Welcome to our website about the nutritional and biochemical roles of selenium in health. The Selenium Nutritional Research Center (SeNRC) is involved with all nutritional and biochemical aspects of selenium research. Selenium is a dietary-essential trace element (nutritional mineral) that is critical to the body’s defense against cancer and other illnesses involving free radicals and other reactive oxygen species (ROS).
At SeNRC, we direct much of our efforts to studying the relationship of various forms of selenium compounds for the prevention of cancer. Our scientists hold patents on the use of selenium compounds and the prevention and treatment of cancer, as well as composition patents on specific selenium compounds and combinations of selenium with other nutrients and/or antioxidants. (See US 6,090,414 and EP 0 750 911 B1) Prevention is the ultimate cure. Our patents issued and allowed also cover the composition of virtually all current multivitamins now made, distributed, or sold in the U. S., whether they contain selenium or not.
SeNRC’s Research Director, Dr. Richard A. Passwater, has been involved with selenium research since 1959, when selenium was postulated to be a component of an unidentified food factor called "factor 3" in livestock feed that was thought to spare the need for vitamin E and possibly be involved in liver and muscle health of poultry and livestock.
Dr. Passwater’s research with selenium as a cancer preventative began more than four decades ago, and over the decades, thousands of mechanistic studies, hundreds of animal studies, dozens of epidemiological (population) studies, and at least three published clinical supplementation trials have verified his findings.
On December 25, 1996, Dr. Larry Clark and his colleagues published their large, prospective, randomized, placebo-controlled, double-blind Nutritional Prevention of Cancer (NPC) clinical study in the Journal of the American Medical Association (JAMA 1996; 276:1957-1963). This landmark research effort showed that daily supplementation of diets with 200 micrograms of selenium yeast cut the cancer death rate in half. That is cancer mortality was reduced 50 percent (p=0.002). Lung cancer deaths were reduced 53% (p=0.03)
Total cancer incidence was reduced 37 percent (p=0.001) and the total carcinoma incidence was reduced 45%. In addition, the three leading sites of cancer had significantly lower incidence; lung cancer incidence was reduced 46 percent (p=0.04), prostate cancer incidence was reduced 63 percent (p=0.002) and colon cancer incidence was reduced 58 percent (p=0.03). There was a 17% reduction in all cause mortality (p=0.14), which when adjusted for sex, current smoking and age yielded a 21% reduction in deaths from all causes (p=0.07).
Throughout all of the mechanistic, animal and clinical studies of selenium it has been observed that not only is the incidence reduced, but also the severity and death rate have been even more greatly reduced suggesting that tumors are being destroyed, not just prevented. At the very least, the progress is delayed.
A large 2003 French study called SU.VI.MAX incorporated 100 micrograms of selenium as selenomethione in its regimen that also included vitamins C and E, beta-carotene and zinc. It found that the supplements reduced cancer deaths by 37% and cancer incidence 30%. (In press)
In Qidong County, China, a four-year study involving 226 hepatitis B antigen carriers demonstrated the protective effects of selenium supplementation. An equal number of participants were given either a supplement containing 200 micrograms of selenium or a placebo containing no selenium. None of the selenium-supplemented participants developed hepatocellular carcinoma, whereas seven participants receiving the placebo without selenium did. (Yu, S. Y. et al., Biol. Trace Elem. Res. 1997)
Another clinical intervention trial involving 130,000 Chinese in five townships also showed that selenium supplementation was protective against cancer. Selenium was added to the table salt in one of the five townships in close proximity to the other four townships. The result was that there was a 35% reduction in hepatocellular carcinoma in the township receiving the selenium supplementation. (Yu, S. Y. 1997)
From March 1986 through May 1991, a randomized nutritional intervention trial called the General Population Trial was conducted with over 30,000 people in Linxian, China. The participants who received 50 micrograms of selenium, beta-carotene, and vitamin E had significantly lower cancer mortality rates than those who did not. After supplements were given for 5.25 years in the clinical trial, significant reductions (P = .03) in total mortality [relative risk (RR) = 0.91] and cancer mortality (RR = 0.87) were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium, with the reduced risk beginning to arise about 1-2 years after the start of supplementation By the last six months of the trial, the degree of cancer reduction was approaching 100%.
