Introduction
- Selenium is a vital trace element nutrient with multiple roles in the growth and functioning of living cells in higher animals and humans. This element is unevenly distributed in the earth’s crust. Almost all of the selenium in animal tissue is found in the proteins. Some of these proteins contain stoichiometric quantities of selenium and are known as selenoproteins. Other proteins contain variable amounts of selenium (which substitutes sulfur randomly in the original protein) and are known as selenium-binding proteins
- The selenoproteins in animal tissues are enzymes that control oxidation-reduction processes. At the molecular level, selenium (as selenocysteine) is an essential component of the active sites of the enzymes glutathione peroxidase, iodothyronine 5′-deiodinase and mammalian thioredoxin reductase, and is also present in several other mammalian selenoproteins. Both glutathione peroxidase and thioredoxin reductase catalyze reactions essential to the protection of cellular components against oxidative and free radical damage. Glutathione peroxidase protects cell membranes from oxidative damage by hydrogen peroxide and a variety of hydroperoxides and supplements the protective action of the antioxidant enzyme superoxide dismutase in quenching free oxygen radicals. Selenium is molecularly integrated at the active sites of these enzymes and it was found that replacing the selenium with sulfur caused marked reduction in the activity of these enzymes
- The primary nutritional source is the soil from which it is absorbed by plants and enters the food chain. Geographical variations in the selenium status of populations therefore exist, necessitating selenium supplementation. The recommended levels for selenium supplementation in humans are 50-200 mcg/day. The recommended daily dietary allowance for selenium is 55 mcg. This recommendation also suggests that intake of selenium from all sources should not exceed 400 mcg
- In recent years, laboratory experiments, clinical trials and epidemiological data have established the role of selenium in the prevention of a number of degenerative conditions including cancer, inflammatory diseases, cardiovascular disease, neurological diseases, ageing, infections, etc. Most of these effects are related to the functionality of selenium in the antioxidant enzyme systems
- Historically, Selenomethionine was definitely identified in plant proteins in the 1950s-1960s. It was also demonstrated that the compound could be produced by yeast, E.coli, rumen bacteria and algae grown in selenium-enriched media. The isotope Selenomethionine was used as a pancreatic radioimaging agent. The use of Selenomethionine as a nutritional supplement was established in the 1970s when researchers determined in metabolic studies that the compound is well absorbed and retained in the body. Concurrently, selenium yeast was introduced as a food source of Selenomethionine. In 1984, L-(+)-Selenomethionine was produced and considered to be comparable to selenium yeast as a source of selenium
- Plants absorbing selenium from the soil usually convert it to the organic forms. Selenium is present as selenomethionine in wheat and other cereals. Selenomethionine therefore represents the major food form of selenium. If ingested in this form, selenium substitutes sulfur in the body proteins in animals and humans. Selenomethionine is thus the predominant storage form of selenium and can be considered as an essential amino acid – as with methionine, selenomethionine cannot be efficiently synthesized by humans and monogastric animals. As in the case of amino acids, natural materials contain Selenomethionine in the L-(+) form. The significance of this fact in selenium supplementation, will be explored in a later section
The biological significance of chirality in Selenomethionine
- In general, the transport of a drug or nutritional compound from the site of administration to the target tissue or organ depends upon the properties and structure of the drug or nutrient molecule. Biologically active agents are known to have discriminatory capacity with regard to their molecular sites of action. Both the sugars and the amino acids have mirror image isomers. Humans can use only one set of these isomers. The preference is based on the enzymatic reactions that are essential to the functions of a living cell. While D-sugars and L-amino acids can bind to the active sites of these enzymes, their mirror images cannot. Thus enzymes are stereoselective.
- The form of selenomethionine that the body can use is L-(+)-Selenomethionine. L-(+)-Selenomethionine is better absorbed and better incorporated into body components than any other known form of selenium. This may be understood by the fact that selenomethionine is incorporated into the body proteins including the antioxidant enzymes.
