Selenium is an essential trace mineral critical for antioxidant defense, fertility, thyroid hormone metabolism, immune response, and muscle development. First discovered in 1817, selenium was considered a toxic substance best avoided. 140 years later, in 1957, the status of Selenium dramatically changed with a report of the first selenium deficiency disease. An obscure biochemist at the NIH, Klaus Schwarz, found that Vitamin E deficient rats were protected from liver degeneration by selenium.(1)
Above Image, Map of Soil Selenium in United States, Red= High Selenium Areas, Courtesy of U.S. Department of the Interior, U.S. Geological Survey, Mineral Resources On-Line Spatial Data. (link )(link)
White Marble Disease in Oregon Cattle
One year later in 1958, scientists at the University of Oregon discovered that selenium deficiency caused “white muscle disease”, a muscle degeneration in cattle foraging grass on selenium depleted soils. They surmised that volcanic soil was low in selenium, and hot volcanic gas caused selenium depletion of the Oregon soil millions of years ago. Selenium supplementation prevented the white muscle disease.(2) See the header image above which shows selenium deficient areas in the United states with a map of soil selenium distribution. Finland is another country plagued with selenium depleted volcanic soils, and in 1984, was the first to add selenium to crop fertilizer in a mandated program of selenium enrichment.(12)(13)
Keshans Disease in China Caused by Selenium Deficency
In the 1960's and 1970's in China, government sponsored research discovered a form of cardiac muscle degeneration in humans called Keshans disease occurring in areas of low soil selenium similar to "white muscle disease" in cattle. Keshans disease caused children to die of a dilated cardiomyopathy and they found that selenium supplements were preventive.(3)(4)
Sudden Death From Selenium Deficent Cardiomyopathy
In the early 1980's, selenium deficiency was recognized in the US when patients on long term artificial feeding were found to die suddenly from cardiomyopathy induced by selenium deficiency. Apparently, the artificial feeding solutions had not been fortified with selenium, resulting in sudden death from heart muscle degeneration. (8)(9)(10)
It's Not the Selenium, It's the Selenoprotein
Selenium is an essential trace mineral because of seleno-proteins which are critical for antioxidant defense, fertility, thyroid hormone metabolism, immune responses, and muscle development and function. Selenoproteins are thought involved in cancer prevention because of inverse correlation between soil selenium, selenium intake, selenium blood levels and cancer incidence. The lower the soil or blood selenium, the higher the incidence of cancer. (5)(6)(7)
Seleno-Proteins: When Stop Doesn't Really Mean Stop
What is Selenocysteine?
The amino acid, cysteine, normally contains a sulfur atom. However, when the sulfur is replaced by selenium it becomes seleno-cysteine. The incorporation of selenocysteine into a protein amino acid sequence is called a seleno-protein.
Left Image: Seleno-cysteine courtesy of Wikimedia commons. Selenium (Se) attached at upper left. Upper Left Image: Stop Sign courtesy of Wikimedia Commons.
The DNA translation table which maps DNA codons to amino acids was completed in the 1960's. It is quite remarkable that 20 years later, it was discovered that the UGA Stop Codon sometimes is NOT a Stop Codon. The UGA stop codon also translates as selenocysteine, the 21st amino acid. This was an unexpected twist which nobody expected, and biochemists were then quite surprised by this.
Note: The Genetic Code is a translation table which maps the code in the DNA (called codons) to one of the twenty amino acids, thereby providing the instruction set for the cell machinery to arrange long strings of amino acids into the proper sequence called a protein. We now know that the UGA Stop Codon also codes for seleno-cysteine, sepending on another instruction set called the SECIS insertion sequence. Thanks to Vadim N. Gladyshev for much of our current knowledge. (Note Vadim N. Gladyshev has since moved from U Nebraska to Harvard). Based on this tricky dual translation of the UGA codon for seleno-cysteine, Gladyshev and his collaborators went about correcting the seleno-cysteine errors in the original DNA database. His new correction software is called Recode2. (14)-(23)
Above Left Image Photo courtesy of Vadim N. Gladyshev Selenium Expert
Selenoproteins- What Do They Do?
A Few Selenoproteins and Their Function
1) Glutathione Peroxidase - Antioxidant, works in harmony with vitamin E which allows for the reduction of hydrogen peroxide to water, preventing lipid peroxidation and cellular damage. (24)
2) Iodothyronine De-iodinase Enzyme- Involved in Thyroid function, converts T4 to T3. (24) See Iodine Book by David Brownstein MD for summary of recent research on selenium and thyroid function.
