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Selenium Biologic Applications

By Dr Liji Thomas, MD

Selenium is vital in maintaining anti-oxidant functions in the body. It is a trace element, and is most often found in the form of the amino acid selenocysteine, a cysteine analog which has a selenium atom inserted in place of sulfur in the cysteine molecule. This amino acid is coded for by the UGA codon when it occurs after a specific DNA sequence. UGA is a termination codon in most other situations.

Selenium compounds have been long sought after because of the various roles of this element in the body. There are at least 30 selenoproteins present in animals, and 25 of them occur in mammals. Selenomethionine is the predominant form of selenium in most of them.

Antioxidant role

Selenium is present in several enzymes which prevent oxidative stress, such as dehydrogenases, glutathione peroxidases, superoxide dismutase, glycine reductase, thioredoxin reductase and hydrogenase. They reduce highly reactive free radicals to alcohols or water, by coupling this reduction with the oxidation of glutathione.

When the body is deficient in selenium, these enzymes fail to function properly, subjecting the body to oxidant damage. The eventual outcome of chronic oxidative stress includes damage to cellular lipids, protein and DNA, which eventually leads to the development of various cancerous changes, chronic inflammatory conditions, and cardiovascular/atherosclerotic disease.

Selenium also helps to regenerate the other important antioxidants in the body, such as vitamin C (ascorbic acid), and vitamin E (α-tocopherol), and so maintains a high level of redox activity in the body systems.

Glutathione peroxidase is the name for a family of similar enzymes that contain selenium at the active site, and act as antioxidants. These selenoenzymes catalyze the reduction of hydrogen peroxide to water. They are made up of four protein subunits, each with one selenium atom. Different isoenzymes occur, glutathione peroxidase being found in the cytosol, gastrointestinal tract, in the plasma, and in the reaction involving phospholipid hydroperoxide.

Thyroid hormones and selenium

Another important role of selenium is as part of the iodothyronine-deiodinase complex of enzymes which is required for the effective production of active thyroid hormones.

Selenium deficiency and disease

Selenium deficiency is thought to precipitate serious health effects in humans, such as a form of cardiomyopathy, called Keshan disease, in certain parts of China. In such areas, a form of osteoarthritis called Kashin-Beck disease is also endemic, causing major disabilities. The deficiency of selenium in the geographical areas where both these conditions are rife has led to the hypothesis that physiological stress responses are inefficient when antioxidant levels are low.

The commonly recommended dietary allowance of selenium is 55 mcg per day at all ages.

Synthetic organoselenium compounds have been researched to mimic its antioxidant properties, making use of the advantages that selenium has over the similar element sulfur. One of the most important among these compounds is ebselen, or 2-phenyl-1,2-benzisoselenazol-3(2H)-one.

Antitumor organoselenium compounds

Selenium supplements of 200 mcg a day have been reported to have anti-tumor activity. Inorganic selenium compounds with such properties act by generating free radical species which damage or kill cancer cells.

Selenium supplementation has been extensively studied to find an association with site-specific cancers as well as cancer-related mortality. However, while many large observational trials pointed to an association between higher selenium levels and significant reductions in prostate and colon cancers, this was not confirmed by interventional trials.

At present, selenium supplementation is known to be related with a 25% increase in the incidence of squamous cell skin cancer, with doubtful effects on the incidence of other cancers.

The first synthetic organoselenium compound to be studied was P-methoxybenzeneselenol, from food. However, today P-phenylenebis (methylene) selenocyanate and other similar compounds have been researched as chemopreventive agents, which show less toxicity than natural selenoamino acids or selenite. Ebselen has also showed carcinostatic activity in human breast, cancer and liver cell lines. Other compounds in this category include triphenylselenonium chloride.

Antiviral organoselenium compounds

Most synthetic organoselenium compounds show activity against viruses, including some types of herpes simplex, parainfluenza, rhinovirus and Semliki Forest viruses. Selenazofurin, and 7-methyl-8-selenoguanosine are good examples of active agents. These include selenium-substituted purine analogs, acyclouridine compounds and 3’-Se-dideoxynucleoside analogs.

These latter act powerfully against both HBV and HIV, and were developed to replace 2’,3’-dideoxynucleoside analogs, which have been effectively used as part of a protocol that includes protease inhibitors. This course of treatment has been shown to significantly reduce mortality rates, especially secondary to infections, in HIV patients.

Selenium supplementation, in combination with multivitamins, showed a powerful effect in delaying the overall progress of HIV infection, in a recent trial which compared selenium alone, multivitamins alone, selenium with multivitamins, and placebo, in their effects on disease activity.

Antibacterial organoselenium agents

Ebselen has been found to be active against Staphylococcus aureus. Other selenium-substituted compounds inhibit the growth of fungi, including Candida albicans and Saccharomyces cerevisiae.

Anti-inflammatory organoselenium compounds

Oxidative damage to body tissues is well-known to be mediated in part by reactive oxygen and nitrogen species. The damage they cause is a potent inducer of inflammation. Glutathione peroxidase levels have also been shown to be low in conditions known to be caused by oxidative stress. However, present research has not shown a benefit for selenium supplementation in the form of reduced incidence of heart disease, or of hyperlipidemia.

Ebselen prevents oxidant damage as well as being a powerful anti-inflammatory agent. It inhibits the production of reactive oxygen species, the nitric oxide synthase by endothelial cells and leucocyte adhesion to endothelium with migration through the endothelial barrier.

This has suggested its use in preventing and treating atherosclerotic heart disease. It has also been shown to inhibit inflammation of the lungs. Other promising compounds include the diselenides bis-(2-hydroxyphenyl) diselenide, bis (3-hydroxyphenyl) diselenide and bis (4-hydroxyphenyl) diselenide.

References

Further Reading

Last Updated: Feb 25, 2016

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