SELENIUM

BACKGROUND METABOLISM RDA SELENIUM AND EXERCISE Description Absorption / Bioavailability Current RDA Requirements  Sources Transport Deficiency Oxidative Stress   Storage Toxicity Exercise Recovery Excretion Physiological Role SUMMARY REFERENCES

A. Background

Description

Selenium is a non-metal that is found in the oxygen series and exists in multiple oxidation states (i.e. -2, +4, +6) Within biological systems the element is a constituent of the amino acids that compromise proteins. The element was first studied around 1930 after scientists noted that cows grazing on plants growing in high-selenium soil suffered from alkali disease. Studies linking nutritional diseases to selenium deficiency in sheep, cattle, and swine continued until 1973 when the biochemical function of the element was discovered. Researchers discovered that selenium was an essential component of the glutathione peroxidase enzyme system (5). The importance of selenium in the human diet was discovered in 1979. Chinese scientists showed that children living in selenium-deficient areas were suffering from a cardiomyopathy known as Keshan disease. The symptoms of the disease were reversed when selenium was added to the diet. These discoveries led to expansive research investigating further unknown roles of selenium within the human body. The massive influx of selenium research led to the establishment of dietary recommendations from the World Health Organization (WHO). In accordance with the WHO a Recommended Daily Allowance (RDA) was established for the element in 1989 (5,13)

Sources

Selenium content of food varies widely between regions throughout the world. Plants acquire selenium from the soil and therefore vary in content depending upon the region they are grown in (13). Some fruits and vegetables also appear to lack a growth-dependence on selenium and in turn have a low content of the mineral regardless of the soil content. Because of the great variance in selenium soil and plant content, tables providing selenium content of foods are difficult to establish. Despite this, some foods are known to be generally high in selenium content. In general animal products, especially organ meats, are greater in selenium content than plant sources (5,13). A common practice in countries where the soil is poor in selenium is the addition of sodium selenite (Na2SeO3) to the feed of animals. Seafood, except some fish, is believed to be the best source of selenium. Mercury compounds found in some fish bind the selenium thereby making it unavailable to humans. However, some speculate that the selenium content of fish containing only traces of mercury is also low (13). Animal sources of selenium also appear to be higher due to a greater homeostatic control of the element during a wide variety of exposure conditions.

B. Metabolism

Absorption and Bioavailability

Several forms of selenium enter the body as part of amino acids within proteins. The two most common forms of the element that enter the body are selenomethionine and selenocysteine which are found mainly in plants and animals respectively (5). The primary sites of absorption are from throughout the duodenum. Virtually no absorption occurs in the stomach and very little takes places in the remaining two segments of the small intestine (13). Selenomethionine is absorbed from the duodenum at a rate close to 100%. Other forms of the element have been shown to also be generally well absorbed. However, absorption of inorganic forms of the element varies widely due to luminal factors (5). This variation in absorption reduces total absorption of all forms to somewhere between 50 and 100%. Selenium absorption is not affected by body selenium status. Absorption of selenium is closely related to multiple nutritional factors that inhibit or promote absorption. Vitamins A, C, and E along with reduced glutathione enhance absorption of the element. In contrast, heavy metals (i.e. mercury) decrease absorption via precipitation and chelation (13).

Transport

The exact mechanisms of selenium transport are thus far unclear and debatable. Some aspects of selenium transport are better understood than others. For example, selenium has been hypothesized to enter red blood cells via diffusion and carried throughout the body. Within the blood, free selenium binds to lipoproteins such as VLDL or LDL. The transport properties of a second protein, identified as selenoprotein P, have been met with opposing viewpoints. The protein is found in the plasma and is believed to be a carrier by some (13). Others believe that the presence of selenocysteine within the structure inhibits the transport abilities of the protein (5). To complicate things even further, the mechanism of selenium release from transport proteins is very vague.

