Selenium in Physiology

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Selenium

Definition: Selenium is an essential trace element. It is an integral part of enzymes. Selenium supports the body's immune system by protecting against the effects of free radicals.

Function: Selenium has a variety of functions. The main one is its role as an antioxidant in the enzyme selenium-glutathione-peroxidase. Selenium also seems to stimulate anti-body formation in response to vaccines. It also may provide protection from the toxic effects of heavy metals and other substances. It may assist in the synthesis of protein, in growth and development, and in fertility, especially in men. Selenium has been shown to improve the production of sperm and sperm motility.

Deficiency: Keshan disease has been documented as being caused by a deficiency of selenium. It causes an abnormality of the heart muscle, and it claimed the lives of many children in China until the relationship to selenium was discovered and selenium supplements were provided. Selenium deficiency may also occur in patients fed intravenously for long periods of time. Increased intake of selenium can lead to toxicity in cattle grazing in selenium-rich soil. The cattle demonstrate muscle, visual and heart problems.

The amount of selenium required to cause toxicity in humans is not known. Excess selenium intake can cause problems with the strength of teeth and the tooth enamel. Other problems may include loss of teeth, hair, and nails. Skin inflammation, nausea, and fatigue can also occur.

In the U.S. a double blind, placebo-controlled study of more than 1300 older adults with a history of nonmelanoma skin cancer found that supplementation with 200 mcg/day of selenium-enriched yeast for an average of 7.4 years was associated with a 51% decrease in prostate cancer incidence in men. The protective effect of selenium supplementation was greatest in those men with lower baseline plasma selenium and prostate-specific antigen (PSA) levels. Surprisingly, the most recent results from this study indicate that selenium supplementation increased the risk of one type of skin cancer (squamous cell carcinoma) by 25%. Although selenium supplementation shows promise for the prevention of prostate cancer, its effects on the risk for other types of cancer is unclear. In response to the need to confirm these findings, several large placebo-controlled trials designed to further investigate the role of selenium supplementation in prostate cancer prevention are presently under way.

Men: the only controlled trial to examine the effect of selenium supplementation on cancer risk in a well-nourished population found that 200 mcg/day of supplemental selenium significantly decreased the risk of prostate cancer in men by 51%. However, the risk of one type of skin cancer was increased by 25%. Although mortality from prostate cancer is considerably higher than mortality from squamous cell cancer of the skin, these findings suggest that the overall effects of selenium supplementation on cancer risk are not yet clear enough to support a general recommendation for an extra selenium supplement. Men taking supplemental selenium in order to reduce the risk of prostate cancer should not exceed 200 mcg/day and should take precautions to reduce the risk of squamous cell carcinoma, such as using sunscreen and avoiding prolonged sun exposure.

Women: Because there is no evidence that selenium supplementation decreases the risk of cancer in women who are not selenium deficient, there is no reason for women to take an extra selenium supplement.

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Before 1957, the only physiological significance of the element selenium was thought to be its toxicity. A watershed change in the concept of selenium metabolism occurred when it was shown to prevent liver necrosis in rats. Selenium was also once thought to be carcinogenic, but now, at least in certain forms, it is considered to be an anticarcinogen.

In the late 1960s, epidemiological surveys suggested an inverse relationship in the incidence of certain cancers, particularly of the breast, and the selenium content of the plants growing in different regions of the United States representing low, adequate, and high selenium areas. Soils of the Pacific Northwest, the upper Midwest, the Northeast, and along the Atlantic coast do not contain enough selenium for the plants growing there to provide protection against selenium deficiency in grazing animals. Vegetables grown in these places also contain low levels of selenium. In other areas of the United States, such as the Rocky Mountain states, selenium is present at elevated levels in soil and, consequently, in plants.

In the 1970s and 1980s, the relationship between selenium and cancer in laboratory animals was extensively investigated, resulting in discoveries that several selenocompounds inhibit or retard carcinogenesis. These experiments in animal carcinogenesis indicated that super-nutritional levels (about 30 times the nutritional requirement) of selenium gave the greatest protection. About 0.1 microgram of selenium per gram of diet is considered to meet the nutritional needs of animals. (1,000 micrograms = 1 milligram; 1,000 milligrams = 1 gram).

