Selenium in Foods

The selenium contents of foods vary widely, primarily because of variability in the soluble selenium content of the soil for plant species and in the biologically available selenium content of livestock diets. Because of the intimate relationship between plants and animals in the food chain, the selenium contents of foods from both plant and animal origins tend to be greatly influenced by the local soil selenium environment. The major forms of selenium in soil are selenite and selenate.

Foods of all types tend to show geographic patterns of variation in selenium content reflecting, in general, local soil selenium conditions. Variation in the selenium content of foods is readily seen by comparing the selenium contents of like foods from different countries (Combs and Combs, 1986). For example, whole wheat grain may contain more than 2 to 5 mg Se/kg (air-dried) if produced in the western parts of North and South Dakota in the United States or in Saskatchewan and Alberta in Canada. However, whole wheat grain may contain as little as 0.1 mg Se/kg if produced in Kansas or New Zealand, and only 0.005 mg Se/kg if produced in Shaanxi Province, China. On a global basis, foods with the lowest selenium contents are found in the provinces of Heilongjiang, northern Shaanxi, and Sichuan in China. Ironically, foods containing the greatest concentrations of selenium have also been found in China, though in different locales.

Most of the selenium taken up by plants is incorporated into organoselenium compounds such as SeMet, Se-methylselenocysteine, SeCys, and other related metabolites (Rayman et al., 2008). The selenoamino acids are synthesized

by plants and microorganisms when Se²⁻ replaces S²⁻ in the biosynthetic pathways for sulfur-amino acid synthesis. The selenoamino acids, particularly SeMet, then are incorporated into proteins. SeMet is the most abundant form of selenium in cereal grains and legumes, due mainly to the nonspecificity of the methionyl-tRNA synthetase which will use SeMet in place of Met for aminoacylation of the tRNA^Met.

Certain plant species called selenium accumulator plants, if grown on high-Se soils, can accumulate very large amounts of Se as non-protein selenoamino acids such as Se-methylselenocysteine, γ-glutamyl-Se-methylselenocysteine, and selenocystathionine. It is thought that these forms are less toxic because their formation prevents excess selenoamino acid incorporation into proteins. Se-methylselenocysteine is a major selenocompound in Se-enriched garlic, onions, broccoli florets, and broccoli sprouts, but γ-glutamyl-Se-methylselenocysteine becomes the major form when these vegetables are grown in soil with high selenium levels.

Animals ingest various forms of selenium, especially SeMet, in their diets. However, they do not have pathways for synthesis of cysteine or methionine from inorganic sulfur and hence do not incorporate large amounts of inorganic selenium into selenoamino acids. Of course, SeCys is synthesized cotranslationally in animals and is incorporated into selenoproteins at specific sites. However, animals can non-specifically incorporate SeMet from the diet into proteins in place of Met. SeMet is the dominant selenoamino acid in tissues of animals that are given high levels of SeMet in their feed, due to the nonspecific incorporation of SeMet in addition to selenoprotein synthesis. On the other hand, animals given selenite or selenate instead of SeMet incorporate selenium mostly as SeCys residues in selenoproteins because this is the only route for de novo selenoamino acid synthesis in animals. Thus, the total concentration of selenium in tissues of animals given selenite or selenate as the source of selenium is lower than that in tissues of animals given SeMet as the source of selenium. Because SeCys and SeMet are found mainly as part of proteins, the selenium content of foods tends to be correlated with protein content.

Small amounts of inorganic selenium compounds, especially selenate, are present in foods. Minor quantities of inorganic selenium are found in the drinking water, although the level depends on characteristics and the selenium concentration of the soil through which the water passes. Larger intakes of inorganic selenium occur only when selenium supplements in the form of selenate or selenite salts are taken.

The selenium content of foods of animal origin depends largely on the amount and form of selenium consumed by livestock. Food animals raised in regions with feeds of low selenium content deposit relatively low concentrations of selenium in their edible tissues and products (e.g., milk, eggs), whereas animals raised with relatively high selenium nutriture yield food products with much greater selenium concentrations, particularly if the feed contains SeMet. Because livestock need selenium to prevent debilitating deficiency syndromes, it is used as a feed supplement, usually as sodium selenite or sodium selenate, in animal agriculture in many parts of the world. This practice has reduced what would otherwise be a stronger geographic variation in the selenium content of animal food products. Within the normal ranges of selenium in livestock diets, muscle meats from most species tend to contain 0.3 to 0.5 mg Se/kg (fresh weight). Organ meats usually contain higher (4 to 15 times) concentrations of Se.

Selenium in Human Diets

The average daily selenium intake of adults is estimated to vary widely among different regions. In most human diets, the dominant food sources of selenium are cereals, meats, and fish. The dominance of cereal-based foods as core

sources of selenium means that, in many countries, selenium intakes can be affected by factors that influence the importation of grain from the world market, most of which is grown in areas of the United States, Canada, and Australia where the soil is rich in selenium.