- In the formation of a protein molecule such as an enzyme, amino acids bond to form chains of peptides. A protein may consist of one or more polypeptide chain twisted, wound and folded into an unique 3D macromolecule. This is known as the native conformation of the protein, that determines its function and activity. In most cases the function of a protein relies on binding or recognizing or interacting with another molecule (enzyme-substrate, antibody-antigen (foreign material), hormone-receptor). It is the unique conformation of the protein that results in this specificity of function
- Primary level structure relates to the sequence of amino acids in the polypeptide chain. Secondary level structure looks at the initial folding and stabilization of the polypeptide chain and assumes several forms such as an alpha-helix, beta-pleated sheet or a random coil, through hydrogen bonding or ionic/electrostatic interactions. Tertiary structure relates to the further stabilization of the conformation by the bonding between the variable side chains of the amino acids in the polypeptide chain. Hydrogen bonds, ionic bonds and hydrophobic interactions may form weak interactions which help to maintain the conformation. Additionally disulfide bridges may form strong covalent bonds between adjacent -SH groups (as from reduced cysteine viz., cystine). Large numbers of amino acids are folded into distinct regions called domains that are responsible for specific functions of the proteins
- Quaternary structure is the formation of proteins from multiple polypeptide chains or subunits. Some proteins consist of two or more polypeptide chains. Each polypeptide chain is called a subunit and the quarternary structure is the relationship between the subunits, held together by hydrogen bonds, ionic bonds, hydrophobic interactions and disulfide bridges
- Thus the protein molecule has a three-dimensional structure. It is evident that the configuration of Selenomethionine would be important in determining its incorporation into this structure
Increasing levels of selenium in the diet could protect the skin against damage caused by ultraviolet rays from the sun, suggests new research from Edinburg University
New role for selenium
- 13/05/03 – Increasing levels of selenium in the diet could protect the skin against damage caused by ultraviolet rays from the sun, suggests new research from Edinburgh University
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Selenium action on cancer explained British consumers not getting enough selenium - In two trials, the researchers found that human skin cells containing the mineral are less likely to suffer the oxidative stress that can lead to unrestrained growth and cancer
- Selenium is an antioxidant, but many nutritionists believe that the average British diet contains less than the ideal amount of this essential trace element, found in Brazil nuts, bread, fish, meat and eggs
- A study published in the Journal of Food Sciences and Agriculture last year confirmed that levels of selenium in British bread-making wheats are up to 50 times lower than their American and Canadian counterparts and levels of selenium in the blood of the British population has been dropping since the 1970s. This is when grain began to be sourced from EU countries where soil is depleted of selenium
- Dermatologist Roddie McKenzie, leading the Edinburgh team, has suggested that people should take selenium supplements as a preventative measure
- “The results indicate it could well be prudent to supplement selenium levels year round along with other sensible precautions in the summer like applying sunscreen creams,” said Dr McKenzie. “Low selenium status is associated with up to a four-fold increased risk of developing cancer and low levels impair the immune system which fights cancer cells.”
- Selenium was one of the minerals reviewed by the recent Expert group on Vitamins and Minerals in the UK. In the US, the Food and Drug Administration recently issued a letter allowing claims that selenium ‘may reduce risk of certain cancers’, along with disclaimers, such as “Some scientific evidence suggests that consumption of selenium may reduce the risk of certain forms of cancer. However, FDA has determined that this evidence is limited and not conclusive.”
- The new study findings are published this month in Clinical and Experimental Dermatology and the British Journal of Dermatology
Selenium supplements stay prostate cancer progression
- 05/02/03 – Dogs fed a diet supplemented with selenium show a lower level of DNA damage in their prostates compared with dogs fed a normal (unsupplemented) diet, report researchers
- The study, published in this week’s Journal of the National Cancer Institute, suggests that taking selenium supplements decreases the cellular changes that may lead to prostate cancer
- David J. Waters, of Purdue University in West Lafayette, Indiana, and his colleagues randomly assigned 49 elderly male dogs to a normal diet or one of four diets supplemented with different amounts of selenium
- After seven months, the prostates of dogs fed diets supplemented with selenium had less DNA damage than the prostates of dogs fed the normal diet. Also, compared with those on the normal diet, dogs fed the supplemented diet had twice the number of prostate cells that had undergone apoptosis, a mechanism that can remove damaged cells
- The authors conclude that “selenium may benefit the aging prostate by decreasing the accumulation of DNA damage in epithelial cells even before these cells show cytotoxic
changes suggestive of malignancy” - The authors did not relate the study to developments in humans, but the trace mineral, present naturally in nuts, vegetables and wholegrains, has been shown to inhibit cancer development in a variety of experimental animal models. In a recent study on former smokers, selenium was associated with a lower risk of bladder cancer. Research is continuing to understand the way in which the mineral acts to prevent cancer.
