Selenium – a fascinating antioxidant of protective properties

Selenium is a trace element which fulfils important functions in the organism. Its deficit may cause acute disorders, but an overdose can also lead to severe consequences. The functions of selenium in the organism are mainly connected with its antioxidant properties, as it is an essential part of important antioxidant enzymes. Disturbances of oxidant balance have been found to be involved in the activity of numerous harmful factors as well as in the pathogenesis of diverse illnesses. Selenium administration has proved to be effective against the toxicity of many agents and the side effects of drugs. However, the narrow range between therapeutic and toxic doses of selenium, as well as the dependence of its effect on the applied form, dose and method of treatment, makes the choice of the most effective supplement a very complex issue. Divergent forms of selenium are still being studied, including both inorganic and organic compounds as well as Se-enriched natural products. The newest research has also involved selenium nanoparticles. The aim of this review is to present the great potential of selenium for protecting the organism against a wide variety of environmental pollutants, drugs and physical factors.


Introduction
Selenium belongs to trace elements essential for humans. In the body it is involved in numerous processes, among other things immune functions and antioxidant defense. Its deficit may result in cardiac, muscular, osseous, and immune disturbances. 1,2 The biological functions of selenium result from the occurrence of the selenocysteine amino acid in proteins. The research has revealed that about a hundred selenoproteins can be found in mammal organisms. 2 The most important of them are the antioxidant enzymes -glutathione peroxidase and thioredoxin reductase, as well as selenoprotein P, responsible for the storage and transport of selenium. [3][4][5][6] Selenium supplementation has been proved to be protective against a very wide range of harmful factors, both chemical, such as drugs exerting severe side effects, heavy metals, carcinogens, mycotoxins, or pesticides, and physical, such as heat stress or magnetic fields. However, the narrow range between therapeutic and toxic doses of selenium, as well as the dependence of its effect on the applied form, dose and method of treatment, make the choice of the most effective supplement a very complex issue. 5,[7][8][9][10] The average lethal dose established in animal models for sodium selenite (7 mg Se/kg b.w.) is almost 20 times smaller than that obtained for selenium sulfides, and more than 900 times smaller than for elemental selenium. 11 According to the US National Academy of Sciences, for adults, 55 µg is the recommended daily selenium intake, whereas 400 µg is the threshold which should not be exceeded. 7 The toxic dose for adults was established as more than 700 µg/day. 12 The symptoms of selenium toxicity include fatigue, disturbances in connective tissue as well as in cardiovascular, gastrointestinal, nervous, and respiratory systems. 11,13 As the interest in selenium and its effects on human health is still growing, diverse compounds of selenium are still being studied, both inorganic and organic, Se-enriched natural products like probiotics, yeast and green tea, as well as selenium nanoparticles. 3,8,10,[14][15][16][17][18] Organic compounds have been widely studied recently due to the similarity of the activity of some of them (e.g., ebselen or diphenyl diselenide) to that shown by glutathione peroxidase. 19 Diphenyl diselenide has also been proved to possess many beneficial pharmacological properties: anti-hyperglycemic, anti-hyperlipidemic, hepatoprotective, antiulcer, and antidepressant. 19,20  The aim of this review is to present the great potential of selenium for protecting the organism against the damage caused by environmental pollutants, drugs and physical factors, as well as the dependence of the selenium impact on the form and model of administration.

