Selenocysteine

Other Names

(2R)-2-amino-3-hydroseleno-propionic acid(2R)-2-amino-3-selanyl-propanoic acid(2R)-2-amino-3-selanylpropanoic acid(2R)-2-amino-3-selenylpropanoic acid(2R)-2-azaniumyl-3-selanylpropanoate(R)-2-Amino-3-hydroselenopropanoic acid3-Selanyl-2-aminopropanoic acid3-Selanyl-L-alanine3-seleno-alanine3-selenoalanine3-selenyl-L-alanineD-selenocysteineDL-selenocysteineL-Alanine, 3-selenyl-L-SelenocysteinL-SelenocysteineL-selenocysteine zwitterionL-SelenozysteinSe-CysSecSelenium cysteineSeleno-(DL)-cysteineSeleno-cysteineselenocystineU

Synopsis

Selenocysteine: A Comprehensive Reference

1. Identity and Chemical Characterization

Nomenclature and Classification

Selenocysteine is the selenium-containing analogue of cysteine and is the twenty-first proteinogenic amino acid. It is designated by the one-letter code U and the three-letter abbreviation Sec (also historically written as Se-Cys in older literature). It is the only amino acid containing an essential dietary micronutrient (selenium) as a constitutive component, the only amino acid encoded by a UGA codon, and the only one synthesized on its tRNA in all domains of life.

Chemical Structure and Properties

Selenocysteine has the same structure as cysteine, but with an atom of selenium taking the place of the usual sulfur; it has a selenol group. The selenium atom gives selenocysteine quite different properties from cysteine. The most obvious difference is the lower pKa of selenocysteine, and it is also a stronger nucleophile than cysteine. Specifically, the Se-H group is more acidic (pKa = 5.43) than the thiol group; thus, it is deprotonated at physiological pH.

The presence of selenium improves the redox properties of a given protein (e.g., GPX family, thioredoxin reductase, selenoprotein P). For example, Maiorino et al. reported that the substitution of sulfur with Se in enzymes bearing cysteine amino acid moiety leads to a substantially enhanced catalytic activity. Furthermore, a study by Ingold et al. suggested that thiol-based catalysis is prone to overoxidation, whereas selenol-based catalysis is resistant to overoxidation. Overoxidation of the selenoprotein would inactivate that protein, and thus prevent it from carrying out its oxidative functions.

Selenocysteine is rarely encountered outside of living tissue (nor is it available commercially) because of its high susceptibility to air-oxidation. More common is the oxidized derivative selenocystine, which has an Se-Se bond. Both selenocysteine and selenocystine are white solids.

Like other natural proteinogenic amino acids, cysteine and selenocysteine have L chirality in the older D/L notation based on homology to D- and L-glyceraldehyde. In the newer R/S system of designating chirality, they have R chirality, because of the presence of sulfur or selenium as a second neighbor to the asymmetric carbon.

Natural Sources and Distribution

Selenocysteine exists naturally in all kingdoms of life as the defining entity of selenoproteins. In terms of dietary exposure, selenocysteine is present in animal-derived foods as a constituent of selenoproteins embedded in muscle and organ tissue. Dietary sources of selenocysteine are predominantly animal products, whereas Brassica and Allium species, including garlic and onions, are sources of the related compound Se-methylselenocysteine (MeSeCys). The major form of selenium in selenium-enriched garlic, onions, broccoli florets, broccoli sprouts, and wild leeks is Se-methylselenocysteine.

Once selenomethionine and inorganic selenium are absorbed, they are rapidly metabolized to a common intermediate that is used for synthesizing selenocysteine, the form of selenium found in the 25 human selenoproteins. Approximately 28% to 46% of the body's total selenium content is found in skeletal muscle. Selenium homeostasis is maintained primarily by urinary excretion.

