The richest food sources of selenium are organ meats and seafoods (0.4 to 1.5 µg/g fresh weight)², followed by muscle meats (0.1 to 0.4), cereals and grains (<0.1 to >0.8), dairy products (<0.1 to 0.3), and fruits and vegetables (<0.1) (14). The wide variation in the selenium content of cereals and grains occurs because plants contain variable amounts, depending on how much soil selenium is available for uptake. For example, the selenium content of corn collected in China ranged from 0.005 to 8.1 µg/g, and the selenium content of the British diet declined from 65 to 31 µg/day after Britain switched its source of wheat from North America to Europe (14). Foods from animal sources vary somewhat in selenium content, but the degree of variation is less than in plants because of the homeostatic control of selenium metabolism in animals. The US Department of Agriculture National Nutrient Database for Standard Reference provides analytic or inferred values for the selenium content of hundreds of food items (17). Drinking water generally contributes negligible selenium to the overall intake, except in some localized highly seleniferous areas (14).

The Dietary Intake Data from the third National Health and Nutrition Survey (NHANES III) Total Diet Study found that median daily selenium intake was 149 and 98 µg for adult (19 to 50 years) men and women, respectively, between 1988 and 1994 (7). Lower daily selenium intakes, 30 µg or less, have been reported in countries with selenium-poor soils, such as New Zealand (14). Extremely low dietary selenium intakes from 3 to 22 µg/day have been reported in areas of China affected by Keshan disease. Conversely, very high dietary intakes (≤6690 µg/day) have been observed in a region of China with endemic human selenosis. The food in this area had been grown on soil contaminated with selenium leached from highly seleniferous coal fly ash (14).

Only a few studies have determined the nutritional bioavailability of selenium in foods consumed by humans. A commonly used experimental procedure to estimate selenium availability has been to follow increases in hepatic GPX activity after feeding various food sources of selenium to rodents previously depleted of selenium. On this basis, selenium fed as mushrooms, tuna, and wheat was 5%, 57%, and 83% as available to rats, respectively, as sodium selenite (14). A human bioavailability trial performed in Finland with men of moderately low selenium status showed significant differences among various forms of selenium tested (e.g., selenate, wheat, yeast), depending on the criterion of availability used (increase in platelet GPX activity, elevation of plasma or red blood cell selenium content, retention of selenium) (14). A 16-week study of US subjects supplemented with 200 to 600 µg selenium/day as selenite, selenomethionine, or selenized yeast showed no effect of any of these supplements on plasma GPX or selenoprotein P (SEPP1) in this already selenium-adequate population, nor any increase with selenite in plasma selenium, but showed rapid increases in plasma selenium with high levels of selenomethionine or selenized yeast (18). These studies point out the need to consider the form of supplemental selenium, biologically active biomarkers and their function versus tissue selenium levels, short-term versus long-term changes in biomarkers, and repletion of deficient subjects versus maintenance of status of selenium-adequate subjects when interpreting the results of such studies.

Because GPXs and most other selenoproteins are potential oxidoreductases (see later), selenium is likely to interact with other nutrients that affect the antioxidant-prooxidant balance of the cell. Selenium also protects against the toxicity of mercury, cadmium, and silver, and a physiologic role for selenium in counteracting heavy metal pollutants has been proposed (14). A novel compound, called selenoneine, has selenium bound to the imidazole ring of modified histidine and is the major form of selenium in liver and blood of tuna (19). The low bioavailability of the selenium in tuna may result from this form or from complexation with mercury (14), but this issue needs further investigation.

Absorption appears to play no role in the homeostatic regulation of selenium. Virtually complete absorption occurs when the element is supplied as selenomethionine and, presumably, as selenocysteine. Absorption of selenite and selenate is greater than 50% but can vary significantly. Thus, selenium absorption is usually in the range of 50% to 100% and is not affected by selenium nutritional status (14).