- Glucose regulation was assessed by standard intravenous glucose tolerance tests after an overnight fast. Memory was assessed by a series of tests in which patients were asked to recall paragraphs and, overall cognitive function was measured on a test called the Mini Mental Status Examination (MMSE)
- The researchers demonstrated that poorer glucose regulation was associated with lower memory performance and smaller hippocampal volumes, which were adjusted for head size. These results were independent of age or overall cognitive performance, meaning that these variables did not affect the results, and suggest that delivery of glucose may influence hippocampal structure and function. Dr Convit stressed however that the observations needed to be confirmed by other investigators
- He said: “If our results are confirmed then they may have significant treatment implications given that diabetes and obesity are reaching epidemic proportions in the United States and there are a large number of middle aged and elderly individuals with impaired glucose metabolism and memory dysfunction.”
- The study was supported by grants from the National Institutes of Health/National Institute on Aging and the General Clinical Research Center (GCRC) at the NYU School of Medicine.
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Selenium may prevent oesophageal cancer
- 21/05/03 – Selenium may inhibit progression toward oesophageal cancer among people with the precancerous condition Barrett’s oesophagus, according to a new study
- Researchers in the US found that Barrett’s patients with low blood selenium levels were two to three times more likely to experience advanced precancerous changes than patients with medium or high selenium levels
- A team from the Fred Hutchinson Cancer Research Center and University of Washington School of Medicine studied the relationship between levels of selenium in the blood and changes in the lining of the oesophagus that represent advancement toward cancer
- However she cautioned that taking high doses of the trace mineral would not prevent the disease. “When it comes to selenium and Barrett’s, there appears to be a law of diminishing return. More selenium is not necessarily better. In fact, laboratory studies indicate that high doses of selenium can be toxic and could even promote cancer, so ‘megadosing’ with selenium supplements is a bad idea,” Rudolph said
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– Selenium action on cancer explained - The US recommended dietary allowance for selenium is 55 micrograms (mcg) for adults, while the UK’s Expert group on Vitamins and Minerals recently recommended no more than 0.35mg in daily supplement intake. The average multivitamin is thought to contain up to 20 mcg. Fish, meat and nuts are also good sources, while bread tends to have much less in Europe than in the US, due to lower levels of the mineral in the soil
- Previous randomized clinical trials in humans have shown that selenium significantly reduces risk and mortality for multiple cancers, including prostate and colorectal. It has also recently been shown to inhibit skin cancer. The mineral is thought to inhibit the changes that cause cells to become cancerous. It has been found to slow abnormal cell growth, prevent DNA damage and facilitate the normal process of cell death, or apoptosis. Selenium is also known to act as an antioxidant, so it may interfere with the cell-damaging effects of free radicals produced during normal cell metabolism
- There is currently no proven, recommended medical therapy for lowering cancer risk in people with Barrett’s, and while only 5 per cent to 10 per cent of Barrett’s patients develop cancer of the oesophagus, if it is not diagnosed early, the outlook is grim, according to researchers. The incidence is also rising faster than that of any other cancer in the United States
- “This research gives us hope that we will be able to develop medical means by which to lower Barrett’s related cancer risk and perhaps even reverse the risk among people who already show signs of progression toward oesophageal cancer,” said Rudolph
- For the study, Rudolph and colleagues analyzed data from 399 people with Barrett’s oesophagus and found that those with higher concentrations of selenium in their blood were less likely to have as many biological markers of progression towards cancer as those with less circulating selenium
- Those with higher levels of selenium were less likely to experience precancerous changes such as dysplasia – abnormalities in cellular size, shape or growth pattern; loss heterozygosity at 17p – partial loss of chromosome 17, which can inactivate the tumour-suppressor gene p53, a gene that is critical for controlling cell growth; aneuploidy – the accumulation of cells with grossly abnormal amounts of DNA, which indicates substantial genetic damage and is a sign of advanced progression towards cancer; and increased 4N fraction – an excessive number of cells with twice the normal amount of chromosomes, which may indicate a problem with cell division