Nearly 200 animal studies have been conducted to evaluate the effects of supernutritional levels of selenium on experimental carcinogenesis using chemical, viral and transplantable tumor models. Of these, two-thirds have found that high levels of selenium reduced the development of tumors at least moderately (by 15 to 35% compared to controls) and in most cases very significantly (more than 35%). Only in a very few cases was selenium found not to be effective.

We now know that there are at least eight enzymes in animals that require selenium for normal activity and that there are two other well-characterized selenoproteins for which a metabolic function has not yet been discovered. Most of the identified selenium-containing enzymes exert antioxidant activities, such as glutathione peroxidase. The activities of the selenoenzymes or the levels of the selenoproteins in blood or tissues have been used to assess selenium status in animals as well as humans. Experiments have also revealed that the physiological and biochemical functions of selenium can be altered by other dietary factors, including vitamin E.

Vegetables and nuts with high sulfur content that are good candidates for enrichment with selenium. In humans, like other animals, selenium supplementation has appeared to offer some anticancer protection. So far; three human studies on the relationship of selenium supplements to cancer have been completed. In the first, selenium was added to salt and shown to significantly reduce the incidence of liver cancer in a Chinese population. Subsequently, it was shown that five years of supplementation with selenium, vitamin E, and carotene significantly reduced the incidence of stomach and esophageal cancer in a Chinese population. However, this experimental design did not allow one to determine whether selenium itself, the two vitamins, or the combination of these substances was responsible for this significant effect.

Since there are many populations in China who live in selenium deficient areas, it was also not clear whether supplemental selenium merely corrected a deficiency or provided protection against cancer. The third trial on selenium and cancer in humans was conducted in the United States by L.C. Clark et al. (published in the Journal of the American Medical Association in 1996) and gave, again, positive results. This study is especially significant because Americans consume enough selenium in the diet to meet their nutritional needs. On average, Americans consume about 100 micrograms of selenium daily from dietary sources, and in this human trial, supplements of 200 to 400 micrograms per day were given.

The cancer incidence was lowered by about the same degree in those subjects taking 200 or 400 micrograms per day, suggesting that 200 micrograms of additional selenium is sufficient to inhibit certain cancers. Combined with the amount consumed dietarily, the beneficial level of intake was about 300 micrograms per day. As can be seen, the incidence of lung, colorectal, or prostate cancers was reduced significantly. Interestingly, skin cancer, which was the target cancer of the study, was not affected by selenium supplementation.

A case control study conducted in Finland by J.T. Salonen et al. (published in the American Journal of Epidemiology in 1984) also supports a protective effect of selenium against cancer. In that study of a random sample of more than 8,100 persons followed for six years, low serum levels of selenium correlated with increased total cancer mortality. The relative risk in low selenium subjects appeared to be greatest if they also had relatively low plasma levels of vitamins A and E, suggesting, again, that other factors influence the anticarcinogenic effects of selenium.

Should people take supplemental selenium for cancer prevention? Even though the results thus far look encouraging, it is premature to make a specific recommendation for cancer prevention. Selenium supplements, many derived from selenium-enriched yeast, are commercially available. In the yeast-derived products, the selenium is present in an organic form. Recently, a supplement with inorganic selenium has been introduced commercially, but the experimental data indicate that inorganic forms of selenium are less effective than organic ones. Special selenium-enriched vegetables may be the most effective form of selenium intake for cancer inhibition. These are not presently available for human consumption, but are predicted to appear on the market within the next few years.

Animal studies have shown that selenium-enriched onions, broccoli, garlic, and Brazil nuts are very effective in the inhibition of tumors. The major selenocompound in these foods has been shown to be one of the most effective selenocompounds tested thus far against chemical carcinogenesis in animals.