3) Thioredoxin reductase -antioxidant responsible for degrading peroxides and hydroperoxides which cause cell death, DNA damage, and tissue atrophy.(24)
4) Sept 15 Selenoprotein- Candidate for cancer prevention. (15)
There are about 40 families of selenoproteins. Most still have unknown functions.
Selenium Deficiency Associated with Increased Cancer Risk
The Nutritional Prevention of Cancer Trial (NPC Trial)
The NPC Trial, published in 1996 in JAMA, was the brainchild of Larry C Clark and Gerald Combs, and the first prospective double-blind, placebo-controlled, randomized trial in the Western world to test a selenium supplement on a large population and measure cancer incidence. Clark chose selenized yeast containing 200 mcg of elemental selenium for residents of the southeastern United States, where soil selenium levels are the lowest in the nation. Between 1983 and 1991, seven dermatology clinics recruited a total of 1,312 patients, with a mean age of 63 years, who had a history of basal and/or squamous cell carcinoma. The NPC Trial showed selenium supplementation significantly decreased the total cancer incidence by 50 percent, and specifically dropped the incidence of lung cancer by 48 percent, prostate cancer by 63 percent, and colorectal cancer by 58 percent. Those who entered the trial with plasma selenium levels less than 106 ng/mL showed both the greatest protection from selenium and the highest rates of subsequent cancer in the control group. (26)(27)
Above Left Image courtesy of Gerald Combs PhD, Selenium Expert
The selenized yeast tablet used in the NPC trial was called Seleno-Excell from Cypress Systems which is available at your local vitamin shop or health food store under various brand names. (Note: I have no financial interest in any selenium products mentioned)
Left Image: Courtesy of Larry C Clark MD, Selenium Expert
The SELECT Study - Selenium and Vitamin E Found Useless at Cancer Prevention
The 1996 NPC trial reigned supreme until it was discredited December 2008, by the disappointing results of the 2009 SELECT study, with Time Magazine and The New York Times proclaiming that selenium and vitamin E useless at prevention of prostate cancer. (32)(33)
The SELECT study was a randomized, placebo-controlled trial of Selenium and Vitamin E given to 35,533 men 50 years or older, and PSA of 4 ng/mL or less to determine if the vitamins reduced risk of prostate cancer. The vitamins used were: 200 µg L-selenomethionine and synthetic vitamin E (400 IU/d of all rac--tocopheryl acetate). The results showed the vitamins did not prevent prostate cancer in this group. (29)
SELECT - Why Did It Fail ?
Hatfield and V Gladyshev summarize the reasons why SELECT failed and why the NPC trial and many previous studies succeeded in showing a benefit of selenium supplementation (30). Rayman and Combs also commented on the SELECT study in a JAMA editorial .(31)
Left Image : courtesy of Professor Margaret Rayman has a doctorate in Inorganic Biochemistry from Somerville College, Oxford and has held post-doctoral fellowships at the Institute of Cancer Research and Imperial College. She is now Professor of Nutritional Medicine at the University of Surrey where she directs the highly respected MSc Programme in Nutritional Medicine.
The major reason for failure is the SELECT patients started with higher serum selenium levels, in the range above 135 mcg/L found not to benefit from selenium supplementation. They already had plenty.
1) SELECT used seleno-methionine whereas the NPC used selenium-enriched yeast.
2) SELECT evaluated prostate cancer. How can selenium be shown to prevent prostate cancer when PSA testing rapidly removes prostate cancers from the population before they progress? The NPC evaluated all cancers in patients with underlying history of skin cancer.
3) The subjects enrolled in SELECT had higher initial plasma levels of selenium than those in the NPC trial (135 ng/ml compared to 113 ng/ml, respectively). The subjects in the NPC trial were selected, in part, on the basis of their having relatively low serum selenium levels it was in this cohort that selenium supplementation was effective in reducing cancer risks.
4) SELECT used synthetic Vitamin E (all racemic). Results may have been different for natural vitamin E.
Blood Selenium Levels below 130 ng/ml benefit from supplementation
Above chart showing low serum selenium to be associated with increased cancer risk. From : Serum Selenium Levels and All-Cause, Cancer, and Cardiovascular Mortality Among US Adults by Joachim Bleys, MD, MPH; Ana Navas-Acien, MD, PhD; Eliseo Guallar, MD, DrPH Arch Intern Med. 2008;168(4):404-410.