Common Forms and Related Selenium Compounds

In the context of dietary supplementation and research, selenocysteine must be distinguished from several chemically related compounds:

Selenocysteine (Sec/SeCys): To the knowledge of researchers studying dietary supplement speciation, selenocysteine is not commercially available as a supplement standard or dietary supplement ingredient. It is the form found endogenously in all selenoproteins in the body.
Se-methylselenocysteine (MeSeCys/MSeC): L-Se-methylselenocysteine is a selenoamino acid found naturally in vegetables such as garlic and broccoli. It is considered a bioavailable and safe form of supplementing the essential trace mineral nutrient, selenium.
Selenomethionine (SeMet): The predominant form found in selenium-enriched yeast and the most studied supplemental form of organic selenium.
Inorganic selenium (selenite, selenate): Supplements commonly include selenium in the forms selenite (Se[IV]) or selenate (Se[VI]), referred to as inorganic selenium. In general, inorganic forms of selenium are absorbed less effectively than the organic forms, with the latter being slightly less toxic.

2. Historical and Traditional Context

Selenium as a Trace Element: Early Recognition

Selenocysteine itself has no traditional herbal or ethnobotanical history of use, because its identity as a distinct amino acid was only elucidated in the twentieth century through laboratory science. However, its parent element, selenium, has a longer documented scientific trajectory.

While selenium itself was isolated in the 19th century, it wasn't until the 1950s that it was first considered to be an essential trace element, and later on, a critical antioxidant that could protect cell membranes against oxidative damage. Selenium was first discovered to be an essential trace element in the 1950s by the German scientist Klaus Schwarz. Experiments with vitamin E–deficient rats subjected to an exclusive diet of torula yeast developed liver necrosis, but they were normal when fed with brewer's yeast.

Selenium was first recognized as an antioxidant from experiments performed by Rotruck and coworkers in rat erythrocytes. In that study, selenium protected the cellular membrane and hemoglobin of erythrocytes against oxidative damage through the utilization of glutathione (GSH). GSH is an essential co-factor of the glutathione peroxidase (GPX) for the catalytic breakdown of hydrogen peroxide and lipid peroxides. Interestingly, the enzymatic activity of GPX was found to be selenium-dependent.

Discovery of Selenocysteine

Terry Stadtman's pioneering work on selenium biochemistry began with her 1972 discovery that protein A, a low-molecular-weight subunit of the clostridial glycine reductase, is a selenium-containing protein. In 1976, she and her colleagues became the first to demonstrate that the selenium was present as selenocysteine. They showed that selenocysteine plays an essential role in the catalytic activity of many selenoenzymes.

This unsolved problem became the subject of intensive research, resulting in the important discovery that the selenium-containing molecular part in glycine reductase, which is essential for the biological activity of this enzyme, is selenocysteine — a new kind of amino acid in which selenium takes the place of sulfur in cysteine. In other words, Thressa Stadtman discovered the twenty-first amino acid that occurs normally in protein in addition to the twenty others previously known.

Shortly thereafter, other scientists confirmed the existence of this new amino acid by showing that the selenium-containing part in glutathione peroxidase was also selenocysteine. In the late 1980s, Stadtman's group at NIH collaborated with August Böck's group in Munich to discover that one of the three stop codons, UGA, is also used as the signal for inserting selenocysteine into a growing polypeptide chain. This discovery helped to establish firmly the acceptance of selenocysteine as the twenty-first amino acid.

Historical Use of Selenium-Rich Foods

While selenocysteine as a molecule was not historically recognized, selenium-rich plant foods — particularly allium vegetables (garlic, onion) and cruciferous vegetables (broccoli, Brussels sprouts) — have been used across many traditional cultures. The selenium content of these plants, partly as Se-methylselenocysteine, contributed to selenium intake but was not specifically attributed to any selenium compound in traditional practice. The scientific characterization of selenium and its amino acid forms belongs entirely to modern biochemistry and medicine.

Selenium, initially described as a toxin, was subsequently shown to be essential for health and development. By the mid-1990s, selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results.

3. Key Constituents, Active Compounds, and Mechanisms of Action

Selenocysteine in the Genetic Code

Selenium is an essential trace element that is incorporated into 25 human proteins as the amino acid selenocysteine. The incorporation of this amino acid is a fascinating problem in molecular biology because selenocysteine is encoded by a stop codon, UGA. In all organisms that contain selenocysteine, both the synthesis of selenocysteine and its incorporation into a selenoprotein requires an elaborate synthetic and translational apparatus, which does not resemble the canonical enzymatic system employed for the 20 standard amino acids.