Further clinical studies are underway in the U. S. including: the Negative Biopsy Trial (NBT) for men at high risk of Prostate Cancer because of a persistent elevation in PSA above 4 ng/ml and had a negative biopsy; the Watchful Waiting Trial: for men diagnosed with Prostate Cancer and under 'Watchful Waiting' of a physician for their disease; the Preprostatectomy Trial (PREP): for men who have been diagnosed with non-metastatic prostate cancer that have not yet had a radical prostatectomy; the Selenium and Lung Trial for former tobacco smokers. And the Selenium and Vitamin E Cancer Prevention Trial (SELECT) will confirm the Clark results for selenium and determine if these two dietary supplements together result in greater synergistic protection than either alone against prostate cancer, the most common form of cancer, after skin cancer, in men. The study will include a total of 32,400 men. The selenium used is selenomethionine at the dosage level equivalent to 200 micrograms of elemental selenium.
The Prevention of Cancer by Intervention with Selenium (PRECISE) clinical trial, a study of 33,000 European individuals from the UK, Denmark and Sweden is at the pilot study stage.
Research on the ways in which selenium-containing compounds prevent cancer formation and/or destroy cancer cells has progressed on several fronts. Inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling are of recent interest. The effect of selenium-containing compounds on gene expression is of special interest. A large number of selenium-responsive genes with diverse biological functions have now been identified. These genes fall into 12 clusters of distinct kinetics patterns. The expression changes of 10 genes known to be critically involved in cell cycle regulation have been noted so far.
Selenium compounds also inhibit signaling enzymes such as protein kinase C (PKC) that play crucial roles in tumor promotion. A selenoprotein (a protein that purposely incorporates selenium as opposed to a protein that merely incorporates selenium by accident) identified in 1998 called Sep15 has now been shown to have redox function. The selenium-containing nutrient, selenomethionine has been shown to regulate the tumor suppresser p53 by the redox factor refl-dependent redox mechanism. Studies continue to support evidence that one important pathway is that many selenium-containing nutrients can be converted in the body to methylselenol.
Methylselenol has been shown to block expansion of pre-malignant cells forming into fully developed cancers. Several pathways have been proposed that could explain how selenium-containing compounds could block mutated cells from progressing to cancer. Methylseleninic acid has been shown to inhibit NF-kappa B and regulate I kappa B in prostate cancer cells. A representative of the hydrogen selenide metabolic pool has been found to protect liver cells against damage to DNA.
Studies continue to confirm that people with higher levels of selenium in their blood have lower rates of prostate and lung cancers. (Vogt, T. M., et al., Int. J. Cancer 2003;103(5):664-70). A new study confirms that selenium supplementation reduces damage to DNA in prostate cells (Waters, D. J., et al., J. Natl. Cancer Inst. 2003;95(3):237-41)
Continued studies in China confirm that those with low levels of selenium before selenium supplementation had significantly lowered incidence of lung cancer due to selenium supplementation. (Reid, M. E., et al., Cancer Epidemiol. Biomarkers Prev. 2002;(11):1285-91). This finding is also supported by a Finnish study showing that low selenium levels lead to an increased incidence of lung cancer. (Hartman, T. J., et al., Cancer Causes Control 2002;13(10):923-8).
In the Netherlands, former smokers with high levels of selenium experienced half as many bladder tumors as their counterparts with low selenium levels. An Indian study found that those with low levels of selenium have significantly more head and neck cancers than those with higher selenium levels. (Yadav, S. P., et al., J. Otolaryngol. 2002;31(4):216-9)
It is important to note, too, that the reduced levels of prostate specific antigen (PSA), a commonly used marker for prostate cancer, observed with selenium supplementation is due entirely to the effect of selenium on the cancer cells and not due to selenium interfering with the production of PSA for any reason other than a decrease in cancer cells. "Changes in serum PSA levels in an individual during selenium supplementation is not an effect specific for PSA secretion, but rather is a useful indicator for changes in the disease progression in individual patients." (Bhamre, S., et al., Prostate 2003;54:315-21)
There is more information about selenium and prevention of cancer in our "Cancer" section and there is much more yet to come regarding the selenium anticancer story.
