cowieson AJ. 2014. Effects of organic selenium supplementation on growth performance, nutrient utilisation, oxidative stress and selenium tissue concentrations in broiler chickens. Animal Production Science 54, 966–971.

Fairweather-Tait SJ, Collings R. Hurst, R. 2010. Selenium bioavailability: current knowledge and future research requirements. American Journal of Clinical Nutrition, 91:1484S-1491S.

Kumar BS and Priyadarsini KI. 2014 Selenium nutrition: How important is it? Biomedicine & Preventive Nutrition 4: 333–341

Schrauzer GN, Surai PF. 2009. Selenium in human and animal nutrition: resolved and unresolved issues. Critical Reviews in Biotechnology. 29:2-9.

Tsuji Y, Mikami T, Anan Y, Ogra Y. 2010. Comparison of selenohomolanthionine and selenomethionine in terms of selenium distribution and toxicity in rats by bolus administration. Metallomics. 2:412-418.

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