Storage

Selenium that is absorbed becomes a part of both transport and storage proteins. Selenium is believed to influence the formation of the proteins. The uptake of selenium is a complex process that involves numerous factors. The heart, kidney, lung, liver, pancreas, and muscle contain very high levels of selenium as a component of glutathione (5,13). In addition, type I (slow twitch) muscle likely contains greater amounts of reduced glutathione than Type IIb (fast twitch) because of their oxidative capacity. The liver is a major supplier of circulating reduced glutathione, which is reflected in the amount of its reserves. The volume of glutathione in the liver is from 5-7 mM (30); that in the heart ranges between 2-3mM (30). With the exception of the lens of the eye (30), the levels found in the liver are the highest within the body (11). Noteworthy is the fact that red blood cells contain four times more GSH than the plasma (2.0mM vs. .5 mM) (30).

Excretion

Selenium homeostasis is regulated primarily through excretion. Selenium is excreted via two main paths: urinary (50-67%) and fecal (40-50%) (13). Extremely high intakes of selenium can lead to ventilatory elimination of the mineral in the form of dimethylselenide. Excretion via the lungs is characterized by a garlic smell odor to the volatile selenium compound (5,13). Fecal excretion does not appear to be a major pathway in regulation. Instead, urinary excretion is the primary route of regulation under normal physiological conditions. Common to all of the excretory pathways is the lack of knowledge regarding metabolite formation (5,13).

Physiological Role

Currently, eleven different selenium-containing proteins (selenoproteins) have are known to be present in animals. Most of these proteins have enzymatic functions that have been characterized. However, the biochemical functions of most have yet to be determined. Some hypothesized functions include: maintenance of the cytochrome P450 system, DNA repair, enzyme activation, and immune system function. Three other roles for the element are better understood and described below. Selenium is best known for the role it plays in the glutathione peroxidase (GSH-Px) enzyme system. Four separate glutathione peroxidases have been identified. Within the cell total (GSH-Px) is distributed ~2:1 between the cytosol and the mitochondrial matrix (19). The distribution of the enzyme allows for increased efficiency of free radicals by the GSH-Px system. These enzyme systems are well established as being the major antioxidant defense systems within the body. Reduced glutathione is the first line of defense against free radicals. The glutathione system is key in the coordination of the water and lipid soluble antioxidant defense systems (2). The peroxidases use reduced glutathione to stop peroxidation of cells by breaking down hydrogen peroxide (H2O2) and lipid peroxides (5,13,19). The majority of research involving the glutathione system has addressed GSH-Px, the enzyme responsible for the breakdown of hydrogen peroxide to water. Adequate levels of the intracellular substrate, reduced glutathione, are required in order for GSH-Px to exhibit antioxidant properties (19). As reduced glutathione is utilized to remove H2O2 from the body oxidized glutathione is formed. An equally important enzyme converts oxidized glutathione back too reduced glutathione for use by the antioxidant defense systems within the body. The enzyme that catalyzes this reaction is glutathione reductase. Iodine metabolism also relies heavily on selenium availability. More specifically the enzyme involved in the conversion of thyroxine (T4) back to tri-iodothryronine (T3) appears to be selenium dependent (10). Both of these enzymes play a very important role during metabolic activities, which in turn demonstrates the importance of selenium in the system. A summary written by Powers and Ji (30) suggests that reduced glutathione may also have the ability to "recharge" other antioxidants in the body. The authors have summarized that GSH donates electrons, which in turn helps restore vitamins C and E to their original electron configuration.

C. Recommended Daily Allowance (RDA)

Current RDA

The National Research Council established an estimated safe and adequate daily dietary intake for selenium in 1980. At that time the recommendation was set from 50 to 200 micrograms. This recommendation was based strictly on extrapolation of animal studies, as very few human studies had been done (5). Since this time human balance studies have been performed along with repletion studies in selenium deficient regions of China. The balance studies have proven to be very poor indicators of selenium intake because the human body adjusts its excretion depending on intake of the element. Repletion studies found that approximately 40 ug per day of selenium maximized glutathione peroxidase activity (13). This was very important as it led to the establishment of a RDA for the element in 1989 (3,5,13). After some corrections for body weight and subject variability the RDA was set at 70 ug for men and 55 ug for women (24). By the year 2001 the National Academy for Sciences will have eliminated the RDAs and established Dietary Reference Intakes for all vitamins and minerals. At the present time selenium is the only antioxidant included herein without a DRI. Once established this web site will reflect the new recommended level. The current levels are easily obtainable through the consumption of a mixed diet in all areas of North America. However, these levels would be very hard to reach for those persons living in countries with selenium poor soil (5,13).