In agreement with Dr Rayman, a 2008 study published by Bleys in the Archives of internal medicine found an inverse correlation between serum selenium and all cause and cancer mortality, with reduced mortality up to a serum selenium level of 130 ng/ml. (34) Above 130 ng per ML, there was no benefit or perhaps a slight increase in mortality.(34)
In conclusion, the evidence is overwhelming that low selenium blood levels (below 130 ng/ml) constitute a health risk. It is suggested that selenium serum levels be routinely evaluated, and when found low, supplementation is indicated with selenium in the form of selenized yeast or L-selenomethionine in the amount of 200 -300 mcg per day.
Above left image: Brazil nuts high in selenium courtesy of wikimedia.
Articles with related interest:
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Links and References
(1) http://jn.nutrition.org/cgi/content/full/133/11/3331 2003 The American Society for Nutritional Sciences J. Nutr. 133:3331-3342, November 2003 History of Nutrition A Short History of Nutritional Science: Part 4 (1945–1985)1 Kenneth J. Carpenter2 Department of Nutritional Sciences, University of California, Berkeley, CA 94720-3104 History of selenium.
Nearly 50 years ago, it was practically impossible to raise livestock profitably in many parts of Oregon. The problem was called “white muscle disease” and it affected heart and skeletal (leg and back) muscles of young calves and lambs. The name “white muscle disease” comes from the characteristic, bleached out color of the affected muscles which is related to two causes: (1) the muscles become inactive and their content of myoglobin, the red pigment in normal muscle is reduced, and (2) calcium salts, which are white, are deposited in the damaged muscle. In 1958, a team of scientists at Oregon State University found the problem was a deficiency of selenium, it could be prevented by the trace mineral. White Muscle disease occurs wherever there are volcanic soils. In the heat of volcanic eruption the selenium became a gas and drifted away, leaving the soil residue deficient. (3) http://www.chiro.org/nutrition/FULL/Selenium_Antioxidant.shtml Selenium: Antioxidant & Cancer Quencher From The March 1999 Issue of Nutrition Science News By Stephanie Briggs, Ph.D Stephanie Briggs, Ph.D. (formerly SB Combs), a nutritional biochemist, spent six months in China as part of a selenium research team. She is co-author of The Role of Selenium in Nutrition (Academic Press, 1986).
(4) http://www.ajcn.org/cgi/reprint/57/2/259S.pdf The epidemiology of selenium deficiency in the etiological study of endemic diseases in China by Kei’ou Ge and Guangqi Yang . This paper reviews the epidemiology of selenium deficiency in China in connection with the etiology of human selenium-responsive diseases, the well-defined Keshan disease (KD) and the less-well-defined Kashin-Beck disease.
Cell Physiology of Selenium
(5) www.jbc.org/content/284/2/723.full Selenoproteins by Jun Lu and Arne Holmgren , Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-17177 Stockholm, Sweden January 9, 2009 The Journal of Biological Chemistry, 284, 723-727.
Selenium was discovered by the Swedish chemist Jöns Jacob Berzelius in 1817 and has been recognized as an essential trace element for many life forms including man since 1957 (1, 2). The main form of selenium in mammalian proteins is selenocysteine encoded by the TGA codon.
One example of severe selenium deficiency causing a human disease is Keshan disease, a potentially fatal form of cardiomyopathy that was first found in northeast China (1). The disease occurs upon selenium deficiency combined with infection by coxsackie B virus and has been prevented by selenium supplementation. A cardiomyopathy that resembles Keshan disease occurs when GPx1 knock-out mice are infected with a benign coxsackievirus, suggesting that GPx1 is closely associated with protection against virus infection (40). These studies reveal that selenoproteins play critical roles in antioxidant defense, fertility, thyroid hormone metabolism, immune responses, and muscle development and functions. Selenoproteins has been believed to be closely linked with cancer and carcinogenesis because there are numerous epidemiological reports on an inverse correlation between selenium intake and occurrence of cancer risk
(6) http://www.gustrength.com/nutrition:selenium-an-essential-micronutrient Selenium: An Essential Micronutrient Molecules 2009, 14(3), 1263-1278; Review - Selenium as an Essential Micronutrient: Roles in Cell Cycle and Apoptosis Huawei Zeng United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota 58202-9034, USA
The recommended daily allowance for selenium is 55µg/d for both men and women. Doses of 100-200 µg Se/d inhibit genetic damage and cancer development in human subjects, and about 400 µg Se/d is considered an upper safe limit .