Selenium incorporation into selenocysteine is a highly complex process, owing to the complex genetic machinery required for both the synthesis of Sec-specific tRNA and the co-translational use of the codon "UGA," which also functions as the stop codon. The biosynthesis of selenocysteine is significantly more complicated than the other proteinogenic amino acids, including cysteine.

Selenoproteins: The Primary Vehicles of Selenocysteine Function

Selenocysteine has been found in 25 human selenoproteins and selenoenzymes important for fundamental cellular processes ranging from selenium homeostasis maintenance to the regulation of the overall metabolic rate. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation, and a wide variety of specific metabolic pathways.

Proteins naturally containing selenocysteine are often enzymes, employing the reactivity of the selenocysteine residue during the catalytic cycle, and therefore selenocysteine is normally essential for their catalytic efficiencies. The known selenocysteine-containing enzymes in humans include:

Glutathione peroxidases (GPx1–GPx4, GPx6): Glutathione peroxidase plays a pivotal role in scavenging and inactivating hydrogen and lipid peroxides. GPx4, also known as phospholipid hydroperoxide glutathione peroxidase, is particularly noteworthy as a monomer capable of reducing complex lipid peroxides and is essential for sperm maturation.
Thioredoxin reductases (TrxR1, TrxR2, TrxR3/TGR): In mammals, thioredoxin reductases are selenoproteins that contain a C-terminal penultimate selenocysteine, encoded by UGA. These enzymes are key components of the thioredoxin system, which is one of the major redox systems in cells. They control the redox state of thioredoxin but have also been implicated more broadly in redox regulation, cell growth, and other functions.
Iodothyronine deiodinases (Dio1, Dio2, Dio3): Iodothyronine deiodinases are selenocysteine-containing membrane enzymes that activate and inactivate the thyroid hormones through reductive iodide eliminations.
Selenoprotein P (SELENOP): A plasma protein that serves as the major selenium transport and distribution protein in the body, containing multiple selenocysteine residues.
Selenoprotein W, Selenoprotein R (Methionine sulfoxide reductase B1), Selenophosphate synthetase 2 (SPS2), and others as listed in a comprehensive classification by enzymes including glutathione peroxidases, tetraiodothyronine 5′ deiodinases, thioredoxin reductases, formate dehydrogenases, glycine reductases, selenophosphate synthetase 2, methionine-R-sulfoxide reductase B1 (SEPX1), and some hydrogenases.

Antioxidant Mechanism

The selenoproteins with identified functions (redox functions) are all oxidoreductases that contain selenocysteine in the catalytic center and participate in various redox processes, such as antioxidant defense, redox signaling, redox regulation of biological functions, and many other processes that regulate intracellular redox homeostasis.

Thioredoxin reductase (TXNRD) is a selenoprotein oxidoreductase which uses NADPH reducing equivalents to catalyze reduction of disulfides, endogenously primarily on thioredoxin (TXN). It is a flavoprotein with a selenolthiol active site on its C-terminal and a dithiol on its N-terminal domain. In its active homodimer formation, electrons flow from the flavin adenine dinucleotide (FAD) to the same-subunit N-terminal dithiol, which subsequently reduces the C-terminal selenolthiol of the other subunit.

Thyroid Hormone Metabolism

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T4) to the more metabolically active 3,3′-5 triiodothyronine (T3). Human and rat type I 5′-deiodinase have been identified as a selenoprotein containing selenocysteine in its active site. The three selenocysteine-containing iodothyronine deiodinases constitute a novel gene family. Selenium is retained and deiodinase expression is maintained at almost normal levels in the thyroid gland, the brain, and several other endocrine tissues during selenium deficiency, thus guaranteeing adequate local and systemic levels of the active thyroid hormone T3.

Metabolism of Supplemental Selenium into Selenocysteine

Selenomethionine, which is estimated to account for at least half of the dietary selenium, is absorbed by the same mechanism as methionine, and its selenium is made available for selenoprotein synthesis when it is catabolized via the transsulfuration pathway. The selenium in selenocysteine, another significant dietary form, is also highly bioavailable. Inorganic selenate and selenite are reduced by glutathione/NADPH to hydrogen selenide, which is the substrate for selenophosphate synthetase 2 (SePHS2) to charge selenocysteine-tRNA for co-translational incorporation into selenoproteins.

