Selenium

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Selenium is one of the 24 essential vitamins and minerals required for optimal human health. It is associated with increased intrinsic anti-oxidant capabilities and prevention of various forms of cancer, but has received notoriety due to its ability to promote cancer in higher dosages.

It is a part of many anti-oxidant enzymes, and is also the main factor in a web of 'selenoamino acids' which are amino acids bound to selenium which can serve as regulatory factors.

Selenium intake is also quite variable depending on soil quantities, so one global area may have different soil quantities than another area; thus for some persons supplementation is advisable.

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An overall intake (foods and supplements) in the range of 200-300ug daily should be the goal for general health and well being with an emphasis on anti-carcinogenic properties.

Edit1. Structure and recommendations

Edit2. Functions in the body in normal dietary ranges

It normally acts in concert with a class of enzymes and transporters called Selenoproteins (proteins with selenium in it), many of which are intrinsic anti-oxidant enzymes. In these selenoproteins, selenium acts as a prosthetic group or active site.^[1]

Edit3. Different forms of selenium in the body

Selenium can take the form of various organic and non-organic compounds.

Non-organic forms typically revolve around Selenite, a triple-oxidized form of selenium. It can be converted via Glutathione into Selenade; this multiple step process produces some superoxide radicals.^[2]

Organic forms include the selenoamino acids, which include selenocysteine, selenomethione, and Se-methylselenocysteine. The main active dietary form is selenomethionine.^[3] Selenomethionine is a relatively stable compound, but has pro-oxidative metabolites such as Selenid and Methylselenol.^[4]

Edit4. Effects of various intake levels

Deficiency of Selenium occurs when overall intake is less than 11ug, and 40ug is typically recommended as the minimum intake.^[5] A slightly higher but still low dietary intake of selenium (55ug) is sufficient to support the needs of 25 selenoproteins^[6][7] although there may be some interindividual differences.^[8] Levels above this, but not yet into therapeutic dosages (200-300ug) are possibly in the range of what is needed to exert anti-carcinogenic effects^[9][10] and doses up to the range of 750-800ug daily seem to be relatively free of harm.^[11] Dosages of 1,500-1,600ug or above start to become associated with harm and doses nearing 3,000-5,000ug can cause direct DNA damage.^[12][13][14]

Selenium metabolites can also regulate cell cycles and apoptosis, and aid in tumor regulation.^[14]

Edit5. Different forms of selenium

The synthetic form called MethylSelenic Acid can be directly reduced into methylselenol and can avoid the B-lysase enzyme intermediate commonly seen with dietary selenium.^[15]

Edit6. Selenium and Glucose Metabolism

Selenium has been noted in the past to aid glucose metabolism via acting as an insulin mimetic^[16] and thus aiding the deposition of glucose into both fat and muscle cells.^[17][18] These effects have also been seen in vivo.^[19]

In populations that have sufficient selenium status, epidemiological research^[20] and one intervention^[21] have suggested that further supplementation may increase the risk for insulin resistance and Type II Diabetes. The intervention was dosed at 200mcg daily.

The theorized mechanism of action is that after a certain threshold of selenium intake (past the RDA, nearing the TUL) selenium builds up in pancreatic tissue^[22] and exerts oxidative stress on beta-cells that secrete insulin.^[23]

This may be an issue of selenium being anti-diabetic acutely (via acting as an insulin-mimetic and aiding in glucose deposition) but over time damaging beta-cells and exerting the opposite effect and being pro-diabetic.^[24]

Edit7. Selenium and Cancer

7.1. General

Selenium was first discovered to be related to cancer via correlational research showing higher cancer rates in areas with lower crop selenium content.^[25]

Several metabolites of selenium may be involved with cancer regulation. Methylselenol is though to play a role^[26][27][14]

Selenoproteins themselves, rather than individual selenoamino acids, are also implicated in cancer prevention. These selenoproteins are typically those that exert anti-oxidative effects^[28] (Glutathione Peroxidases and Selenoprotein P) and alleviate cancer during the promotion stage.^[29][30]

Specific selenoproteins that have been investigated for being linked to specific cancers include Glutathione Peroxidase 1 being associated with head and neck, lung and breast, and bladder and prostate cancers,^{[31][32][33][34]} Glutathione Peroxidase 2 being associated with colorectal adenoma,^[35][36] Selenoprotein P being associated with both colorectal adenoma and Prostate cancer,^[37][38] Selenoprotein 15 being associated Head, Neck, breast and lung cancer,^[39][40][41] and Thioredoxin reductase 1 being associated generally with most cancers.^[42][43]

7.2. Prostate

Circulating selenium (independent of supplementation) is associated with a decrease in prostate cancer as assessed by a relatively small meta-analysis in a relatively dose-dependent manner up to 170ng/mL, where it results in a relative risk ratio of 0.8 relative to 60ng/mL (set as baseline).^[44]

Edit8. Safety and Toxicity

Much danger of excessive selenium comes through the pro-oxidant compound sodium selenite (thrice oxygenated selenium bound to sodium); this compound is able to induce tumor death via its pro-oxidant abilities, but is also toxic to other cells.^[5]