Two selenoproteins, SEPP1 and extracellular GPX (GPX3), have been identified in plasma, and both contain the element as selenocysteine. Work using mice with targeted deletion of the SEPP1 gene has shown that this protein is involved in supplying selenium to the brain and testes, results in marked decreases in testes selenium even in mice supplemented with normally adequate levels of selenium (20, 21), and results in sperm defects indistinguishable from those elicited by dietary selenium deficiency (22, 23). Deletion of SEPP1 also results in neurologic dysfunction in the form of motor incoordination that can be prevented but not reversed by supernutritional selenium supplementation (21, 24). Supernutritional selenium supplementation largely restores selenium levels in brain but not testes (20). A SEPP1-specific receptor, the apolipoprotein E receptor (ApoER2), is expressed in brain and testes, and deletion of ApoER2 in mice results in marked reduction in brain and testes selenium concentration and in neurologic dysfunction and sperm defects that are identical to those present in SEPP1-deletion mice or in selenium-deficient mice and rats (25, 26). Finally, transgenic restoration of SEPP1 expression in liver alone is fully sufficient to restore selenium uptake by the brain and testes and to prevent the neurologic and fragile sperm phenotypes (23). These studies illustrate how molecular and genetic research is leading to detailed understanding of the targeted selenium delivery to testes and brain.

In addition to the ApoER2 receptor, the megalin receptor mediates SEPP1 uptake by the kidney and thus provides a second targeting mechanism for selenium (27). In SEPP1 knockout mice, the ability of higher levels of dietary selenium to restore brain selenium levels (20), or to provide selenium for development in fetuses and nursing pups (28), indicates that other, perhaps low-molecularweight, forms may provide additional transport functions.

Mammalian selenoproteins contain selenocysteine in their primary structure. The mechanism by which selenocysteine, the twenty-first amino acid, is synthesized and then incorporated into selenoproteins is complex (see Fig. 14.3, steps 4 to 7). Serine provides the carbon skeleton for selenocysteine (29), and inorganic selenium at the selenide level provides the selenium (30). The serine is acylated to tRNA^[ser]sec, a unique tRNA with the anticodon for UGA, by regular seryl tRNA ligases. The serine while bound to the ser-tRNA^[ser]sec is then converted to selenocysteine, as described in Figure 14.3 (31).

Figure 14.4A represents a typical selenoprotein mRNA. A selenoprotein mRNA requires a UGA in the open reading frame to code for insertion of selenocysteine and a stem-loop structure in the 3′ untranslated region (3′ UTR). This stem-loop structure is known as a selenocysteine insertion sequence (SECIS) element. Absence of the SECIS element or modification of its essential features causes the UGA to function instead as a termination codon (32). In eukaryotes, the 3′ UTR serves as a tether that allows the SECIS to loop back to interact with the UGA codon and facilitate selenocysteine incorporation. The SECIS in prokaryotes is adjacent to the UGA codon (33).

In eukaryotes, two selenium-specific protein factors facilitate selenocysteine insertion at the UGA (see Fig. 14.4B). One factor, selenocysteine binding protein 2 (SBP2), binds to the SECIS element (34). The other, elongation factor for selenocysteine (EF_sec), binds to the sec-tRNA^[ser]sec (35, 36). These two proteins bind to each other to form a complex that delivers the sec-tRNA^[ser]sec to the ribosome for incorporation of selenocysteine into the growing polypeptide chain. It is becoming clear that several additional factors with roles in the usual ribosomal complex for peptide synthesis are also important for incorporation of selenocysteine into the peptide backbone of selenoproteins (37, 38).

Homeostasis of selenium in the body is achieved through regulation of excretion. As dietary intake increases from the deficient range into the adequate range, urinary excretion of the element increases and accounts for maintenance of homeostasis. At very high intakes, volatile forms of selenium are exhaled, and the breath becomes a significant route of excretion. No evidence indicates that fecal selenium is regulated. Thus, under physiologic conditions,
urinary excretion is the primary means whereby body selenium is regulated (14).

Most excretory metabolites of selenium appear to be methylated forms produced in the liver or kidneys. Under deficient to adequate conditions, a large fraction of urinary selenium is present as a methylated selenosugar (15), and a much smaller percentage is trimethylselenonium ion. Selenium in the breath is largely dimethylselenide, especially with high levels of selenium intake. The biochemical mechanisms that regulate formation of these metabolites are not known (14).