For selenoamino acids, tissue cysteine β-lyases release hydrogen selenide and methylselenol from selenocysteine and Se-methylselenocysteine, respectively.

4. Scientific Evidence by Area of Use

Note: Because selenocysteine itself is not commercially available as a supplement, clinical research pertains to selenium in general or to related organic selenium compounds (selenomethionine, Se-methylselenocysteine, selenium-enriched yeast). The biological outcomes are mediated through selenocysteine-containing selenoproteins in the body, making the following evidence directly relevant to understanding selenocysteine's physiological roles.

4.1 Antioxidant Defense and Redox Biology

Dietary selenium acts principally through selenoproteins, most of which are oxidoreductases involved in diverse cellular functions. The mechanistic basis is well-established at the molecular level: selenocysteine in the active sites of GPx and thioredoxin reductase enzymes enables efficient catalytic reduction of reactive oxygen and nitrogen species.

Evidence strength: The role of selenocysteine-containing enzymes in antioxidant defense is among the most thoroughly characterized in biochemistry, established through decades of structural, enzymatic, and genetic studies across multiple organisms. This represents strong, foundational scientific consensus. Direct evidence in intact human subjects confirming that supplemental selenium augments specific selenoprotein-mediated antioxidant activity in vivo is well-documented through biomarker studies (e.g., plasma GPx activity), though variability in baseline selenium status across populations affects the magnitude of effects observed.

4.2 Thyroid Function and Disease

Selenium is a micronutrient essential for the biosynthesis of selenoproteins containing selenocysteine. In adults, the thyroid contains the highest amount of selenium per gram of tissue. Most known selenoproteins, such as glutathione peroxidase, are expressed in the thyroid and are involved in thyroid hormone metabolism, redox state regulation, and maintenance of cellular homeostasis.

Some clinical studies have shown that lack of selenium will increase the prevalence of several kinds of thyroid diseases. Clinical data have specifically investigated selenium supplementation in autoimmune thyroid conditions:

Hashimoto's thyroiditis: Selenium supplementation in Hashimoto's thyroiditis was associated with the decreased levels of anti-thyroid peroxidase antibody and improved thyroid ultrasound structure.
Graves' orbitopathy: Selenium treatment in patients with Graves' orbitopathy has been shown to delay disease progression and improve the quality of life. This finding is supported by a randomized controlled trial published in the New England Journal of Medicine in 2011.
In vitro data on selenocysteine (SeMCys) specifically: By treating adipose/connective tissue in the orbital region with selenocysteine (SeMCys), researchers found that SeMCys appeared to reduce the toxic effects of hydrogen peroxide by reducing cell necrosis and apoptosis. This represents in vitro evidence only.

Individuals with inherited defects in selenocysteine insertion sequence (SECIS) binding protein 2 display a syndrome of selenoprotein-related defects including abnormal thyroid hormone metabolism.

Evidence strength: Moderate to moderately strong for selenium's role in thyroid function, supported by randomized controlled trials in specific thyroid conditions (particularly Graves' orbitopathy and Hashimoto's thyroiditis). The direct contribution of selenocysteine, as opposed to total selenium metabolism, is established at the mechanistic level.

4.3 Cancer Chemoprevention

By the mid-1990s, selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results.

The Nutritional Prevention of Cancer (NPC) Trial: The NPC trial randomized 1,312 patients with a history of nonmelanoma skin cancer to 200 mcg selenium per day in selenized yeast or to a yeast placebo. NPC patients were treated and followed for an average of 7.4 years, and patients randomized to selenium experienced significantly decreased total cancer incidence, mainly of the lung, colon, and prostate, as well as significantly decreased total cancer mortality.

The SELECT Trial: The SELECT study, largely motivated by the NPC trial and enrolling nearly 40 times as many subjects, showed unequivocally that selenium 200 mcg/day, with selenium in the form of selenomethionine, does not protect selenium-replete men against prostate or other major cancer.