References

1. Papp LV, et al. From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal. (2007)
2. Suzuki KT, Kurasaki K, Suzuki N. Selenocysteine beta-lyase and methylselenol demethylase in the metabolism of Se-methylated selenocompounds into selenide. Biochim Biophys Acta. (2007)
3. Schrauzer GN. Selenomethionine: a review of its nutritional significance, metabolism and toxicity. J Nutr. (2000)
4. Seitomer E, et al. Analysis of Saccharomyces cerevisiae null allele strains identifies a larger role for DNA damage versus oxidative stress pathways in growth inhibition by selenium. Mol Nutr Food Res. (2008)
5. Letavayová L, Vlcková V, Brozmanová J. Selenium: from cancer prevention to DNA damage. Toxicology. (2006)
6. Stadtman TC. Discoveries of vitamin B12 and selenium enzymes. Annu Rev Biochem. (2002)
7. Moghadaszadeh B, Beggs AH. Selenoproteins and their impact on human health through diverse physiological pathways. Physiology (Bethesda). (2006)
8. Rayman MP. Selenoproteins and human health: insights from epidemiological data. Biochim Biophys Acta. (2009)
9. Rayman MP. Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc Nutr Soc. (2005)
10. Combs GF Jr, Clark LC, Turnbull BW. An analysis of cancer prevention by selenium. Biofactors. (2001)
11. Schrauzer GN. Nutritional selenium supplements: product types, quality, and safety. J Am Coll Nutr. (2001)
12. Reid ME, et al. A report of high-dose selenium supplementation: response and toxicities. J Trace Elem Med Biol. (2004)
13. Whanger PD. Selenium and its relationship to cancer: an update. Br J Nutr. (2004)
14. Brozmanová J, et al. Selenium: a double-edged sword for defense and offence in cancer. Arch Toxicol. (2010)
15. Ip C, et al. In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res. (2000)
16. Stapleton SR. Selenium: an insulin-mimetic. Cell Mol Life Sci. (2000)
17. The Insulin-Like effects of Selenate in Rat Adipocytes
18. Fürnsinn C, et al. Insulin-like vs. non-insulin-like stimulation of glucose metabolism by vanadium, tungsten, and selenium compounds in rat muscle. Life Sci. (1996)
19. Ghosh R, Mukherjee B, Chatterjee M. A novel effect of selenium on streptozotocin-induced diabetic mice. Diabetes Res. (1994)
20. Laclaustra M, et al. Serum selenium concentrations and diabetes in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2003-2004. Environ Health Perspect. (2009)
21. Stranges S, et al. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med. (2007)
22. Selenium and Diabetes: More Bad News for Supplements
23. Fridlyand LE, Philipson LH. Oxidative reactive species in cell injury: Mechanisms in diabetes mellitus and therapeutic approaches. Ann N Y Acad Sci. (2005)
24. Introduction: The selenium conundrum
25. Shamberger RJ, Frost DV. Possible protective effect of selenium against human cancer. Can Med Assoc J. (1969)
26. Spallholz JE, Palace VP, Reid TW. Methioninase and selenomethionine but not Se-methylselenocysteine generate methylselenol and superoxide in an in vitro chemiluminescent assay: implications for the nutritional carcinostatic activity of selenoamino acids. Biochem Pharmacol. (2004)
27. Kim A, et al. Methylselenol generated from selenomethionine by methioninase downregulates integrin expression and induces caspase-mediated apoptosis of B16F10 melanoma cells. J Cell Physiol. (2007)
28. Valko M, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. (2007)
29. Valko M, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. (2006)
30. Valko M, et al. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. (2004)
31. Hu YJ, et al. Allelic loss at the GPx-1 locus in cancer of the head and neck. Biol Trace Elem Res. (2004)
32. Ichimura Y, et al. Increased risk of bladder cancer associated with a glutathione peroxidase 1 codon 198 variant. J Urol. (2004)
33. Hu YJ, Diamond AM. Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res. (2003)
34. Moscow JA, et al. Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer. Carcinogenesis. (1994)
35. Al-Taie OH, et al. Expression profiling and genetic alterations of the selenoproteins GI-GPx and SePP in colorectal carcinogenesis. Nutr Cancer. (2004)
36. Mörk H, et al. Inverse mRNA expression of the selenocysteine-containing proteins GI-GPx and SeP in colorectal adenomas compared with adjacent normal mucosa. Nutr Cancer. (2000)
37. Calvo A, et al. Alterations in gene expression profiles during prostate cancer progression: functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors. Cancer Res. (2002)
38. Méplan C, et al. Relative abundance of selenoprotein P isoforms in human plasma depends on genotype, se intake, and cancer status. Antioxid Redox Signal. (2009)
39. Hu YJ, et al. Distribution and functional consequences of nucleotide polymorphisms in the 3'-untranslated region of the human Sep15 gene. Cancer Res. (2001)
40. Kumaraswamy E, et al. Structure-expression relationships of the 15-kDa selenoprotein gene. Possible role of the protein in cancer etiology. J Biol Chem. (2000)
41. Jablonska E, et al. Lung cancer risk associated with selenium status is modified in smoking individuals by Sep15 polymorphism. Eur J Nutr. (2008)
42. Lincoln DT, et al. The thioredoxin-thioredoxin reductase system: over-expression in human cancer. Anticancer Res. (2003)
43. Gladyshev VN, et al. Contrasting patterns of regulation of the antioxidant selenoproteins, thioredoxin reductase, and glutathione peroxidase, in cancer cells. Biochem Biophys Res Commun. (1998)
44. Hurst R, et al. Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr. (2012)

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