Comparison of the effect of different selenium forms on organisms
The effect of selenium on organisms shows strong dependence on its form. A distinct difference between organic and inorganic compounds has been found. The forms of selenium used are presented in Fig. 1.
Sodium selenite remains the most often studied inorganic form of selenium, containing Se(IV), but other forms are also commonly studied. A comparison of selenite and selenate, containing Se(VI), was performed on the mycelia of Pleurotus ostreatus exposed to cadmium and silver (1.25 mg/L, 2.5 mg/L and 5 mg/L). Selenium (2.5 mg/L or 5 mg/L) prevented the malonyldialdehyde (MDA) increase caused by the metals, but while Se(IV) showed full effectiveness, Se(VI) was either less effective or even intensified the pro-oxidant processes. 21 The research more and more often includes selenoorganic compounds -either naturally occurring forms or newly synthesized substances, e.g., selenomethionine, naphthalimide-based selenocyanates, 2-(5-selenocyanatopentyl)-benzo[de]isoquinoline-1,3-dione, diphenyl diselenide, selenofuranoside, p-methoxyldiphenyl diselenide, selenocyanates, and diphenylmethyl selenocyanate. [4][5][6]9,16,17,19,20,[22][23][24][25][26] The results regarding the comparison of inorganic and organic compounds are not fully consistent, although the newest studies usually reveal  that the organic forms are more beneficial and less likely to induce their own toxic effects. In mice treated with either sodium selenite or naphthalimide-based synthetic organoselenocyanates (oral gavage; 1.2 mg/kg b.w. and 3 mg/kg b.w., respectively), selenite significantly decreased hemoglobin as well as increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hepatic lipid peroxidation. Organic selenium depressed AST and ALT as well as blood urea nitrogen and creatinine, indicating the potential hepatoprotective and nephroprotective effects of this form. Histopathological studies have confirmed these outcomes. The advantage of the organic form was also observed in the case of liver antioxidant parameters. 24 In one of the newest studies, sodium selenite, selenomethionine and selenium yeast were compared in vitro (1 μg/mL in cell medium). In HepG2 cells exposed to lead nitrate (40 μg of Pb/mL or 80 μg of Pb/mL), DNA damage was reduced by organic selenium, whereas selenite not only was ineffective as a protective agent, but also intensified DNA injury. 6 Four dietary selenium forms (selenite, lactate-protein complex, Se-proteinate, and Se-yeast), given to goats before (0.3 mg/day/goat) and after parturition (0.9 mg/day/goat), were studied as potential Se-supplements. Tissue selenium content in different organs of the younglings were the highest in the Se-yeast group, but the other organic forms were also more effective as supplements than selenite. 27 Sodium selenite was also compared with dextrin stabilized selenium nanoparticles (both forms used at doses 10-100 μg/mL). An in vitro investigation revealed that the viability of the nanoparticle-treated cells was much higher than in the case of those treated by selenite. In an in vivo  study, rats with arthritis showed depletion of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in the liver, kidney and spleen as well as an increase in serum C-reactive protein. These disturbances were reversed by oral administration of nanoparticles (100 µg/kg b.w., 250 µg/kg b.w., 500 µg/kg b.w., or 750 µg/kg b.w.). 28 On the other hand, treatment with selenium nanoparticles (5-25 μg/mL) was reported to cause dose-dependent malformations in zebrafish embryos, whereas the same doses of sodium selenite did not show any harmful effects. 29 A comparison of Se-enriched probiotics and sodium selenite was performed on rats exposed to carbon tetrachloride. CCl 4 significantly increased serum ALT and AST, and disturbed liver oxidant balance. Both selenium forms alleviated the harmful effects, but the Se-enriched probiotics were more effective. 3

Protecting effect of selenium against toxicity of different substances
Protective properties of selenium against toxicity of diverse drugs: Animal model research Administration of drugs can be connected with side effects causing the impairment of organism functions. Selenium was found to protect against the toxicity of different drugs, including the chemotherapeutic agents -cisplatin and cyclophosphamide, antibiotics and dermatological medications as well as aspirin. The research also showed the pretreatment application to be more effective. The details of the studies performed and their results are presented in Tables 1 and 2.

Protective properties of selenium against environmental contaminants and physical factors: Animal model research
Selenium has been studied in regard to its possible protective effect against numerous environmental pollutants, and the results obtained seem to be very promising. The harmful effects of toxic elements (cadmium, aluminum, mercury, arsenic, lead, chromium) and compounds, e.g., carbon tetrachloride, carcinogens (acrylamide, hydrocarbons), mycotoxins (patulin, aflatoxin), and pesticides (beta-cyfluthrin), diazinon, acephate) were found to be reversed or alleviated by selenium treatment. Sodium selenite was most often used, but organic forms were also studied. Some researchers applied very interesting, new natural forms like polysaccharides isolated from selenium-enriched Ziyang tea, or meat from lambs receiving Se-nanoparticles in drinking water. 7,10 Synthetic organoselenium compounds also revealed their advantage over inorganic forms. Diphenyl diselenide was proved effective against the toxicity of mercury in rodents, while selenite showed no efficacy. 1,19 It was also found that the influence of selenium was dependent on its dose. 10,36 The detailed information is collected in Tables 3-8.

