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Commentary |
Department of Chemistry and Biochemistry, University of California San Diego, and, Biological Trace Element Research Institute, San Diego, California
Address reprint requests to: Gerhard N. Schrauzer, PhD, CNS, FACN, Biological Trace Element Research Institute, 11526 Sorrento Valley Rd., Ste. A., San Diego, CA 92121.
ABSTRACT
Selenium supplements contain selenium in different chemical forms. In the majority of supplements, the selenium is present as selenomethionine. However, in multivitamin preparations, infant formulas, protein mixes, weight-loss products and animal feed, sodium selenite and sodium selenate are predominantly used. In some products, selenium is present in protein- or amino acid chelated forms; in still others, the form of selenium is not disclosed. Current evidence favors selenomethionine over the other forms of selenium. Extradietary supplementation of selenium at the dosage of 200 micrograms per day is generally considered safe and adequate for an adult of average weight subsisting on the typical American diet.
Key words: selenium, selenomethionine, selenium yeast, sodium selenite, sodium selenate, dietary supplements
The typical American diet provides the average adult with about 80 to 150 micrograms of selenium per day, which is more than the newly revised RDA for selenium of 55 µ [1], but less than one half of the amount considered optimal for utilization of the protective potential of selenium, especially for cancer prevention [2,3]. Accordingly, extradietary selenium supplementation is increasingly recommended by health professionals. Pending the outcome of ongoing human cancer prevention trials, selenium supplementation is likely to be officially recognized as a means of lowering cancer risk. These developments raise the question as to which form of selenium is the most desirable for supplementation. In addition, the quality and safety of the selenium supplements become matters of concern.
Nutritional Forms of Selenium
Ideally, selenium should be supplemented in the form or forms in which it occurs in major staple foods. Since more than 80% of the total selenium in seleniferous corn, wheat and soybeans consists of L(+)-selenomethionine [4], this amino acid is the most appropriate supplemental form of selenium. Some other compounds, namely Se-methylselenocysteine and selenocystathionine are present primarily in selenium accumulator plants [5], but also in broccoli, garlic and onions if these are grown in Se-rich media [6]. Se-methylselenocysteine has recently been suggested as a possible form of selenium for cancer prevention [7], but its value relative to selenomethionine as a supplemental source of selenium still remains to be demonstrated. Moreover, Se-methylselenocysteine, as well as selenocysteine (or -cystine), selenohomocysteine (or homocystine), selenocystathionine and 
-glutamyl-Se-methylcysteine are normally found in edible plants only in nutritionally insignificant amounts. Selenomethionine, however, replaces methionine in plant proteins and thus is the major form of selenium for higher animals and humans. Selenomethionine is well absorbed and is either metabolized directly or is incorporated into body proteins in place of methionine. The extent of selenomethionine incorporation into proteins depends on the dosage and methionine status and diminishes at high methionine intakes [8,9]. Selenomethionine is incorporated primarily into the proteins of the skeletal muscles, erythrocytes, pancreas, the liver, stomach, the kidneys and the gastrointestinal mucosa [10]; its release from body proteins is linked to protein turnover and occurs continuously. At constant intakes of selenomethionine, a steady state is established which is maintained indefinitely and over a large range of intakes.
Blood Se levels and dietary Se intakes thus primarily reflect the selenomethionine content of foods [11]. Selenomethionine not used for protein synthesis is degraded by the transulfuration pathway to selenocysteine and subsequently, in the liver, to serine and selenide [3]. In the liver of the rat, selenomethionine is in part also degraded by a -lyase to methylselenol and homoserine[12]. Just as methionine can serve as the sole source of sulfur, selenomethionine provides all forms of bioactive selenium needed for selenoprotein biosynthesis. However, since selenomethionine belongs to the group of amino acids which higher animals and humans cannot synthesize, selenomethionine may also be needed for some specific functions in the organism. For example, selenomethionine has been suggested to act as a cellular antioxidant; on reaction with peroxynitrite, selenomethionine oxide formed which is reduced back to selenomethionine by ascorbic acid [13].
Supplemental Forms of Selenium
Unfortunately, not much was known about selenomethionine in the early 1970s, when regulatory agencies had to decide which selenium compounds to allow for use in animal feed. The approval in 1974 of sodium selenite and sodium selenate as feed additives created an unsatisfactory situation. First, the approval suggested that these inorganic selenium salts are nutritional forms of selenium, which they are not. Secondly, the approval diverted attention from selenomethionine, which was soon recognized to be superior to the inorganic selenium salts [14]. However, at the time the regulatory action was taken, only the inorganic selenium salts were available at a cost permitting their use in animal feed.