Deficiency

Selenium deficient diets can induce a wide host of responses in humans, some of which are fatal. The first evidence for this was shown in 1979 when a group of Chinese scientists correlated selenium deficiency with Keshan disease and Kashin-Beck's disease. Keshan disease is a cardiomyopathy that leads to cardiogenic shock and in some cases congestive heart failure. Those with an acute case suffer from sudden cardiac insufficiency. In chronic cases subjects suffer from heart enlargement with varying degrees of insufficiency. The heart also undergoes necrosis and is replaced with bone (5,13). Through an intervention study the protective effects of selenium were discovered. The research showed that supplementation with selenium had protective benefits, but could not reverse heart failure (5). While Keshan disease mainly affects children and young women, a second disease, Kashin-Beck's Disease, attacks during pre-adolescence. Kashin-Beck's disease results in severe osteoarthritis. The disease is often characterized by degeneration of the nerves and cartilage cells (chondrocytes) of the body. Damage to the chondrocytes results in dwarfism and joint deformation (5). Selenium deficiency is often observed in people on total parenteral nutrition (TPN). Symptoms of selenium deficiency include muscle pain, weakness, and loss of pigment in the hair and skin and the whitening of the nail beds (13). Selenium deficiency can also occur from interaction with other elements. Lead reacts with selenium and significantly lowers the tissue concentration of the mineral. The mechanism behind this is presently unclear, but it has been speculated that the binding of both elements to sulfhydryl groups may be involved. Iron and copper also seem to interact with selenium and inhibit uptake of the element. When the body experiences decreased levels of methionine it compensates by incorporating seleno-methionine into body proteins. This leads to a concomitant decrease in free available selenium within the body.

Toxicity

Multiple toxicity studies have been performed with a wide array of outcomes. Studies carried out in areas having a high selenium content have failed to establish any specific symptoms of selenium toxicity. Indices of high selenium diets appear to be hair and nail loss, along with lesions of the scalp, skin and nervous system, vomiting, nausea, and fatigue (13). Despite these symptoms no changes were observed in the various biochemical tests performed. Intakes as high as 724-ug/ day have not resulted in adverse side effects or indices as mentioned above. One known episode of selenium poisoning did occur in 1984 in the United States. Thirteen people whom consumed supplements from a health food store complained of nausea, vomiting, weakness, and hair and nail loss. It was later determined that the supplement contained 182 times the selenium content listed on the label. Therefore, the subjects were consuming from 27 to 2387 mg of selenium (5,13). In accordance with early Chinese studies the United States Environmental Protection Agency (U.S. EPA) established a reference dose (Rfd) for selenium. The Rfd serves as a toxicological standard that is defined as "an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime". The EPA has set the ceiling for selenium at 400 micrograms (ug) (5).