HIV and AIDS
The Human Immunosuppression Virus (HIV) causes a depletion of body stores of selenium, which then in turn cause the immune system failures manifested as Acquired Immunodeficiency Disease Syndrome (AIDS). Selenium supplementation has been shown to forestall the progression of HIV infection to developing AIDS, to reduce the symptoms of AIDS and to improve the lifespan of AIDS patients.
The dietary essentiality of selenium was not established until 1973 when Dr. J. T. Rotruck and his colleagues at the University of Wisconsin determined selenium was a component of glutathione peroxidase (GPX). (Rotruck et al., Science 1973) GPX is an antioxidant enzyme produced in cell membranes to protect cells against free radicals that can destroy cells or impair cell function, mutate DNA and initiate many of the diseases associated with aging. GPX repairs peroxide damage in membranes, thus breaking the peroxidation chain reactions that damage cell components. Since that time, several more glutathione peroxidases and other selenoproteins (Sep) have been identified.
Selenium does not function directly in the body in its elemental or ionic form. Selenium atoms do function as reducing centers in organic compounds and as components of proteins. Selenium atoms in their oxidized forms are reduced by body pathways from their oxidized states (with the most oxidized state possible being plus 6) to the most reduced state, which is negative 2. Selenium in the most reduced (negative 2) oxidation state is defined as a selenide.
Selenium is an essential component of several important compounds that have wide-ranging functions in the body. Selenium-containing compounds are involved in the life processes ranging from apoptosis, to immune function, to the protection and repair of DNA. Many of these selenium-containing compounds are selenoproteins that incorporate the selenium-containing amino acid selenocysteine as the penultimate amino acid. Selenocysteine, the 21st amino acid identified as being a component of human proteins, can also be termed a selenide or selenol. Selenocysteine is genetically expressed by the codon UGA.
Some of the seleno proteins are selenoenzymes that have important enzymic functions. In selenoenzymes, selenocysteine is generally at the active site where the selenium atom functions as a redox center. One extremely important role for selenoenzymes is to maintain the intracellular redox milieu. The cellular redox-milieu involves several metabolic, antioxidative and regulatory aspects that are maintained and regulated largely by two enzyme-based systems: the glutathione and thioredoxin systems. (Gromer et al.) The thioredoxin and glutathione systems constitute a balanced redox network. The thioredoxin system may influence virtually all phases of tumorgenesis via its involvement in transcription and translation (Gromer et al.)
The family of selenoenzymes called thioredoxin reductases catalyze the NADPH-dependent reduction of oxidized thioredoxin, hyperoxides, dehydroascorbate, ubiquinol and other substrates. (May et al., J. Biol. Chem. 1997) The action of thioredoxin reductases in recycling dehydroascorbate to ascorbate (vitamin C) now explain the synergistic action of selenium and vitamin C discovered by Dr. Passwater in the early 1960s and described in the patent US 6,090,414. The same mechanism recycles ubiquinol to ubiquinone (Coenzyme Q-10). The thioredoxin system is also capable of regenerating proteins inactivated by ROS.
The selenoenzyme, thioredoxin glutathione reductase (TGR) was originally thought to be a typical thioredoxin reductase, but is now considered to be a testis specific combination glutathione reductase and thioredoxin reductase enzyme.
