Selenium is an essentialmineralmicronutrient for animals, though it is toxic in large doses. In plants, it sometimes occurs in toxic amounts asforage, e.g.locoweed. Selenium is a component of theamino acidsselenocysteine andselenomethionine. In humans, selenium is atrace element nutrient that functions ascofactor forglutathione peroxidases and certain forms ofthioredoxin reductase.[1] Selenium-containing proteins are produced from inorganic selenium via the intermediacy ofselenophosphate (PSeO33−).
Selenium is an essentialmicronutrient in mammals, but is also recognized as toxic in excess. Selenium exerts its biological functions throughselenoproteins, which contain theamino acidselenocysteine. Twenty-five selenoproteins are encoded in thehuman genome.[2]
Theglutathione peroxidase family of enzymes (abbreviated GSH-Px) catalyze reduction ofhydrogen peroxide and organichydroperoxides:
The two H atoms are donated by thiols in a process that begins with oxidation of aselenol side chain in GSH-Px. Theorganoselenium compoundebselen is a drug used to supplement the action of GSH-Px. It functions as a catalyst for the destruction of hydrogen peroxide.[3]
A related selenium-containing enzyme in some plants and in animals (thioredoxin reductase) generates reduced thioredoxin, a dithiol that serves as an electron source for peroxidases and also the important reducing enzymeribonucleotide reductase that makes DNA precursors from RNA precursors.[4]
Selenium also plays a role in the functioning of thethyroid gland. It participates as acofactor for the threethyroid hormonedeiodinases. These enzymes activate and then deactivate various thyroid hormones and their metabolites.[5] It may inhibitHashimoto's disease, an auto-immune disease in which the body's own thyroid cells are attacked by the immune system. A reduction of 21% on TPO antibodies was reported with the dietary intake of 0.2 mg of selenium.[6]
Some microorganisms utilize selenium informate dehydrogenase. Formate is produced in large amounts in the hepatic (liver cells) mitochondria of embryonic cells and in cancer cells by the folate cycle.[7]
Formate is reversibly oxidized by the enzymeformate dehydrogenase:[8]
Thioredoxin reductase uses a cysteine-selenocysteine pair to reduce thedisulfide inthioredoxin. The selenocysteine is arranged in an unusual Sec-His-Glucatalytic triad, which tunes its pKa.[9]
Selenocysteine-containingselenoproteins are found in a wide range of organisms, though they are not universal. In other words, some forms of life do not have a requirement for selenium.[10]
Besides theselenocysteine-containing selenoproteins, there are also some selenoproteins known from bacterial species, which haveselenium bound noncovalently. Most of these proteins are thought to contain a selenide-ligand to amolybdopterin cofactor at their active sites (e.g.nicotinate dehydrogenase ofEubacterium barkeri, orxanthine dehydrogenases). Selenium is also specifically incorporated into modified bases of some bacterialtRNAs (as5-methylaminomethyl-2-selenouridine).[11]
Plants known as selenium hyperaccumulators are able to concentrate selenium into their aerial parts. They not only are able to tolerate high levels of selenium in their bodies, but also actively seek out selenium in soil. This is believed to work as a defense against herbivores and pathogens, as these other organisms do not have the same level of resistance to selenium toxicity. This may also have an allelopathic effect against competing plants.[12]
The US Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for selenium in 2000. If there is not sufficient information to establish EARs and RDAs, an estimate designatedAdequate Intake (AI) is used instead. The current EAR for selenium for people ages 14 and up is 45 μg/day. The RDA is 55 μg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher-than-average requirements. RDA for pregnancy is 60 μg/day. RDA for lactation is 70 μg/day. For children ages 1–13 years, the RDA increases with age from 20 to 40 μg/day. As for safety, the IOM setsTolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of selenium, the UL is 400 μg/day. Collectively the EARs, RDAs, AIs and ULs are referred to asDietary Reference Intakes (DRIs).[13]
TheEuropean Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women and men ages 15 and older, the AI is set at 70 μg/day. AI for pregnancy is 70 μg/day; for lactation, 85 μg/day. For children ages 1–14 years, the AIs increase with age from 15 to 55 μg/day. These AIs are higher than the U.S. RDAs.[14] The European Food Safety Authority reviewed the same safety question and set its UL at 300 μg/day, which is lower than the U.S. value.[15]
In the United States, selenium deficiency is not common. A federal survey of food consumption determined that for women and men over the age of 19, average consumption from foods and beverages was 89 and 125 μg/day, respectively. For women and men of all ages fewer than 3% consumed less than the EAR.[16]
For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For selenium labeling purposes, 100% of the Daily Value was 70 μg, but as of 27 May 2016 it was revised to 55 μg.[17][18] A table of the old and new adult daily values is provided atReference Daily Intake.