- Those with higher levels of selenium were less likely to experience precancerous changes such as dysplasia – abnormalities in cellular size, shape or growth pattern; loss heterozygosity at 17p – partial loss of chromosome 17, which can inactivate the tumour-suppressor gene p53, a gene that is critical for controlling cell growth; aneuploidy – the accumulation of cells with grossly abnormal amounts of DNA, which indicates substantial genetic damage and is a sign of advanced progression towards cancer; and increased 4N fraction – an excessive number of cells with twice the normal amount of chromosomes, which may indicate a problem with cell division
- Most significantly, the researchers found that higher blood levels of selenium were associated with a threefold decreased risk of aneuploidy and a two-fold decreased risk of cellular dysplasia and loss of the p53 gene
- Selenium appeared to have the greatest effect on markers associated with advanced progression of Barrett’s, which suggests that the nutrient might be most beneficial for people with later-stage disease, they reported
- “While blood levels of selenium weren’t associated with one of the earliest markers of Barrett’s progression, people with selenium levels in the middle or upper range of normal were less likely to have advanced precancerous changes than those with lower selenium levels,” Rudolph said
- Rudolph and colleagues noted that selenium might reduce Barrett’s-related cancer risk by preventing the inactivation of the p53 tumour-suppressor or preventing further progression towards cancer after the gene has been shut off
- While the results are promising, more research is needed, Rudolph said. A limitation of the study is its cross-sectional design; the analysis was based on data collected from Barrett’s patients at a single point in time, representing an isolated snapshot of biological activity
- “Following these same people over time eventually will give us a stronger understanding of how selenium and other dietary factors affect precancerous progression,” Rudolph said. “If the results of our study are confirmed in longitudinal studies and randomized controlled trials, the public-health impact could be substantial,” she added
Fast facts – Selenium study
- Lead investigators: Dr. Scott Lippman, MD Anderson Cancer Center and Dr. Charles Coltman, Jr., Chairman, Southwest Oncology Group (SWOG)
- Subjects: US multi-center population of 32,000 men with an average age of 55 years old. The confirmatory trial will involve 5 years, with active intervention lasting between 7 – 12 years, with an average of 8 – 9 years. Recruitment began in January, 2001
- Dosages: The study will consist of four groups of equal size, with one group receiving 200 ug per day elemental Selenium alone, another 400 mg per day vitamin E alone, the third both Selenium and Vitamin E and the fourth an identical looking placebo
L–, D- and DL forms of Selenomethionine – A brief explanation
A molecular model for Selenomethionine is shown below:
L-(+)-Selenomethionine
From above structure, that the Carbon atom indicated is attached to four different chemical groups and is “asymmetric”. The molecule, therefore, has one chiral center at this point and exhibits “chirality”.
Chirality
- Chiral compounds are chemical compounds that exist in two forms (enantiomers) that are non-superimposable mirror images of each other, and so are asymmetrical. The word “Chiral” comes from a Greek word meaning hand, applied here because our hands are mirror images of one another
- Chiral center (asymmetric atom, stereocenter): Appears in compounds that lack reflection symmetry. For organic compounds, the presence of four different moieties about a central carbon atom, constitutes the chiral center
- Enantiomers: Non-superimposable mirror images that must contain a chiral center
- Racemic Mixture (Racemate): A 1:1 mixture of enantiomers
- The Selenomethionine molecule has one chiral center, similar to amino acids such as methionine. Because one carbon atom is asymmetric, Selenomethionine can occur as two optical isomers (enantiomers). These isomers rotate the plane of polarization of plane-polarized light in opposite directions
- Optical activity (quantified by the rotation of the plane of polarized light as it passes through a substance) was measured long before the three dimensional structure of molecules could be determined by methods such as X-ray Crystallography. Based on experimental results for the direction of rotation of plane-polarized light, optical activity was then symbolized with the letter “d” or the “+” sign (for dextrorotatory, right handed or clockwise rotation of the plane of polarized light when viewed toward the light source) and “l” or “-” (for levorotatory, left hand or counterclockwise rotation)
- Later the “D” and “L” symbols were associated with absolute configuration based on the arbitrary, but correct assignment of the absolute configuration of the dextrorotatory and levorotatory forms of glyceraldehyde. Here, absolute configuration is based on chemical synthesis with glyceraldehyde as the starting material and optical activity is specified using the “+” and “-” notation. Thus L-Selenomethionine is dextrorotatory (+) and D-Selenomethionine is levorotatory (-). L -amino acids are found in naturally produced proteins. D and L amino acids as well as the racemic DL- mixture can be synthetically produced.