At nutritional doses, Se is an essential component of SeCys in selenoproteins, and it promotes cell cycle progression and prevents cell death. In contrast, at supranutritional doses that are greater than the nutritional requirement but not toxic, Se induces cell cycle arrest and apoptosis.
(7) http://physiologyonline.physiology.org/cgi/content/full/21/5/307 Physiology, Vol. 21, No. 5, 307-315, October 2006 Int. Union Physiol. Sci./Am. Physiol. Soc. EMERGING TECHNOLOGIES . Selenoproteins and Their Impact on Human Health Through Diverse Physiological Pathways by Behzad Moghadaszadeh and Alan H. Beggs, Program in Genomics and Division of Genetics, Children’s Hospital Boston, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts,
Similarly, at the physiological level, these enzymes are involved in diverse metabolic and physiological functions ranging from antioxidant defense (6) to fertility (30), muscle development and function (65), thyroid hormone metabolism, and immune function (4). Consequently, the range of pathologies associated with primary or secondary defects of selenoprotein function is enormous, with no easily definable unifying feature to tie together this disparate group of phenotypes at the pathophysiological level.
Selenium and Cardiomyopathy in TPN
(8) www.ncbi.nlm.nih.gov/pubmed/6807740 Gastroenterology. 1982 Sep;83(3):689-93. Selenium deficiency and fatal cardiomyopathy in a patient on home parenteral nutrition. by Fleming CR, Lie JT, McCall JT, O'Brien JF, Baillie EE, Thistle JL. An adult patient on home parenteral nutrition for 6 years died from cardiomyopathy and ventricular fibrillation. Postmortem examination of the heart revealed widespread myocytolysis and replacement fibrosis similar to that seen in the selenium deficient cardiomyopathy in China (Keshan disease) and animal models. Selenium deficiency in this patient was documented with extremely low concentrations of selenium and decreased activity of the selenoprotein, glutathione peroxidase, in blood, heart, liver, and skeletal muscle.
(9) http://www.ncbi.nlm.nih.gov/pubmed/6435941 Clin Pharm. 1984 Sep-Oct;3(5):531-5. Selenium deficiency and fatal cardiomyopathy in a patient receiving long-term home parenteral nutrition. Quercia RA, Korn S, O'Neill D, Dougherty JE, Ludwig M, Schweizer R, Sigman R.
Fatal cardiomyopathy in a patient who received home parenteral nutrition (HPN) for eight years is reported, and the relationship of selenium deficiency to cardiomyopathy and other adverse effects is discussed. A 42-year-old white man with Crohn's disease who was receiving HPN was admitted to the hospital with severe chest pain and dyspnea. During the three days following admission, his symptoms of congestive heart failure and compensated metabolic acidosis persisted despite treatment. On hospital day 6, the patient developed increased ventricular irritability and refractory ventricular fibrillation and died. At autopsy, the heart weighted 500 g, all chambers were dilated, and the myocardium was grossly flabby. Extremely low concentrations of selenium (5-12% of normal) were found in plasma, heart, liver, and kidney tissue samples. The pathological findings in this patient were similar to those in two previously reported cases and strongly suggest that the fatal cardiomyopathy was secondary to selenium deficiency.
(10) http://www.ncbi.nlm.nih.gov/pubmed/11848134 Med Sci Law. 2002 Jan;42(1):10-3. Fulminant heart failure due to selenium deficiency cardiomyopathy (Keshan disease). Burke MP, Opeskin K. Victorian Institute of Forensic Medicine, Department of Forensic Medicine, Monash University, Southbank, Australia.
Selenium deficiency is a rare cause of cardiomyopathy that may be encountered by the forensic pathologist. Selenium deficiency is associated with a cardiomyopathy, myopathy and osteoarthropathy. In Asia and Africa, dietary selenium deficiency is associated with a cardiomyopathy known as Keshan disease and an osteoarthropathy called Kashin-Beck disease. Chronic selenium deficiency may also occur in individuals with malabsorption and long term selenium-deficient parenteral nutrition. Selenium deficiency causes myopathy as a result of the depletion of selenium-associated enzymes which protect cell membranes from damage by free radicals. We present a case of fulminant heart failure in a middle aged woman with a complex medical and surgical history including documented malabsorption and selenium deficiency. Pathological examination of the heart showed features consistent with Keshan disease.