Dietary selenium comes from nuts,cereals,meat,mushrooms,fish, andeggs.Brazil nuts are the richest ordinary dietary source and could cause selenium toxicity if consumed regularly – though the actual concentration of selenium (as with any plant-based food sources, such as another selenium-accumulating "paradise nut"Lecythis, belonging to the same familyLecythidaceae) is soil-dependent and may vary significantly by geographic location. In descending order of concentration, high levels are also found inkidney,tuna,crab, andlobster.[19][20]
The human body's content of selenium is believed to be in the 13–20 milligram range.[21]
There is an optimal range of selenium concentration in animals (or broadly speaking, in almost every selenium-dependent lifeform). Too much results in toxicity, too little results in deficiency.
Although selenium is an essentialtrace element, it is toxic if taken in excess. Exceeding theTolerable Upper Intake Level of 400 micrograms per day can lead to selenosis.[22] This 400 microgram (μg) Tolerable Upper Intake Level is based primarily on a 1986 study of five Chinese patients who exhibited overt signs of selenosis and a follow-up study on the same five people in 1992.[23] The 1992 study actually found the maximum safe dietary Se intake to be approximately 800 micrograms per day (15 micrograms per kilogram body weight), but suggested 400 micrograms per day to not only avoidtoxicity, but also to avoid creating an imbalance of nutrients in the diet and to account for data from other countries.[24] In China, people who ingested corn grown in extremely selenium-rich stony coal (carbonaceousshale) have suffered from selenium toxicity. This coal was shown to have selenium content as high as 9.1%, the highest concentration in coal ever recorded in literature.[25]
Symptoms of selenosis include a garlic odor on the breath, gastrointestinal disorders, hair loss, sloughing of nails, fatigue, irritability, and neurological damage. Extreme cases of selenosis can result incirrhosis of the liver,pulmonary edema, and death.[26] Elemental selenium and most metallicselenides have relatively low toxicities because of their lowbioavailability. By contrast,selenates andselenites are very toxic, having an oxidant mode of action similar to that of arsenic trioxide. The chronic toxic dose of selenite for humans is about 2400 to 3000 micrograms of selenium per day for a long time.[27]Hydrogen selenide is an extremely toxic, corrosive gas.[28] Selenium also occurs in organic compounds, such as dimethyl selenide,selenomethionine,selenocysteine andmethylselenocysteine, all of which have highbioavailability and are toxic in large doses.
TheOccupational Safety and Health Administration (OSHA) has set the legal limit (permissible exposure limit) for selenium in the workplace at 0.2 mg/m3 over an 8-hour workday. TheNational Institute for Occupational Safety and Health (NIOSH) has set aRecommended exposure limit (REL) of 0.2 mg/m3 over an 8-hour workday. At levels of 1 mg/m3, selenium isimmediately dangerous to life and health.[29]
Selenium pollution of water systems may result whenever new agricultural runoff courses through normally dry, undeveloped lands. This process leaches natural soluble selenium compounds (such as selenates) into the water, which may then be concentrated in new "wetlands" as the water evaporates. High selenium levels produced in this fashion have been found to have caused certain congenital disorders in wetland birds.[30]
On 19 April 2009, 21polo ponies died shortly before a match in the United States Polo Open. Three days later, a pharmacy released a statement explaining that the horses had received an incorrect dose of one of the ingredients used in a vitamin/mineral supplement compound that had been incorrectly prepared by acompounding pharmacy. Analysis of blood levels ofinorganic compounds in the supplement indicated the selenium concentrations were 10 to 15 times higher than normal in theblood samples and 15 to 20 times higher than normal in the liver samples. Selenium was later confirmed to be the toxic factor.[31]
Selenium deficiency can occur in patients with severely compromisedintestinal function, those undergoingtotal parenteral nutrition, and[32] in those of advanced age (over 90). Also, people dependent on food grown from selenium-deficient soil are at risk. AlthoughNew Zealand has low levels of selenium in its soil, adverse health effects have not been detected.[33]
Selenium deficiency as defined by low (<60% of normal) selenoenzyme activity levels in brain and endocrine tissues only occurs when a low selenium status is linked with an additional stress, such as high exposures to mercury[34] or as a result of increased oxidant stress due to vitamin E deficiency.[35]