In the 1980s, Passwater and Olson determined that relatively small, readily absorbable selenium-containing compounds can mimic the function of enzymes including GPX, a glutathione-S-transferase (GST) which was originally called epoxide reductase, and mimics their function in repairing epoxide damage in DNA. The repair of damaged DNA prevents mutations that can lead to cancer. These selenium-containing compounds include selenides, such as triphenyl phosphine selenide, and 3-methylbenzothiazole-2-selenone, and isoselenocyanates, and have the general formulas of R3P=Se and R2C=Se. These selenides also include tris(methylseleno)methane, and allylselenocysteine, and methylselenocysteine, and diselenides such as diallyldiselenide. (European Union Patent issued September 10, 2003 and US Patent Application filed June 7, 1995.)
Selenophosphate synthetase (SPS) forms selenophosphate (SePO3H3) from ATP and selenide. (Allan, Lacourciere and Stadtman, Annu. Rev. Nutr. 1999;19:1-16.) SPS generates selenophosphate from selenite reacting with a disulfide bond to yield a selenotrisulfide, which then reacts through the selenium enzyme SPS with phosphate to generate the selenophosphate. This molecule is very similar to triphenylphosphine selenide, since both contain a P=Se bond.
Another important family of selenoproteins is the Iodothyronine Deiododinases, which has three known members that catalyze the activation and deactivation of the thyroid hormones that play important roles in regulating various metabolic processes and are important for the normal development of the fetal brain.
Selenoproteins include Sep A, Sep P, Sep R, Sep T, Sep W, Sep 15, Sep 18 and at least 35 other selenoproteins (Behne et al., l0th International Symposium on Trace Elements in Man and Animals, 2000). There are probably many more than suggested by these studies. There are also eight selenoproteins in artery walls, eight selenoproteins in brain tissue and nine selenoproteins in testis. (Qu et al., Biolog. Trace Element Res. 2000) Comparatively little is known about the functions of these selenoproteins at this time.
Selenium deficiency in animals can result in liver and muscle disorders. In humans, selenium deficiency has been linked to a cardiomyopathy called Keshan Disease. Selenium deficiency also increases the risk of free-radical related diseases associated with aging. The evidence is strong that selenium is protective against many forms of cancer.
In 1980, the official U. S. recommended intake range for selenium in all forms regardless of their nutritional value was 50 to 200 micrograms per day. In 2000, this was reduced to 70 micrograms of selenium per day for men and 55 micrograms per day for women. (Food and Nutrition Board, Institute of Medicine, DRI: dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids. Washington, D.C., National Academy Press 2000; 284-324.) This was done mistakenly on faulty assumptions in our opinion. We believe that this is a case where a little knowledge was extended to draw conclusions that require additional knowledge than what the reviewers examined. Our research suggests that these nutritionally-recommended intakes for selenium are not high enough to activate the full health benefits of selenium. Others have expressed the same concerns.
Dr. Gerald Combs, Jr. concludes that the nutritional requirements should be 175% higher for women and 218% higher for men. (Nutrition and Cancer 40(1) 6-11, 2001)
Dr. Jean Neve stated "… it is more evident that conclusions drawn from the response of one particular selenoprotein do not apply to all biologic functions demonstrated to depend on the element. Moreover, accumulating evidence suggests that selenium has further beneficial effects at doses higher than those regarded as adequate based on the previous criteria. This is, for example, the case for immunostimulant and anticarcinogenic actions of selenium that have consistently associated with supranutritional levels of exposure to the element, i. e., for dietary intakes of 150 -–250 micrograms of selenium per day, or more …" (Nut. Rev. 58(12): 363-369, Dec. 2000)
Dr. Margaret Rayman also disagreed, questioning whether the measure of selenium repletion used should be the amount of selenium needed to achieve plateau concentrations of plasma GPX, or should the measure be the amount needed to achieve GPX saturation in the platelets be used. She suggests the latter, which would equate to around 80 – 100 micrograms of selenium per day" [The Lancet 356(9225): 233-241, July 15, 2000]
Our research has found that all selenium-containing nutrients do not have equal nutritional value or anti-cancer value. The anti-cancer effect of selenium-containing nutrients is not related to their nutritional value or toxicity. With many selenium-containing compounds in the diet, intakes exceeding the levels needed to maximize known plasma selenoproteins may be required to observe anti-cancer effects. There is more to optimal health than merely maintaining adequate levels of selenoproteins in plasma – the anti-cancer effects are also important. With other selenium compounds, significant anti-cancer effects may be reached before plasma selenoproteins are maximized.