If one chooses to take selenium supplements to reduce the chance of contracting cancer, it is important that the maximum daily intake from all sources be less than 400 micrograms. Toxic effects of excessive selenium include hair loss, fatigue, immune impairment, weakened fingernails, and other problems. Since the trial conducted in the United States indicated that 200 micrograms per day was just as effective as 400 micrograms per day in preventing certain types of cancer; there is no compelling reason to take a daily amount of selenium greater than 200 micrograms.

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1. Low Selenium Linked to Higher Risk of Osteoarthritis by Dominique Patton, 14/11/2005.

A team from the University of North Carolina at Chapel Hill found that for every additional tenth of a part per million of selenium in volunteers' bodies, there was a 15-20 per cent decrease in their risk of knee osteoarthritis.

The work, based on data gathered from 940 participants, is thought to be the first to link the trace mineral to joint health. Arthritis severity was directly related to how low selenium levels were. The results suggest that we might be able to prevent or delay osteoarthritis of the knees and possibly other joints in some people if they are not getting enough selenium.

Research published in 2002 revealed that selenium levels in British bread-making wheats are 10 to 50 times lower than in their American or Canadian counterparts, owing to reduced levels of the mineral in UK soil and lower pollution. Daily intake of the mineral is therefore often lower than the recommended amount in Britain.

At the same time, incidence of osteoarthritis is rising in most developed countries in conjunction with an ageing population and obesity, a major risk factor for osteoarthritis of the knee. The UK currently has the eighth highest obesity rate in the world. In the past year, more than 2 million Britons visited their GP because of osteoarthritis. The US team first suspected that selenium might play a role in preventing osteoarthritis after observing that in severely selenium-deficient areas of China, people frequently develop Kashin-Beck disease, which causes joint problems relatively early in life.

They selected pariticipants in the major Johnston County Osteoarthritis Project, and divided them into three groups based on the selenium levels measured in toenail clippings. Those with the highest selenium levels faced a 40 per cent lower risk of knee osteoarthritis than those in the lowest-selenium group. Those in the highest selenium group had only about half the chance of severe osteoarthritis or disease in both knees. Some of the findings were even stronger in African-Americans and women.

2. Rayman. Selenium in Cancer Prevention: A Review of the Evidence and Mechanism of Action. Proc Nutr Soc. 2005 Nov;64(4):527-42.

Se is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (SeCys), by means of a mechanism requiring a large SeCys-insertion complex. This exacting insertion machinery for selenoprotein production has implications for the Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence, which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colo-rectal and lung cancers. The effect seems to be strongest in those individuals with the lowest Se status.

As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti- cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from gamma-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and Se-enriched yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA, including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) relating to prostate cancer, although a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.

3. Whanger. Selenium and its Relationship to Cancer: An Update Dagger. Br J Nutr. 2004 Jan;91(1):11-28.

Selenomethionine (Semet) is the major seleno-compound in cereal grains and enriched yeast whereas Se-methylselenocysteine (SeMCYS) is the major seleno-compound in Se- accumulator plants and some plants of economic importance such as garlic and broccoli exposed to excess Se. Animals can metabolize both Semet and SeMCYS. Epidemiological studies have indicated an inverse relationship between Se intake and the incidence of certain cancers. Blood or plasma levels of Se are usually lower in patients with cancer than those without this disorder, but inconsistent results have been found with toenail-Se values and the incidence of cancer. There have been eight trials with human subjects conducted on the influence of Se on cancer incidence or biomarkers, and except for one, all have shown a positive benefit of Se on cancer reduction or biomarkers of this disorder. This is consistent with about 100 small-animal studies where Se has been shown to reduce the incidence of tumours in most of these trials. Se-enriched yeast is the major form of Se used in trials with human subjects. In the mammary-tumour model, SeMCYS has been shown to be the most effective seleno-compound identified so far in reduction of tumours. Several mechanisms have been proposed on the mechanism whereby Se reduces tumours. Even though SeMCYS was shown to be the most effective seleno-compound in the reduction of mammary tumours, it may not be the most effective seleno-compound for reduction of colon tumours.