Selenium interacts with other nutrients, such asiodide andvitamin E. The interaction is observed in theetiology of many deficiency diseases in animals, and pure selenium deficiency is rare. The effect of selenium deficiency on health remains uncertain, particularly in relation toKashin-Beck disease.[36]
In the regions (e.g., regions within North America) where low selenium soil levels lead to low concentrations in the plants, some animal species may be deficient unless selenium is supplemented with diet or injection.[37]Ruminants are particularly susceptible. In general, absorption of dietary selenium is lower in ruminants than in other animals and is lower in forages than in grain.[38] Ruminants grazing certain forages, e.g., somewhite clover varieties containingcyanogenic glycosides, may have higher selenium requirements,[38] presumably because cyanide is released from theaglycone byglucosidase activity in the rumen[39] and glutathione peroxidases are deactivated by the cyanide acting on the glutathionemoiety.[40] Neonate ruminants at risk ofwhite muscle disease may be administered both selenium and vitamin E by injection; some of the WMDmyopathies respond only to selenium, some only to vitamin E, and some to either.[41]
In fish and other wildlife, selenium is necessary for life but toxic in high doses. Forsalmon, the optimal selenium concentration is about 1 microgram selenium per gram of whole body weight. Much below that level, young salmon die from deficiency;[43] much above, they die from toxic excess.[42]
TheE. coli bacterium andS. cerevisiae yeast are two model organisms commonly used for biological study. They are also used asexpression systems for producing selenium-substituted proteins, which are used in a form ofX-ray crystallography calledsingle- ormulti-wavelength anomalous diffraction to determine thetertiary structure of a protein.[45] For these organisms to produce substituted proteins, they are grown in high-selenium environments, which also results in signs of toxicity. Part of this toxicity is due to the random substitution of methionine and cysteine in proteins with the selenium-containing version. Although this is the precise goal of this kind of protein production, alternation of the organism's own proteins in this way can render them nonfunctional.[46][47]
Selenium interactes with iodine and vitamin E; see section "Deficiency" above.
Selenium interacts with other minerals, such aszinc andcopper. High doses of selenium supplements in pregnant animals might disturb the zinc:copper ratio and lead to zinc reduction; in such treatment cases, zinc levels should be monitored. Further studies are needed to confirm these interactions.[48]
Selenium may be measured in blood, plasma, serum or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in a forensic investigation in a case of fatal overdosage. Some analytical techniques are capable of distinguishing organic from inorganic forms of the element. Both organic and inorganic forms of selenium are largely converted to monosaccharide conjugates (selenosugars) in the body prior to being eliminated in the urine. Cancer patients receiving daily oral doses of selenothionine may achieve very high plasma and urine selenium concentrations.[49]
Certain species of plants are considered indicators of high selenium content of the soil, since they require high levels of selenium to thrive. The main selenium indicator plants areAstragalus species (including somelocoweeds), prince's plume (Stanleya sp.), woody asters (Xylorhiza sp.), and false goldenweed (Oonopsis sp.)[50]
The substance loosely calledselenium sulfide (with the approximate formula SeS2) is the active ingredient in some anti-dandruff shampoos.[51] The selenium compound kills the scalp fungusMalassezia, which causes shedding of dry skin fragments. The ingredient is also used in body lotions to treatTinea versicolor due to infection by a different species ofMalassezia fungus.[52]
Several clinical trials have assessed the use of selenium supplements in critically ill adults; however, the effectiveness and potential benefits of selenium supplementation in this context is not well understood.[53]
Selenium has bimodal biological action depending on the concentration. At low nutritional doses, selenium acts as anantioxidant throughselenoproteins, scavengingROS, supporting cell survival and growth; while, at supra-nutritional higher pharmacological doses, selenium acts as apro-oxidant generatingROS and inducingcell death. In cancer, studies have been conducted mostly on the benefits of selenium intake in reducing the risk of cancer incidence at the nutritional level; however, fewer studies have explored the effects of supra-nutritional or pharmacological doses of selenium on cancer.[54]