There is more than a thousand-fold difference between selenium compounds in preventing cancer when both toxicity and effectiveness are considered. Small changes in chemical structure of selenium compounds cause dramatic changes in biological activity. The most effective anti-cancer selenium compounds are the selenides, such as triphenylphosphine selenide and allylselenocysteine, which have or induce the greatest levels of epoxide-reducing activity. How directly the selenides are provided or the pathways the body uses to process other selenium forms, determine overall effectiveness.
It is not as much a question of "selenium deficiency" or "selenium adequacy" – or even concentrations of any one or two selenoproteins circulating in the blood -- but a question of optimal amounts of certain effective forms of selenium compounds.
Please come back and visit our website regularly to keep informed about the role of selenium in health. In the meantime, please be sure you are well nourished with selenium.
A protein that purposely incorporates selenium as opposed to a protein that merely incorporates selenium by accident. Some selenoproteins are important enzymes. Generally, selenoproteins have selenocysteine is the active site with selenium functioning as a redox center. There are also specific proteins in which selenium is only attached to the molecules. The chemical forms of selenium in the two known examples (14 kDa and 56 kDa) found in liver have not yet been elucidated, but it is known that the TGA codon responsible for selenocysteine incorporation is not involved.
More than 35 selenoproteins have been identified, although as of yet, the functions of several of these selenoproteins have not been determined.
Tumor Suppresser p53
The tumor suppresser p53 is a cell cycle checkpoint protein that contributes to the preservation of genetic stability by mediating either a G1 arrest or apoptosis in response to DNA damage. p53 causes growth arrest through transcriptional activation of the cyclin-dependent kinase inhibitor p21.
Glutathione peroxidases (GPx) are a family of selenium-containing enzymes (selenoenzymes) that protect cellular membranes and maintain membrane integrity and function. GPx accomplishes this by reducing potentially damaging peroxides including hydrogen peroxide, lipid hydroperoxides and phospholipid hydroperoxides. Glutathione normally serves as the electron donor in these reactions. Reduced glutathione (GSH) is oxidized to oxidized glutathione which is called glutathione disulfide (GSSG) while the peroxides are reduced. Other thiols can be oxidized as well. Such is the case with plasma glutathione peroxidase where glutathione levels in plasma are too low to serve as substrate for plasma glutathione peroxidase so thioredoxin and glutaredoxin are normally the electron donors.
Five GPx have been identified; the "classical" cytosolic glutathione peroxidase (cGPx), gastrointestinal glutathione peroxidase (GI-GPx), plasma glutathione peroxidase (pGPx), phospholipid hydroperoxide glutathione peroxidase (PHGPx) and sperm nuclei glutathione peroxidase (snGPx).
An enzyme having antioxidant properties. Antioxidant enzymes are large proteins that can terminate free radical reactions. Generally their molecular structure is too large and delicate to survive the digestive process, thus, the diet is not a meaningful source of antioxidant enzymes. The body manufactures several antioxidant enzymes including glutathione peroxidase, catalase, and superoxide dismutase.
Apoptosis can be thought of as a type of cell suicide. Apoptosis is a gene-directed process of cellular deletion that establishes equilibrium between cell birth and cell death. This is an important defense against many types of biological damage such as radiation, viral infections, drug toxicity and cancer. By this process, the cell can exert a direct control on its own death, sacrificing itself to protect its host. Apoptosis of cancer cells can be blocked by Nuclear Factor - kappa B (NF-kB) proteins. Antioxidants inhibit NF-kB, thus helping to fight cancers.
Electrons, via the antioxidant network, send signals to redox sensitive transcription factors such as NF-kB, API and p53). These factors control the expression of protective genes that repair damaged DNA, power the immune system, arrest the proliferation of damaged cells, and induce apoptosis.