Milk and milk products contribute small amounts of selenium to the total intake in most countries, although these foods may contribute a large proportion of total selenium intake in countries where their consumption is relatively high or where the rest of the diet provides little selenium, or both (e.g., New Zealand). Vegetables and fruits are uniformly low in selenium (fresh weight) and provide only small amounts (<8% of total Se intake) of the mineral in most human diets.

An analysis of American diets based on the U.S. Department of Agriculture 1977–1978 Nationwide Food Consumption Survey and published selenium contents of American foods revealed that a core of only 22 foods provided 80% of the total dietary selenium intake (Schubert et al., 1987). Five foods contributed half of total selenium in the “typical” American diet; these foods were beef, white bread, pork, chicken, and eggs.

The major forms of selenium in plant and animal tissues are analogs of the sulfur-containing amino acids, SeMet and SeCys. Plants tissues contain mostly SeMet, which plants synthesize. Animal and human tissues contain both SeMet obtained from dietary sources and SeCys in specific selenproteins which animals synthesize in conjunction with a specific tRNA. SeCys is the dominant form of selenium in livestock supplemented with inorganic forms of selenium.

Selenium Absorption

In general, the apparent absorption of selenium from food is efficient. Inorganic Se salts appear to be absorbed across the gut by diffusion, whereas SeMet is actively transported by the same system that transports methionine (Met). Accordingly, the enteric absorption of relatively large single doses (200 μg Se) was estimated to be 84% for selenite and 98% for SeMet (Patterson et al., 1989). The majority of selenium appears to be taken up by liver to reenter the circulation as selenoprotein P (SepP), which is essential for the normal distribution of selenium to extrahepatic tissues (Burk and Hill, 2009).

Selenium Metabolism

Recognition that the metabolic function of selenium is related to that of vitamin E (α-tocopherol) emerged with the demonstration that selenium could prevent pathological conditions in vitamin E–deficient rats (Schwarz and Foltz, 1957) and chicks (Schwarz et al., 1957). From this origin came the view of selenium as an antioxidant nutrient. Indeed, combined deprivation of selenium and vitamin E yields elevated levels of products of free radical attack on polyunsaturated fatty acids that are detectable in tissues (malonyldialdehyde, F₂-isoprostanes) and exhaled breath (ethane, pentane). Thus it is clear that selenium and vitamin E function in concert in cellular antioxidant protection. In this system, α-tocopherol functions as a lipid-soluble, chain-breaking antioxidant, whereas selenium is involved as one or more SeCys residues in one or more redox-active selenoproteins. Because the physiological role of selenium is as SeCys residues in selenoproteins, an important aspect of selenium metabolism is the incorporation of dietary selenium into these selenoproteins.

Reduction of Selenate and Selenite to Selenide

The various forms of selenium that are taken up from the gastrointestinal tract are metabolized ultimately to selenide (Ganther, 1999) (Figure 39-1). For the oxidized inorganic forms, this involves reduction. Selenate is converted to selenite via activation to adenosine phosphoselenate and reduction by reactions with reduced glutathione (GSH). Selenite, whether from the diet or formed from selenate, is converted to selenide by reactions that require GSH and NADPH as reductants and involve formation of a glutathione selenopersulfide (GSSeH) intermediate.

Plasma Forms of Selenium

The circulating plasma pool of selenium comprises two functional, specific selenoproteins (SepP1 and GPX3); the general non-specific SeMet in albumin and other plasma proteins; and a small amount of selenium in forms other than amino acid residues in proteins (e.g., selenosugars). SepP1 and GXP3 accounted for about 34% and 20%, respectively, (or a total of 54%) of the total plasma selenium pool in a group of healthy adult subjects in North Dakota in the United States, a region with relatively high selenium intakes and a mean plasma selenium level of 142 ng/mL (Combs et al., 2011). The proportion of plasma selenium contributed by the two plasma selenoproteins was estimated to be slightly larger (64%) in a group of subjects with plasma total selenium concentrations of 125 ng/mL, which are closer to mean values for the U.S. population (Burk et al., 2006). Maximal expression of the plasma selenoproteins occurs at intakes yielding plasma levels above 70 ng/mL, which is close to the plasma selenium levels estimated to be contributed by maximal expression of SepP1 and GPX3. Higher intakes of foods containing SeMet result in increases in the nonspecific incorporation of SeMet into plasma proteins and thus higher plasma selenium levels. Intake of inorganic forms of selenium does not result in an increase in this component of plasma selenium because animals do not incorporate inorganic selenium into SeMet (Burke et al., 2001).