Preclinical research has investigated the relative chemopreventive potencies of different selenium compounds. The chemopreventive index of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) was the highest, followed by Se-methylselenocysteine, and then selenomethionine; the latter was comparable to that of inorganic sodium selenite.

Results from preclinical studies indicate that the chemopreventive efficacy of selenium depends not only on the dose, but also on the chemical form in which it is administered. The bulk of current knowledge on the mechanisms of cancer prevention by selenium is based on data from animal experiments and studies conducted using in vitro systems.

The mechanistic context for the dual role of selenocysteine-containing enzymes in cancer is complex: selenium-containing antioxidant enzymes — specifically, glutathione peroxidases and thioredoxin reductases — play dualistic and context-dependent roles in the development and progression of human cancers. These crucial components of cellular redox homeostasis can function as either potent oncogenes or tumor suppressors depending on the tissue of origin, cancer stage, genetic background, and tumor microenvironment.

Evidence strength: Inconsistent and insufficient to support a blanket clinical recommendation. Large-scale RCT evidence (SELECT) did not confirm the cancer protection signal seen in the earlier NPC trial. The discrepancy appears to relate importantly to baseline selenium status in study populations, selenium speciation, and biological context. Despite extensive efforts to evaluate the beneficial and detrimental effects of selenium in human clinical trials, critical barriers remain, including significant gaps in knowledge of how selenium and selenoproteins act metabolically to prevent and, in some cases, promote cancer.

4.4 Cardiovascular Health

Selenoproteins number at least 25 in mammals, and function to regulate redox balance and thyroid hormone metabolism, and probably other as yet unidentified roles, since the functions of all selenoproteins have not yet been clarified. Because oxidant stress plays a major role in several cardiometabolic diseases, selenium status and selenium supplements have been widely investigated in relation to cardiometabolic health.

One randomized, double-blind, placebo-controlled trial examining cardiovascular mortality: In 668 healthy elderly individuals from a municipality in Sweden, 219 individuals received daily supplementation with selenium (200 μg Se as selenized yeast) and coenzyme Q10 (200 mg) combined for four years, while the remaining participants received either placebo or no treatment. Among the non-treated participants, lower cardiovascular mortality was found in the high selenium group as compared with the low selenium group. In the group with the lowest selenium basal concentration, those receiving placebo or no supplementation had a mortality of 24.1%, while mortality was 12.1% in the group receiving the active substance — an absolute risk reduction of 12%. In those with serum selenium above 85 μg/L and no apparent deficiency, there was no effect of supplementation.

The results of epidemiologic and clinical investigations are inconclusive regarding the relation of the plasma selenium level to cardiometabolic parameters, and do not support the routine use of selenium supplements to prevent cancer or cardiovascular disease.

Evidence strength: Preliminary and inconclusive for cardiovascular benefit in well-nourished populations. Signals of benefit appear most consistently in selenium-deficient populations.

4.5 Male Reproductive Function

Both animal and human evidence indicates that selenium is essentially required for spermatogenesis and male fertility, presumably because of its vital role in modulation of antioxidant defense mechanisms and other essential biological pathways and redox-sensitive transcription factors.

The selenocysteine-containing enzyme GPx4 (phospholipid hydroperoxide glutathione peroxidase) is specifically implicated: both thioredoxin-glutathione reductase (TGR) and GPx4 can serve as a novel disulfide bond formation system, and both enzymes contain a catalytic selenocysteine consistent with the role of selenium in male reproduction. Selenium has a very specific role in spermatogenesis that is essential for male fertility. The selenoprotein phospholipid hydroperoxide glutathione peroxidase was found to play important roles during sperm maturation.

As for the implication of selenium in fertility and reproduction in men, though a few clinical trials explore the effects of selenium supplementation on male fertility, there are inconsistencies in the recruitment of subjects that limit definitive conclusions.

Evidence strength: Mechanistically strong at the molecular and animal level; clinical evidence in humans is limited and calls for further rigorous trials.

4.6 Immune Function

There is evidence for a role of selenoproteins in antioxidant defence, redox state regulation, and a wide variety of specific metabolic pathways relevant to immune cell function. Selenium deficiency has been associated with impaired immune responses in multiple experimental models. However, direct clinical evidence specifically attributable to selenocysteine as a supplemental compound — as distinct from total selenium status — is not yet established in high-quality human trials.