Selenocysteine is the 21st amino acid identified as being a component of human proteins. Selenocysteine is genetically expressed by the codon UGA. It is important to understand that selenocysteine is not the compound formed by adding selenium to a molecule of cysteine. Selenocysteine is the compound formed when selenium is inserted rather than sulfur is a compound that otherwise would resemble cysteine. The sulfur-containing amino acid cysteine has the structure HS-CH2-CH(NH2)-COOH. (The other sulfur-containing amino acid found in proteins is methionine.) The selenium-containing compound selenocysteine has the structure HSe-CH2-CH(NH2)-COOH. Several selenoproteins contain selenocysteine as the penultimate (next to the last) amino acid.
At SeNRC, we use the traditional definition for selenide. A selenide is simply a very broad category of selenium compounds having the structure –Se-, regardless of how they are individually named. We have used this terminology for over 40 years and have used this terminology in all of our articles and patents, and most earlier publications used this definition as well. This includes classes of compounds conforming to the general structure R-Se-R as well as R=Se. As an example, selenocysteine is a selenide, as are Se-methylselenocysteine, diphenylselenide, di-allyl-selenide, N=C=Se (isoselenocyanate) and the R3P=Se family of phosphine selenides.
We are aware of the newer IUPAC terminology, which is more restrictive in limiting selenides to R-Se-R, where R is not H. Also see selenols.
A selenol is a specific refinement of the class of compounds called selenides. Selenols have the general structure of R-Se-H, where R is not H. Thus, selenocysteine can be called either a selenide or a selenol.
Enzymes are proteins that facilitate reactions without themselves being consumed in the reactions. Selenoenymes are enzymes that contain selenium, normally in the form of selenocysteine. One important function of selenoenzymes is in maintaining the intracellular redox milieu. Glutathione peroxidases, thioredoxin reductases, iodothyronine deiodinases and selenophosphate synthetase are examples of selenoenzymes.
A redox reaction involves a simultaneous reduction and oxidation. Whenever there is an oxidation, there must also be a reduction in that same system. The actions of antioxidants are redox reactions. The cellular redox-milieu is largely maintained and regulated by two enzyme-based systems, i. e., the glutathione and thioredoxin system.
Glutathione is a sulfur-containing multi-purpose reducing agent found in nearly all cells and is very important to health and longevity. Reduced glutathione is designated as GSH and is the "foot soldier" of the body’s antioxidant network. Antioxidants are usually recycled until there are no longer molecules of glutathione to regenerate them as antioxidants. Thus, we need to eat foods producing more or conserving more glutathione than we do the antioxidant vitamins.
GSH is the molecule oxidized by glutathione peroxidase (GPx) to destroy peroxides and so protect cellular membranes and maintain membrane integrity and function. GSH is also the molecule that is consumed by being oxidized to glutathione disulfide (GSSG) to recharge the other antioxidants in the antioxidant cycle. In the process where other antioxidants are recycled from their oxidized or free radical states back to their active antioxidant forms, GSH is often the compound that supplies the reducing hydrogen. Glutathione is required by enzymes such as glutathione reductase in which two molecules of GSH are converted to GSSG to provide hydrogen.
GSH is a tripeptide consisting of the amino acids glutamate, cysteine and glycine. Its chemical name is gamma-glutamylcysteinylglycine. In GSH, the N-terminal glutamate is linked to cysteine via a non-alpha- peptidyl bond. The body produces GSH in two steps. First, glutamate condenses with cysteine with the gamma-, rather than the alpha-, carboxyl of glutamate forming the peptide bond with alpha-amino group of cysteine. This reaction requires the enzyme gamma-glutamylcysteine synthase and ATP and the product formed are the dipeptide gamma-glutamylcysteine plus ADP and phosphate. In the second step, the dipeptide is condensed with glycine via a normal peptide linkage. This reaction requires glutathione synthase plus ATP. The active site in GSH is sulfhydryl (SH) group in the cysteine portion, hence the designated symbol "GSH."