In the search for an economical source of organic nutritional forms of selenium, attempts were made to increase the normally low selenium content of yeast by growing it in selenium-enriched media. Yeast was chosen because it can be produced in quantity under controlled conditions and was known to contain a highly bioactive organic form of selenium. Yeast had also played a major role in the discovery of the nutritional essentiality of selenium, when it was shown to contain ‘Factor 3,’ the naturally occurring selenium compound most effective in preventing dietary liver necrosis in the rat [15]. Although Factor 3 was as such not identified, from what is known today, it must have consisted primarily of selenomethionine. By the mid 1970s, the first ‘high selenium yeasts’ became commercially available. Today’s commercial products typically contain from 1,000 to 2,000 micrograms of selenium per gram, with 90+% of the selenium in the form of L(+)selenomethionine [3,16]. In 1983, this selenomethionine-rich yeast was chosen as the source of selenium for a large-scale cancer prevention trial [17]. This trial showed that taking an extra 200 micrograms of selenium per day significantly lowered the risks of developing prostate, lung and colorectal cancer.
In 1984, synthetic selenomethionine became available. It is used in supplements specifically formulated to be yeast-free or when a concentrated, compact source of selenium is required. Since selenomethionine, like all amino acids, can exist in the L- and in the D-form and since only the L-isomer occurs naturally in foods, this form is preferable for use in supplements intended for humans; for use in animal feed, the D,L-mixture of the isomers is deemed acceptable [3].
Yeast-selenium at the level of 0.3 ppm in feed dry matter was twice as effective as selenite in increasing the selenium content of the sirloin muscles in pigs [18]; it also raised the selenium levels in serum and the liver significantly more than selenite [19]. Selenium yeast accordingly has been recommended for general use in animal nutrition [20]. In June, 2000, the use of selenium yeast in poultry broiler and layer diets was FDA approved. This is only the beginning of a development which will eventually result in the complete replacement of the inorganic selenium compounds as feed additives by selenomethionine or nutritional sources thereof.
Quality Concerns
Popular demand for selenium supplements requires the cautionary note that the quality of some of the presently marketed supplements is questionable. Some products, for example, are made with yeasts containing inorganic selenium (selenite or selenate) instead of selenomethionine [21,22]. Since only selenomethionine-containing yeast was used in the cancer prevention trial, the form of selenium actually present should be indicated, but this is often not done. In other supplements, the form of selenium is stated but is ill-defined. Supplements containing ‘selenium proteinates‘ or ‘selenium amino acid chelates‘ belong to this category. In some multivitamin preparations, both sodium selenite and vitamin C are present. In such supplements, elemental selenium may gradually form by the reaction of selenite with vitamin C [23]. Although the quality of selenium supplements is steadily improving, the supplement industry has still a ways to go before its selenium products can be generally recommended.
Selenium in Infant Formulas, Protein Mixes and Weight-Loss Products
Infant formulas, protein mixes and weight loss products still use almost exclusively sodium selenite or sodium selenate. The continuing use of the inorganic selenium compounds is difficult to justify. This is especially true for infant formulas, which through the use of the inorganic selenium salts deprive the growing infant of the benefits which only selenomethionine can provide. Studies with preterm infants [24,25] have already demonstrated that selenium yeast is safe and effective for enteral selenium supplementation. Selenium yeast and selenomethionine were furthermore shown to be superior to selenite in studies with nursing mothers; specifically, more selenium appeared in the milk of mothers obtaining selenium from selenomethionine than from selenite [26].
Safety of Selenium Supplements
As to the safety of selenium, a supplemental dose of 200 micrograms per day would cause the total daily selenium intake of an average adult to increase to 280 to 350 micrograms. This is a safe amount since it is below or equal to the Reference Dose (RfD) for selenium, which, for an adult of 70 kg, was set by the EPA at 350 micrograms [27]. The RfD is defined as ‘an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.‘ In line with this definition, studies have shown that prolonged daily selenium intakes of 750 to 850 micrograms do not produce adverse effects. Intakes of selenium of this magnitude were provisionally suggested to represent the ‘No Adverse Effect Level’ (NOAEL). The ‘Lowest Adverse Effect Level’ (LOAEL), defined as the ‘average daily selenium intake causing individuals within a population to develop overt signs of toxicity,’ is believed to be in the order of 1540±653 micrograms/day [28]. ‘Low Adverse Effects’ of selenium usually do not develop after a single dose of this magnitude, but only after weeks or months of exposure. Moreover, the early warning signs of selenium overload are easily recognized. Accordingly, a wide margin of safety exists when 200 micrograms of selenium are taken daily, and even if this amount is temporarily exceeded, no adverse affects need to be feared. Indeed, selenium has an excellent safety record, and the only cases of selenium toxicity, which occurred several decades ago, were due to inadvertent dosage errors by inexperienced supplement manufacturers which were not using selenium yeast or selenomethionine in their products.
Received August 8, 2000. REFERENCES
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