Evidence strength: Preliminary in humans; well-characterized mechanistically through selenoprotein biology.

4.7 Neurological and Cognitive Function

In relation to selenoprotein functions, selenoproteins have emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Brain selenoprotein expression, particularly of selenoprotein P and thioredoxin reductase, has been studied in relation to neurodegenerative disease. The EFSA risk assessment for selenium excess identified potential associations of excess selenium with Alzheimer's dementia and amyotrophic lateral sclerosis (ALS) as areas of concern, based on emerging evidence. Effects prioritized for risk assessment include Alzheimer's dementia, amyotrophic lateral sclerosis (ALS), impaired neuropsychological development in children, thyroid diseases, prostate cancer, skin cancer, type 2 diabetes mellitus, and overall mortality.

Evidence strength: Very preliminary in humans; more research is needed to establish direction, dose-dependence, and clinical significance.

4.8 Selenium Deficiency States

Selenocysteine-mediated biology is most clearly demonstrated in states of selenium deficiency. Keshan disease (an endemic cardiomyopathy in selenium-deficient regions of China) and Kashin-Beck disease (an osteoarthropathy) are the most thoroughly characterized selenium-deficiency syndromes in humans. These conditions are corrected by selenium repletion, which restores the synthesis of selenocysteine-containing selenoproteins. This relationship is considered established scientific consensus.

5. Body Systems Associated with Selenocysteine-Containing Selenoproteins

Systemic redox/antioxidant system: GPx and thioredoxin reductase families are the primary selenocysteine-dependent antioxidant systems, active in essentially all tissues.
Endocrine system (thyroid): One of the critical functions of selenoenzymes is participation in the synthesis of thyroid hormones regulating basal metabolism in all body tissues.
Cardiovascular system: Selenoproteins protect against oxidative injury in cardiac and vascular tissue; deficiency is linked to cardiomyopathy.
Reproductive system: Findings from studies in experimental and domestic animals, cell cultures, and humans confirm the role of selenium and selenoproteins in male fertility, suggesting multiple mechanisms involved at various levels of the male reproductive system.
Immune system: Selenoproteins modulate T-cell proliferation and function, cytokine signaling, and oxidative burst in immune cells.
Central nervous system: Selenoprotein P is a primary supplier of selenium to the brain; GPx4 prevents ferroptotic cell death in neurons.
Musculoskeletal system: Selenium deficiency contributes to myopathy; skeletal muscle accounts for a large fraction of total body selenium as selenocysteine in selenoproteins.

6. Dosage and Forms Reported in Research

Because selenocysteine itself is not sold as a dietary supplement, dosing data in the clinical literature pertains to selenium supplements that are ultimately metabolized to selenocysteine in vivo. The following are dosages as reported in clinical studies and regulatory documents:

Recommended Dietary Allowance (RDA) for selenium: The Recommended Dietary Allowance (RDA) for selenium is 55 μg/day for adults.
Multivitamin/mineral supplements: The doses of selenium in multivitamin/mineral supplements vary, but many contain 55 mcg.
Selenium-only supplements: Supplements that combine selenium with vitamin E or other ingredients generally contain 50 to 200 mcg of selenium. Selenium-only supplements typically contain 100 to 400 mcg.
NPC trial dose: In the Nutritional Prevention of Cancer trial, a selenized yeast supplement containing 200 mcg/day of selenium was used.
Cardiovascular trial dose: In the Swedish cardiovascular study, participants received daily supplementation with selenium (200 μg Se as selenized yeast) combined for four years.
Se-methylselenocysteine (SeMC) subchronic toxicology: A repeated dose study indicated little systemic toxicity of Se-methylselenocysteine at supernutritional levels (0.5, 0.7, 0.9 mg/kg body weight/day) after 90-day oral exposure.

Selenocysteine and selenomethionine have been shown to be incorporated into proteins in humans and plants. The bioavailability of selenium in the form of selenomethionine is greater than 90 percent. The selenium in selenocysteine, another significant dietary form, is also highly bioavailable.