(11) http://www.ncbi.nlm.nih.gov/pubmed/2168125 Am J Clin Nutr. 1990 Sep;52(3):572-7. Cardiomyopathy associated with nonendemic selenium deficiency in a Caucasian adolescent. Lockitch G, Taylor GP, Wong LT, Davidson AG, Dison PJ, Riddell D, Massing B. Department of Pathology, University of British Columbia, Vancouver, Canada.
We describe a girl aged 17 y who died after a cardiac arrest secondary to septic shock. At autopsy, the enlarged, soft, and flabby heart showed microscopic evidence of acute myocardial infarction, myocardial edema, myocardiocyte loss, replacement fibrosis in the interventricular septum, and right and left ventricular hypertrophic nucleomegaly. The pathological diagnosis was that of cardiomyopathy due to prolonged selenium deficiency. The patient had been on total parenteral nutrition for 17 mo, following extensive bowel resection for intractable pain, nausea, and vomiting caused by chronic idiopathic intestinal pseudoobstruction.
(12) http://www.springerlink.com/content/pt21161703q7hp6v/ The effect of nationwide selenium enrichment of fertilizers on selenium status of healthy finnish medical students living in south western Finland Journal Biological Trace Element Research Publisher Humana Press Inc. Issue Volume 36, Number 2 / February, 1993 In Finland commercial fertilizers have been enriched with sodium selenate since July 1, 1984 in order to compensate for the poor selenium content of the soil.
(13) http://www.asas.org/Bios/Oldfieldhist.pdf A brief history of selenium research: From alkali disease to prostate cancer (from poison to prevention) J. E. Oldfield1 Oregon State University, Corvallis 97331
When Berzelius discovered selenium in 1817, as a toxic element that was contributing to worker illness in the acid plant. In 1957, Klaus Schwarz, working at the National Institutes of Health in Bethesda, identified the first “selenium-responsive” disease
(14) http://www.nature.com/embor/journal/v5/n2/full/7400080.html EMBO reports 5, 2, 140–141 (2004) Finding needles in a haystack, In silico identification of eukaryotic selenoprotein genes by Donna M. Driscoll & Laurent Chavatte Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation
The dual function of the UGA codon poses a serious challenge for the annotation of genomes. Although UGA usually signals the termination of protein synthesis, it can also be decoded as selenocysteine (Sec), which is incorporated into a small but important group of proteins that are known as selenoproteins. Standard gene-analysis programs cannot predict whether a UGA codon encodes Sec or Stop. Bioinformatic tools for recognizing selenoproteins in complementary DNA (cDNA) databases are available, but they are not effective when analysing genome sequences.
15 kDa Selenoprotein (Sep15). Sep15 is a mammalian protein, but its homologs are found in other eukaryotes (mostly in animals) (Chapter 13) . It resides in the endoplasmic reticulum where it binds UDP-glucose:glycoprotein glucosyltransferase, a sensor of protein folding . Recent structural analyses revealed its redox function. Sep15 is characterized by the thioredoxin-like fold and is implicated in the cancer prevention effect of dietary selenium [36,37].
A decade ago, only several selenoproteins were known. Largely due to remarkable progress in genomic research and bioinformatics, we now have information on more than 40 selenoprotein families. In selenoproteins with known functions. Sec is a key functional group that carries out redox catalysis. Therefore, identification of each new selenoprotein provides information on the possible role of this protein in redox biology and identifies the candidate catalytic group in this protein.
In mammals, two major redox systems, thioredoxin and glutathione systems, are dependent on the trace element selenium, which is an essential component of various redox enzymes. Selenium is present in proteins in the form of the 21st amino acid, selenocysteine (Sec). Sec is co-translationally inserted in protein in response to the UGA codon with the help of the SECIS element, an mRNA stem-loop structure present in 3'-untranslated regions of selenoprotein genes. Because UGA is interpreted as a stop signal by available gene annotation tools, selenoprotein genes are typically annotated incorrectly in sequence databases, including published human genome assemblies. To overcome this problem, we are identifying selenoprotein genes by genome-wide searches for structural and thermodynamic properties of SECIS elements.
One of our current projects involves the 15 kDa selenoprotein (Sep15). We identified Sep15 as a candidate protein that mediates the cancer chemopreventive effect of selenium.