Selenium Excretion

Metabolic tracer studies have shown that over a 12-day period, Se-adequate adults excrete a total of 17% of selenium from an oral selenite dose, but only 11% of selenium from an oral SeMet dose (Patterson et al., 1989). The primary route of selenium excretion is across the kidney; the dominant urinary metabolite in individuals with low-to-moderate Se intakes is the selenosugar 1β-methylseleno-N-acetyl-galactosamine (Kobayashi et al., 2002). Individuals with relatively high selenium intakes may excrete other compounds such as trimethylselenonium or other selenosugars in the urine and methylselenol in the breath.

Selenium Incorporation into Selenoproteins

Selenium is incorporated as SeCys in some 25 selenoproteins in animals (Kryukov et al., 2003). Neither SeCys from the diet or endogenous protein turnover nor SeCys formed in the body during SeMet catabolism can be used directly for the specific incorporation of SeCys into selenoproteins. Instead, inorganic selenide is activated and added in a cotranslational conversion of serine (Ser) to SeCys while the amino acid is bound to a specific tRNA (tRNA^[Ser]SeCys) (Figure 39-2). The selenium in selenoamino acids is used for selenoprotein synthesis only after the selenoamino acids have been catabolized to yield inorganic selenium.

The UGA Codon in Selenoprotein mRNA

Each SeCys center of a selenoprotein is encoded by a TGA in the respective gene, which is transcribed as UGA in the mRNA. This phenomenon, first recognized with the sequencing of the cDNA for GPX1, was unexpected because a UGA in mRNAs typically serves as a stop codon in mammalian protein synthesis. Studies on translation of selenoprotein mRNAs revealed that the 3′-untranslated region (3′-UTR) of the mRNA was necessary for UGA-encoded SeCys incorporation. Berry and colleagues (1991) identified a consensus 87-base stem–loop element necessary for the insertion of Se in two selenoproteins of the rat (iodothyronine 5′-deiodinase-1 and GPX1). This SeCys insertion sequence (SECIS) element has been found in the 3′-UTRs of the mRNAs of all selenoproteins. Most selenoprotein mRNAs contain a single UGA codon encoding a single SeCys residue per polypeptide chain and a single SECIS element. Selenoprotein P is unique in that its mRNA encodes multiple SeCys residues and contains two SECIS elements in its 3′-UTR.

As shown in Figure 39-3, the mammalian SECIS element consists of a stem–loop structure with an apical loop and an internal loop between two helical regions (stems). The apical loop consists of 7 to 10 unpaired bases, including a consensus AA (adenine–adenine) sequence. The helix between the apical and the internal loops contains an AUGA (adenine–uracil–guanine–adenine) sequence 5′ to the apical loop, and a GA (guanine–adenine) sequence 3′ to the apical loop. This AUGA … AA … GA motif is key to functionality, although a few mammalian SECIS elements have been found with a variant motif, AUGA … CC … GA. The conserved UGA and GA sequences form the core of a quartet motif of non–Watson and Crick base pairs (i.e., U-U and G-A), resulting in a greater than 90-degree kink in the stem–loop. Half of mammalian SECIS elements have an additional stem extending from the apical loop; it is thought that these specific secondary structures may affect the rate of SeCys insertion into various selenoproteins.

Archaea have the same SECIS element as eukaryotes. However, the prokaryotic SECIS consists of a 38-nucleotide stem–loop element located in the open reading frame of the selenoprotein mRNA immediately following the UGA codon (Bock et al., 2006). It is thought that constraints of maintaining this secondary structure may limit the capacity of bacterial genes to place SeCys at the active site of enzymes. In bacteria, a single elongation factor is required to bind the SECIS element and the SeCys-tRNA, whereas in eukaryotes and archaea, those roles are filled by different proteins: SECIS-binding protein (SBP2), which appears to bind to the AUGA/GA stem nucleotides, and a SeCys-specific elongation factor (eEFSeCys) that partners with SBP2 for incorporation of UGA-encoded SeCys. That eEFSeCys binds to SeCys-tRNA^[Ser]SeCys but not to Ser-tRNA^Ser prevents misincorporation of Ser in place of SeCys. Like other elongation factors, eEFSeCys binds GTP and is dependent upon GTP hydrolysis for activity.

This process of SeCys incorporation into selenoproteins is accomplished by a complex of these proteins on the ribosome: selenoprotein mRNA, SBP2, eEFSeCys–GTP, and SeCys-tRNA^[Ser]SeCys. The bases between the UGA and the SECIS element of the selenoprotein mRNA serve as a flexible tether, enabling the complex to orient the anticodon on the tRNA to interact with the approaching acceptor site on the ribosome. Peptide bond formation between SeCys and the nascent polypeptide is catalyzed by peptidyltransferase, as is the case for addition of other amino acids to the growing peptide chain.