7. Safety Considerations and Interactions

Tolerable Upper Intake Level

The Tolerable Upper Intake Level for selenium is 400 mcg for adults, and it ranges from 45 mcg to 400 mcg for infants, children, and adolescents, depending on age. The European Food Safety Authority (EFSA) has established a lower tolerable upper intake level: A lowest-observed-adverse-effect-level (LOAEL) of 330 μg/day was identified from the large randomized controlled SELECT trial in humans, to which an uncertainty factor of 1.3 was applied, resulting in a UL of 255 μg/day for adult men and women (including pregnant and lactating women).

Selenosis: Chronic Toxicity

Selenosis is the result of chronically high intakes of selenium. It is most commonly characterized by hair loss and nail brittleness or loss, but other signs and symptoms can include a garlic odor in the breath, a metallic taste in the mouth, skin rash, nausea, diarrhea, fatigue, irritability, and nervous system abnormalities. In an area of China with a high prevalence of selenosis, toxic effects occurred with increasing frequency when blood selenium concentrations reached a level corresponding to an intake of 850 μg/day.

Acute Toxicity

Se-methylselenocysteine, with the Median Lethal Dose (LD50) of 12.6 and 9.26 mg/kg body weight in female and male mice respectively, was considered of high potency of health hazard under acute oral exposure, but a battery of tests including the Ames test, micronucleus assay, and mouse sperm malformation assay suggested that it was not genotoxic.

Risk of Type 2 Diabetes

The results of two large cancer prevention trials that demonstrated an increase in the risk of diabetes with modest selenium supplementation suggest a narrow therapeutic range for selenium. Because some evidence suggests that high serum selenium concentrations may have adverse effects on glycemic control, individuals with high selenium status and/or those at risk for type 2 diabetes mellitus should avoid taking selenium supplements.

Cancer Risk at High Status

The SELECT trial raised concern about prostate cancer risk in individuals with already-adequate or high selenium baseline levels. Effects prioritized for risk assessment by EFSA include prostate cancer and skin cancer, among others, in the context of selenium excess.

EFSA-Prioritized Adverse Effects at Excess Intake

Alopecia, as an early observable feature and a well-established adverse effect of excess selenium exposure, was selected as the critical endpoint on which to base a tolerable upper intake level for selenium.

Drug and Nutrient Interactions

Anticoagulants: Selenium may increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs like warfarin, heparin, and aspirin. This interaction is supported primarily by animal study data and theoretical mechanisms.
Statins: Statins may interfere with the body's ability to synthesize selenoproteins, potentially depleting selenium and contributing to muscle-related side effects.
Chemotherapy (Cisplatin): The chemotherapy drug cisplatin can lower selenium levels, although selenium supplementation might protect against some toxicities under medical supervision.
Selenium and Population Status: Variability in the selenium status of the populations studied and lack of standardization of measures of selenium status may account for part of the confusion regarding selenium and cardiometabolic health.

Inherited Defects in Selenocysteine Incorporation Machinery

Individuals with inherited defects in selenocysteine insertion sequence (SECIS) binding protein 2 display a syndrome of selenoprotein-related defects including abnormal thyroid hormone metabolism. Selenocysteine incorporation sequence binding protein 2 (SBP2) represents a key trans-acting factor for the co-translational insertion of selenocysteine into selenoproteins. In individuals with SBP2 deficiency due to mutations in the SBP2 gene, the dietary selenium intake is not the limiting factor when regular daily selenium intake is provided. This rare genetic condition demonstrates that selenocysteine's biological role depends not only on adequate dietary selenium but also on intact molecular machinery for its synthesis and incorporation.

Population Vulnerability and Adequacy

While selenium intakes and serum concentrations can vary by region, most people in the United States consume adequate amounts of selenium. However, people who follow a vegetarian or vegan dietary pattern may have lower selenium intakes, and people who smoke tend to have lower selenium status than those who do not. Over the last decades, optimization of population selenium intake for prevention of diseases related to selenium deficiency or excess has been recognized as a pressing issue in modern healthcare worldwide.

References

Health Conditions

Health conditions that Selenocysteine may help support.

No conditions available.

Body Systems

Body systems that Selenocysteine may help support.

No body systems available.