GSH also serves as a reduced carrier for the reduction of glutaredoxin which is an hydrogen donor for nucleotide reductase (NADPH) in a manner similar to the role of thioredoxin.
Oxidized glutathione, which is called glutathione disulfide (GSSG), can be reduced back to reduced glutathione (GSH) with the aid of glutathione reductase. The reaction is H+ + GSSG + NADPH = 2GSH + NADP+ .
GSH is also involved in the detoxification of foreign molecules to the body. Potentially toxic electrophilic xenobiotics (pollutants, toxins and other compounds foreign to the body) such as certain carcinogens are conjugated to GSH. The reaction is R + GSH = R-S-G, where R is an electrophilic xenobiotic. These reactions are catalyzed by "phase II" enzymes called glutathione S-transferases that are present in high amounts in liver cytosol and lower amounts and other cells. The products of the conjugation with glutathione are soluble and excreted from the body. Xenobiotics are first "activated" by "Phase I" enzymes to form the electrophilic xenobiotics.
If these xenobiotics were not removed via conjugation to GSH, they could be free to react covalently with DNA, RNA and cell proteins leading to cancer or other serious cellular damage. Thus, GSH is an extremely import in defending the body against carcinogens and other toxins as well as defending the body against ROS.
A thioredoxin is defined as a protein of approximately 12 kDa that contains the active site referred to as the "thiodeoxin-motif" that contains the amino acid sequence cysteine-glycine-proline-cysteine. The active site cysteines form a disulfide that can be reduced by thioredoxin reductase.
See review by Stephan Gromer, Sabine Urig and Kata Becker (Heidelberg, Germany) in Medical Research Reviews (2003) "The thioredoxin system – From science to clinic."
Mammalian thioredoxin reductases (TrxR) are a family of selenoproteins that catalyze the NADPH-dependent reduction of oxidized thioredoxin, hyperoxides, dehydroascorbate, ubiquinol (oxidized coenzyme Q-10) and other substrates. The thioredoxin/thioredoxin reductase system influences all 4 phases of tumorgenesis via its involvement in transcription and translation.
A family of three selenoenzymes that catalyze the activation and deactivation of the thyroid hormones that play important roles in regulating various metabolic processes and are important for the normal development of the fetal brain. Thyroid hormones regulate gene expression, protein synthesis, tissue differentiation and general development. The two main hormones produced by the thyroid gland are the iodoamino acid hormones, 3,5,3’-triiodothyronine (T3) and 3,5,3’,5’-tetraiodothyronine (T4 or thyroxin). T3 is much more potent than T4. In essence, the predominant thyroid enzyme T3 is very dependent on the selenoenzymes deiodinases and that selenium deficiency impairs thyroid function.
Type 1 deiodinase (D1) is located mainly in the thyroid, liver, kidney and pituitary. The biological role of D1 is to provide T3 to the plasma, to inactivate T4 and T3 and to eliminate reverse T3 from the circulation.
Type 2 deiodinase (D2) is membrane bound. Its biological role is the local intracellular production of T3 from circulating T4.
Type 3 deiodinase (D3) is mainly located in the central nervous system, skin and the placenta. D3 protects the fetal brain from excessive amounts of T3 and regulates the supply of T3 and T4 from the mother. D3 inactivates the thyroid hormones by producing reverse T3 from T4 and T2 from T3.
Selenoprotein P (Sep P)
Selenoprotein P (Sep P) function is unproven, but it is thought to be a transporter of selenium, however, there is evidence that Sep P also acts as an antioxidant. Sep P is one of two known glycoproteins in plasma and accounts for more than 60 % of the plasma selenium level. The other selenium-containing glycoprotein is the glutathione peroxidase, pGPx. Sep P is very responsive to changes is dietary selenium levels. Sep P contains up to 10 selenocysteine residues per 43-kDa polypeptide chain, whereas other selenoproteins identified so far have one selenocysteine residue per molecule. A second selenoprotein P of 12-kDa may exist.