Enantiomers of Selenomethionine
Selenium supplementation
- Cell mediated immunity is primarily affected in cases of selenium deficiency, (particularly when vitamin E levels are also low), as the antioxidant actions of selenium and vitamin E protect the immune system from damage by oxidative free radicals and hydroperoxides. As selenium is unevenly distributed in the earth’s crust, endemic selenium-deficient zones occur in several parts of the world. Selenium deficiency has been implicated in Keshan’s disease (a degenerative heart condition related to dysfunctional glutathione peroxidase), white muscle disease in animals, and Keshan-Beck disease (a disabling joint disease seen in children aged 5-13 years in low selenium zones of East Asia). Residents of low selenium zones in Finland and New Zealand, appear to be pre-disposed to cardiovascular disease or the complications of pregnancy. Infants are more susceptible to selenium deficiency on account of their increased biological demands. Thus dietary supplementation with selenium sources becomes necessary. The total selenium content of a food does not provide an adequate measure of the utilization and bioavailability of the element. It is important that supplemental selenium be administered in bioavailable form
- The inorganic salts and chelates are not normal dietary forms of selenium. Selenium derived from selenite and selenate cannot be stored in significant amounts in the body proteins. These compounds also failed to raise blood
- Selenium levels in human subjects. Sodium selenite is chemically unstable and is degraded to elemental selenium by ascorbic acid. It is important to note that elemental selenium is not bioavailable and may have toxic effects at levels only four to five times the amounts normally ingested in the human diet. Sodium selenate is almost completely absorbed, but a significant fraction is lost in the urine before it can be incorporated into the body tissues
- Selenomethionine contains selenium in a molecularly integrated form and is therefore directly incorporated into the proteins in the body in place of the amino acid, methionine . It is reported that the replacement of methionine by selenomethionine in the protein structure does not induce any functional changes in the protein molecule. In fact, selenium in the protein structure protects DNA from oxidation more efficiently than the original sulfur in methionine. The carbon-selenium bond is more easily broken during photochemical reactions as compared to the carbon-sulfur bond. Thus L-(+)-Selenomethionine preferentially “accepts” the energy from light. Therefore topical or orally administered L-(+)-Selenomethionine offers greater protection to the skin against damage by ultraviolet light
- One study reports that selenium levels in the red blood cells of subjects treated with selenomethionine (in the form of selenium yeast) increased by 100% after 16 weeks supplementation. Neither selenite nor selenate supplementation produced significant increases under the same conditions. Thus L-(+)-selenomethionine and yeast containing L-(+)-Selenomethionine are the appropriate forms of selenium for use in nutritional supplements and foods including infant formulas. L-(+)-Selenomethionine administered in the form of selenomethionine containing yeast was found to be effective in reducing the risk of cancer. L-(+)-Selenomethionine is the preferred form of selenium supplementation due to its inherent safety and its scientific recognition as the most bioavailable form of selenium
- In the preparation of selenium yeast, Saccharomyces species are grown on selenium-enriched media, so that their protein contains selenomethionine and 90+% of the total selenium is in the form of L-(+)-Selenomethionine. Saccharomyces cerevisiae may accumulate up to 3000 mcg/g selenium
Metabolism of L-(+)- Selenomethionine
- More than 90% of L-(+)-Selenomethionine which is the major dietary form of selenium, is absorbed by a mechanism similar to that for the essential amino acid, methionine. L-(+)-Selenomethionine has the sulfur atom in L-(+)-Methionine replaced by selenium. It is converted to selenocysteine in the body. Selenocysteine is then incorporated into selenoproteins. The sequence is schematically represented in the Figures and the metabolism of all forms of selenium supplementation is presented in Figure 3. However, if Selenomethionine is supplied in the form of pure selenomethionine or selenium yeast, it is important to ascertain that the selenium is present in the form of L-(+)-Selenomethionine. Good commercial samples of selenium yeast typically contain 1000-2000 ppm of selenium, most of which is in the form of L-(+)-Selenomethionine. However, some samples may contain substantial amounts of inorganic selenium compounds instead of L-(+)-Selenomethionine. Similarly, some commercial samples of “pure” Selenomethionine may actually be mixtures of inorganic selenium salts with methionine or could contain selenomethionine in the DL- or D- forms that do not provide efficient supplementation.