In vitro studies of protective properties of selenium
The beneficial impact of different forms of selenium against the toxicity of diverse factors has also been confirmed by in vitro studies.
In neuronal cells exposed to the addictive drug methamphetamine, a decrease in GPx isoforms (GPx 1 and GPx 4), and the depletion of GPx activity and intracellular reduced glutathione (GSH) was observed. However, in cells cultured in Se-containing media (10 nM or 100 nM as sodium selenite), before and during methamphetamine exposure, these effects were alleviated, although in the case of GPx      blood total antioxidant capacity, total white blood cells counts ↓; impaired granulopoiesis meat from lambs receiving selenium nanoparticles in drinking water (0.1%) blood total antioxidant capacity (+); total white blood cells counts (±); granulopoiesis (±) blood total antioxidant capacity ↑; intensified granulopoiesis ↓ -decrease; ↑ -increase; (+) -full protection; (±) -partial protection; (0) -lack of protection; DMBA -7,12-dimethylbenz(a)anthracene; GPx -glutathione peroxidase; MDA -malonyldialdehyde; ALT -alanine aminotransferase; AST -aspartate aminotransferase; LDH -lactate dehydrogenase; SOD -superoxide dismutase; ALP -alkaline phosphatase. activity only the low dose, and in the case of GSH only the high one, were found to be effective. 51 In vitro experiments have also shown the efficacy of selenium nanoparticles. This form was proved to prevent DNA damage and cell death in lymphocytes exposed to UVB radiation. 52 Another study performed on cardiomyoblast H9c2 cells revealed the occurrence of changes in the antioxidant level as well as in mitochondrial functions during ischemia and reperfusion which were prevented by selenium in the form of selenium incorporated guar gum nanoparticles. 53 Natural selenium forms have also been found to show a protective effect under in vitro conditions. Two seleniumenriched medicines of herbal origin (IMOD and Angipars) (Rose Pharmed Biotechnology Co., Iran) were studied in an experiment performed on human lymphocytes. Both substances prevented the toxicity of an organophosphorus pesticide -chlorpyrifos. The beneficial influence included the amelioration of the chlorpyrifos-induced increase in TNF-α and reduction in cell apoptosis and necrosis. 54   plasma glucose (±); plasma corticosterone (0); plasma triglycerides (+); cerebral AChE (0); liver tyrosine aminotransferase: lower dose (0), higher dose (±) none ↓ -decrease; ↑ -increase; (+) -full protection; (±) -partial protection; (0) -lack of protection; (-) -intensification of harmful effects; GPx -glutathione peroxidase; GR -glutathione reductase; TrxR -thioredoxin reductase; TBARS -thiobarbituric acid-reactive substances; ALT -alanine aminotransferase; AST -aspartate aminotransferase; LDH -lactate dehydrogenase; GSH -reduced glutathione; ALP -alkaline phosphatase; SOD -superoxide dismutase; CAT -catalase; AChE -acetylcholinesterase.

Protective properties of selenium: Human model research
Diverse human studies have also revealed the beneficial effects of selenium supplementation.
In young children (4.4-5.4 years) in rural Bangladesh, an inverse relationship between the exposure to cadmium (evaluated by the assay of its urinary level) and glomerular filtration rate was found, particularly in girls. This effect was alleviated in subjects with higher urinary selenium, which led the authors to suggest that higher Se-status seemed to exert a protective influence against cadmium nephrotoxicity. 55 An interesting study on 933 mother-newborn pairs, performed in China, revealed that umbilical cord serum manganese was related to the risk of lower Neonatal Behavioral Neurological Assessment rank. However, this effect was alleviated in the cases where umbilical cord serum selenium was higher. The authors suggested that selenium supplementation might be considered in pregnant women, particularly in regions of low environmental selenium level. 56 Based on a study involving cancerous patients subjected to cisplatin therapy, Ghorbani et al. suggested that selenium might prevent the renal toxicity of the drug. They found that acute kidney failure occurred in 11.5% of patients treated with cisplatin, whereas in those pretreated with a single selenium tablet (400 mcg), no such cases were observed. 57 Similarly, Mix et al. observed some protective influence of selenium treatment (selenomethionine, 1 week before as well as during therapy) in patients with inoperable, stage III non-small cell lung cancer undergoing concurrent chemoradiation (radiation, paclitaxel and cisplatin). 23

Conclusions
In conclusion, the presented studies make it possible to suggest that selenium seems to be one of the most appealing agents to be examined in relation to its protective role against the toxic effects induced by different harmful factors, both chemical and physical. But it must be serum glucose (±); serum uric acid, copper, iron and zinc (0); skeletal muscle SOD (-) higher dose: skeletal muscle MDA, serum glucose, copper and uric acid (±); serum iron and zinc (0); skeletal muscle SOD (-) emphasized that its effect depends on many factors, such as its chemical form as well as the applied dose and experimental model, so supplementation must be performed taking proper precautions to obtain the best results and avoid the toxicity of selenium itself. 5,10,24,36