D. Selenium & Exercise

Effects of Exercise on Selenium Requirements

The majority of selenium research has addressed the possible role selenium may have in preventing heart disease and some cancers. A body of evidence has been established in regards to exercise and selenium. Multiple studies agree that the glutathione peroxidase (GSH-Px) system increases as a chronic exercise training adaptation (8,12,15,18,21-22,28-29). The enzyme, glutathione peroxidase (GSH-Px), is dependent upon selenium. Without selenium GSH-Px relinquishes the ability to degrade H2O2 (30). Burk and Levander (5) report in their summary of selenium that deficiency of the mineral rarely exists in western populations, but may be more prevalent in areas with selenium poor soil, such as parts of China. The most likely cause of selenium deficiency in North Americans could likely be traced back to a diet lacking adequate fruits and vegetables. Exercise training does not appear to increase the need for selenium intake. Eleven "moderately trained" males cycled on three consecutive days at 65% VO2 max. Each cycling session was 90 minutes in duration. During each exercise session reduced glutathione levels fell approximately 55% in the first 15 minutes whereas oxidized glutathione levels increased 28% in the same time period. These results were similar throughout the three day period (35). A limited number of studies have shown that selenium supplementation can decrease oxidative stress and improve antioxidant levels of the mineral. Tessier et al. (32) concluded that after a ten-week endurance and supplementation program plasma and erythrocyte GSH-Px activity was significantly increased when compared with a control group who only trained. Interestingly, glutathione reductase activity was reduced in both groups of subjects. Two separate studies utilized sedentary men (25) and both men and women (12). In both studies the training protocol consisted of a running regimen. Ohno et al. (25) implemented a ten-week training program of 30 km (18 miles) per week, whereas Evelo et al. (12) utilized a training program that trained the participants for a half-marathon (13.1 miles) at the end. The studies were published four years apart, but both found that erythrocyte glutathione reductase activity was increased after the training regimens. Endurance and high intensity training both correlate highly with increased cytosolic and mitochondrial reduced glutathione and GSH-Px activities. Adaptation of the enzyme is limited to only Type I and Type IIa muscles. A known adaptation to endurance training is an increase in oxidative enzyme activity, which increases to a greater percent than the reduced glutathione antioxidant defense system does. The mechanism for these increases has yet to be understood. A seven-week training regimen involving intermittent cycle sprint training was used to determine changes in glutathione reductase and GSH-Px activity. After six weeks no differences in enzyme activity were noted. However, muscle biopsies taken 3, 24, and 72 hours after one additional week (week 7) of more frequent training resulted in significant increases in both enzymes and markers of anaerobic capacity (15). Tiddus et al. (34) performed an eight-week study with 13 sedentary human subjects divided into two groups (7 male, 6 female). After the eight-week training period, working for 30 minutes at a workload equivalent to seventy percent of VO2 max (followed by 0-5 minutes of work at 100% VO2 max), both groups had a significantly higher VO2 max. However, antioxidant status in the pre and post training measurements was not significantly different. The scientists acknowledged that their findings were contradictory to some studies. They attributed these findings to their protocol, which may have not been intense enough to induce changes in free radical production and hence the antioxidant defense system (34). However, the protocol used closely resembles the training intensity of a large majority of recreational exercisers. The degree of adaptation may be limited in humans also as the body has been shown to have internal excretion mechanisms that control the amount of endogenous selenium. It should be noted that the lack of positive adaptations has also been exhibited using the laboratory rat. Some will argue that the results found in the rat may be difficult to extrapolate to humans. However, rat studies permit more invasiveness than those on humans. Criswell et al. (8) measured the activity of GSH-Px in gastrocnemius and soleus muscles. Two exercise protocols were used. The first involved endurance training while the second involved use of interval training. The results along with those from an exercise and aging study (21) found that GSH-Px activity was significantly increased in the soleus muscle of interval-trained rats (8). Similar results have also been found in the costal diaphragm of rats (29). Leeuwenburgh and colleagues (22) have shown evidence that contradicts those previously mentioned for the soleus. GSH-Px activity of the soleus did not change in animals on a ten-week training program. Furthermore, glutathione reductase activity in the soleus decreased (22). These results are in stark contrast to the results published by the same group of researchers three years earlier. However, it should be noted that the sex, age, and type of rat used in the confounding studies were different. Powers et al. (28) used the rat model exercising at 30, 60, or 90 minutes at either low (65% VO2 max), medium (75% VO2 max), or high (85%VO2 max) exercise intensities to investigate antioxidant enzyme activity. Activity of red gastrocnemius, white gastrocnemius, and soleus were determined. GSH-Px activity was elevated in the red gastrocnemius muscle only and was directly related to the duration of the exercise, but not its intensity. The conflicting results of the studies provide further evidence that reduced glutathione upregulation may vary from individual to individual. These discrepancies could be linked to training protocols, experiment design, age, sex, or genetic factors.