"Although an inverse association between selenium exposure and the risk of some types of cancer was found in some observational studies, this cannot be taken as evidence of a causal relation, and these results should be interpreted with caution... Conflicting results including inverse, null and direct associations have been reported for some cancer types... RCTs assessing the effects of selenium supplementation on cancer risk have yielded inconsistent results... To date, no convincing evidence suggests that selenium supplements can prevent cancer in humans."[55]
To date, many studies have been conducted on the benefits of selenium intake in reducing the risk ofcancer incidence at the nutritional level, indicating that likely selenium functions as animmunostimulator, i.e. reversing theimmunosuppression intumour microenvironment towards antitumourimmunity by activatingimmune cells (e.g.M1 macrophages andCD8+ T-lymphocytes, the elevated number ofneutrophils and activated cytotoxicNK cells) and releasingpro-inflammatorycytokines such asIFNγ andTNFα.[54]
AIDS appears to involve a slow and progressive decline in levels of selenium in the body. Whether this decline in selenium levels is a direct result of the replication of HIV or related more generally to the overall malabsorption of nutrients by AIDS patients remains debated. Observational studies have found an association between decreased selenium levels and poorer outcomes in patients with HIV, though these studies were mostly done prior to the currently effective treatments with highly active antiretroviral therapy (HAART). Currently there is inadequate evidence to recommend routine selenium supplementation for HIV patients, and further research is recommended.[56]
Selenium supplementation has no effect on overall mortality.[57]
As with other types of supplementation, there is no good evidence selenium supplementation helps in the treatment of tuberculosis.[58]
A meta-analysis of four RCTs concluded that there is no support for selenium supplementation for prevention of type 2 diabetes mellitus in Caucasians.[59]
Abnormally high or low levels of dietary selenium can have an adverse effect on sperm quality, with a consequent lowering of fertility.[60]
Selenium has a protective effect towards mercury toxicity. Mercury binds to selenium with high affinity, so this metal can inhibit selenium-dependent enzymes. However, increased selenium intake can preserve the enzyme activities, reducing the adverse effects caused by mercury exposure.[61][62]
From about three billion years ago,prokaryotics evolved selenoprotein families centering around the selenocysteine machinery. Several selenoprotein families are known in bacteria, archaea, and eukaryotes, invariably owing to the presence of selenocysteine. They protect their host cells from oxidative damage. Selenium enzymes are involved in utilization of the small reducing moleculesglutathione andthioredoxin, common intracellular antioxidants and redox partners.[63][64][65][66]
Selenoprotein families of GSH-Px and the deiodinases of eukaryotic cells seem to have a bacterialphylogenetic origin. The selenocysteine-containing form occurs in species as diverse as green algae, diatoms, sea urchins, fish, and chickens.[67]
Typical GSH-Px and superoxide dismutase enzymes requrire trace elements including selenium,vanadium,magnesium,copper, andzinc. These elements tend to be abundant in marine environments but can be lacking in some terrestrial mineral-deficient areas.[63] Organisms have accordingly expanded or reduced their seleno-proteomes (arsenal of selenoproteins) to adapt to the situation.[68][69]
Asland plants adapted to the terrestrial environment from about 500 million years ago, they too faced the problem of a lack of these elements. Accordingly, most land plants do not produce selenoproteins.[68] For their anti-oxidation needs, they slowly optimized the production of "new" endogenous antioxidants such asascorbic acid (Vitamin C),polyphenols (including flavonoids),tocopherols, etc. A few of these appeared more recently, in the last 50–200 million years, in fruits and flowers of angiosperm plants. In fact, the angiosperms (the dominant type of plant today) and most of their antioxidant pigments evolved during the lateJurassic period.[70]
Thevertebrates of 500 million years ago were marine fishes. They opted to expand their seleno-proteomes, most notably evolving athyroid gland with high concentration of selenium and iodine and associated systems. A group of them, thetetrapoda, later adapted to life on land but retained many of the ancestral selenoproteins. Not all selenoproteins were retained, however: theselenoprotein U contains selenocystine in fishes and chicken, but mammals (including humans) have a selenium-free version of this protein, replacing the selenocystine with cysteine (human genesPRXL2A,PRXL2B,PRXL2C).[68] Another example is the humanGPX5 and rodentGPX6, both of which have a vestigialSECIS element pointing clearly to a selenocystine past.[71]
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