Selenoprotein W (Sep W) is a family of four known selenoproteins (9.5 – 10 kDa) of unknown function. Sep W was first called a selenoprotein of the muscle, but it is widely distributed in tissues. It was considered necessary for muscle function. Sep W levels in the testes rise quickly in selenium-deficiency states with increasing dietary selenium. The brain conserves Sep W most strongly, but Sep W levels in the brain do not rise quickly with increasing dietary selenium.
Two 15-kDa selenoproteins (Sep 15) have been identified. Their function is unknown at this time, but evidence links them to protection against prostate cancer. Sep 15 is highly expressed in prostate epithelial cells. The gene for Sep 15 is located on a chromosome often affected in cancer.
Selenophosphate synthetase 2 (SPS)
Selenophosphate synthetase is critical for the biosynthesis of most selenoproteins, which contain selenocysteine as their active site. Selenophosphate synthetase catalyzes the reaction of selenides with AMP to form selenophosphate. Selenophosphate becomes the selenium donor for the production of selenocysteine. So far, two selenophosphate synthetases (1 & 2) have been identified, one being the SPS 2, which has selenocysteine as its active site, the other being SPS 1, which has threonine as its active site.
SPS forms selenophosphate (SePO3H3) from ATP and selenide. SPS generates selenophosphate from selenite or selenide reacting with a disulfide bond to yield a selenotrisulfide, which then reacts via SPS with phosphate to generate the selenophosphate. This molecule is very similar to triphenylphosphine selenide, since both contain a P=Se bond.
Glutaredoxin (Grx) is also known as thioltransferase.
Nuclear Factor – kappa B (NF-kB) is a ubiquitous family of inducible transcription factors. NF-kB controls about 180 genes. NF-kB is activated by a large variety of stimuli, mainly as the result of ROS, carcinogens, inflammatory cytokines, infections, cellular stresses and apoptosis inducers. NF-kB consists of five subunits. NF-kB can be split into its subunits, which can travel into the cell nucleus where interaction with DNA can occur. Thioredoxin is involved in reducing the cysteine residue (Cys62) needed for DNA binding by the subunits and thus alteration of DNA. Thus, thioredoxin and other antioxidants can prevent the alteration of DNA caused by NF-kB.
The decrease of oxidation number to a more negative value. It is the result of a gain in electron(s) or the addition of H2 or H- (hydrogen anion) Organic chemists like to think of reduction as the result of adding a reducing agent such as H2, NaBH4, etc., or the loss of O or O2. The addition or loss of H+ (hydrogen cation) or H2O is neither an oxidation nor a reduction.
The increase of oxidation number to a more positive value. It is the result of a loss of electrons or the loss of H2. Organic chemists like to think of oxidation as the result of adding an oxidation agent such as O, O2, Br2 etc. The addition or loss of H+ (hydrogen cation) or H2O is neither an oxidation nor a reduction.
Glycoproteins are proteins that have oligosaccharide (glycan) (having two or more monosaccharide units) chains covalently attached to their polypeptide backbones. Glycoproteins are a class of glycojungate or complex carbohydrate.
The generic name for derivatives of alkanes (saturated hydrocarbons).
The allyl radical is the univalent unsaturated organic radical C3H5 derived from propylene. Its structure is CH2=CH-CH- . Garlic and onions are rich in allyl compounds. ("Allyl" is not to be confused with "Alkyl.")
A family of cytosolic selenoenzymes that catalyze the conjugation of electrophilic xenobiotics to glutathione. The electrophilic xenobiotics are formed by cytochrome P450 enzymes (Phase I enzymes) and are detoxified by the Phase II enzymes including GST. There are four classes of GST; alpha (GSTA), pi (GSTP), mu (GSTM) and theta (GSTT). There are several isoenzymes in each class.
Besides their role in conjugation of xenobiotics to glutathione, an important action of GST is the conjugation of hyperoxides and epoxides. Cruciferous and allium vegetables (garlic, onions) increase GST levels.
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