Prevention of Oxidative Stress / Lipid Peroxidation

A strong body of evidence suggests that free radical production does increase during times of elevated oxygen intakes, such as those levels that accompany exercise (1,9,11,16,31). An indirect, but significant function of selenium is to protect the cell from the oxidative stress and free radical formation that occurs during exercise. Selenium can be considered the "rate-limiting" substrate in the GSH-Px system. Without selenium the peroxidase enzyme cannot be formed and consequently antioxidant protection by the GSH-Px system is compromised. Multiple studies (21,25) have shown that glutathione reductase levels are elevated in both skeletal muscle and erythrocytes after exposure to chronic exercise. Reduced nicotinamide adenine dinucleotide phosphate (NADPH), along with glutathione reductase as a catalyst, convert oxidized glutathione back to the reduced form. As free radical peroxidation increases the ratio of reduced glutathione:oxidized glutathione decreases, hence the ratio is often used as a marker of radical formation within the body (19). The endogenous increase in the reduced glutathione antioxidant defense system with chronic training likely acts as a protective mechanism to help prevent oxidative stress within the body. Furthermore, it has been established that both free radical production and GSH-Px activity increase with exercise. Ortenblad et al. (26) performed a study using a short-term maximal exercise protocol. Briefly, free radical muscle damage was evaluated after a continuous 30-second maximum jump test in both trained and untrained subjects. The resting muscle levels of glutathione reductase were significantly higher in the trained (elite volleyball players) versus untrained groups. Creatine kinase, an indicator of muscle damage, was significantly higher in the untrained group after exercise. The research supported the notion that the reduced glutathione defense system is upregulated and better able to protect muscle from lipid peroxidation in trained individuals (23). Thus, a likely hypothesis is that the endogenous upregulation of the GSH system via chronic exercise is an adaptive mechanism established to counter-act free radical formation.

Selenium in Exercise Recovery

The role selenium plays in exercise recovery has yet to be established. As for other roles it would be as a part of the glutathione system. Glutatione reductase works to remove H2O2 from the body. One can conclude that as long as excess hydrogen peroxide and singlet oxygen is present the glutatione system will work to remove the radicals. As part of the initial repair of muscle damage an acute inflammatory process takes place. The immune system, specifically neutrophils, uses free radicals to "mark" bad or damaged tissue for removal from the body. Instances of severe muscle damage (i.e. unaccustomed exercise) cause infiltration of neutrophils and macrophages into the tissue. Neutrophils and macrophages have a tendency to overkill in order to get all of the bad tissue. In turn this means that some healthy tissue is likely to be damaged in the process (33). Earlier research (33) has shown that in damaged muscle immune system responses peak between days two and seven. Thus, studies showing the relationship between the delayed onset of muscle damage and response of the antioxidant defense system need to be conducted. Superoxide production can be controlled by antioxidants, such as the glutathione system. Control of post-exercise free radical production could actually end up being a counter-productive measure. By removing free radicals that neutrophils have established to mark tissue, the body is in fact delaying the exercise recovery process (33). Removal of the oxidative markers decreases the amount of damaged tissue that is targeted by the immune system. Endogenous regulation of the reduced glutathione system could play a role in maintaining the fine balance of oxidative by-products to antioxidants. Thus, selenium may play an indirect, but significant role in exercise recovery. Research addressing this possibility does not exist. Therefore, the hypothesis presented could be a key in understanding the possible inhibitory effects of selenium on muscle damage and antioxidant function.

E. Summary and Current Recommendations

The glutathione peroxidase enzyme system is very important in controlling free radicals in vivo. This particular antioxidant system has no performance-enhancing benefit. The system is upregulated with exercise, which allows for better control of the free radicals and lipid peroxidation increases that occur during unaccustomed or strenuous exercise. The role GSH-Px plays in exercise recovery has yet to be established. The author of this literature review has formed a hypothesis that could be used to explore the topic further. The GSH-Px system has been shown to have the ability to up-regulate itself via endurance and/or high intensity training. Furthermore, selenium soil content is adequate in North America and most of the world. Those places with low selenium add the mineral to livestock feed. The adequacy of selenium warrants no need for supplementation with the mineral. Athletes will gain no competitive advantage by utilizing selenium as an ergogenic aid or exercise recovery aid. The toxic effects of the mineral are devastating and can be detrimental. Therefore, supplementation with the mineral is not recommended.

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