(17) http://gladyshevlab.bwh.harvard.edu/contact.html Vadim N. Gladyshev Professor Division of Genetics Department of Medicine Brigham and Women's Hospital Harvard Medical School New Research Building, Room 435 77 Ave. Louis Pasteur Boston, MA 02115
(18) http://scarlet.unl.edu/?p=8 Selenium research lauded Jun 2nd, 2008 | By admin | Category: Uncategorized BY TROY FEDDERSON, UNIVERSITY COMMUNICATIONS ORCA WINNER – Vadim Gladyshev, professor of biochemistry and director of the UNL’s Redox Biology Center, received the ORCA award for his research. View a video of Gladyshev’s work by clicking “Recognition and Awards” Photo by Troy Fedderson/University Communications.
(19) http://scarlet.unl.edu/?p=953 Their discovery of the multi-tasking codon, called UGA, in the microscopic marine protozoan, Euplotes crassus, raises the question of whether codons in other organisms can do the same thing. They’re now investigating UGA’s function in mammals.
Recode-2: new design, new search tools, and many more genes BY Michaël Bekaert, Vadim N. Gladyshev et al. ‘Recoding’ is a term used to describe non-standard read-out of the genetic code, and encompasses such phenomena as programmed ribosomal frameshifting, stop codon readthrough, selenocysteine insertion and translational bypassing. Although only a small proportion of genes utilize recoding in protein synthesis, accurate annotation of ‘recoded’ genes lags far behind annotation of ‘standard’ genes. Recode-2 is an improved and updated version of the database. Recode-2 is available at http://recode.ucc.ie
(21) http://recode.ucc.ie/about What is Recode2 Recode2 is a database of genes that utilize non-standard translation for gene expression purposes.
(23) http://www.ncbi.nlm.nih.gov/pubmed/8744353 Trends Biochem Sci. 1996 Jun;21(6):203-8. Knowing when not to stop: selenocysteine incorporation in eukaryotes.Low SC, Berry MJ. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Abstract The regulation of translation frequently involves protein-RNA interactions. An intriguing example of this is the alternative decoding of UGA, typically a stop codon, as selenocysteine. Two RNA structures, the mRNA selenocysteine insertion sequence (SECIS element) and a unique selenocysteyl-tRNA, are required for this process. In prokaryotes, a single RNA-binding protein, a selenocysteine-specific elongation factor, interacts with both the tRNA and mRNA to confer decoding.
Review Selenium as Cancer Preventive by Lyn Patrick
Selenium Biochemistry and Cancer: A Review of the Literature Lyn Patrick, ND
Selenium deficits, correlated with serum selenium concentrations less than 85-90 mcg/L, are common in parts of China where juvenile cardiomyopathy (Keshan disease) and chondrodystrophy (Kaschin- Beck disease) result from selenium deficiency.17 In the United States, however, most soils are selenium replete, and whereas low serum selenium levels of 11-20 mcg/L in parts of China are common, serum levels in South Dakota and Maryland have been reported to be as high as 133-197 mcg/L.
A further trial of selenium in biopsy proven prostate cancer in which patients were randomized to 1,600 or 3,200 mcg/day selenized yeast for 12 months did not report any selenium related toxicity signs or symptoms.23
Normal controls also demonstrated an inverse relationship between TSH and serum selenium: when serum levels were below 80 mcg/L, TSH levels were correlated at 2.1 mU/L, significantly higher than in those with serum selenium above 80 mcg/L who demonstrated median TSH levels of 1.28-1.29 mU/ L. Serum selenium was also inversely correlated with thyroid autoantibody levels. Those with thyroperoxidase antibody (TPO Ab) levels > 600 IU/mL had a mean serum selenium of 83.6 IU/L, while those with TPO Ab levels lower than 600 had mean serum selenium levels between 92.9 and 95.6 mcg/L.31
In a prospective study of 39,268 men and women in Finland, risk for several cancers was significantly elevated in men who had the lowest level of serum selenium – for cancers of the stomach, pancreas, and lung specifically.56 The mean levels of serum selenium found in those who developed cancer – 53-63 mcg/L – would be considered low in the United States.57
A U.S. study of 11,000 hypertensives followed for five years showed a two-fold increase in risk for all cancers in those in the lowest (< 115 ng/mL) quintile compared to those in the highest quintile (> 154 ng/mL) of plasma selenium.42
These data encouraged a study of the effects of selenium supplementation in cancer prevention and led to the now well-known Nutritional Prevention of Cancer Trial (NPC Trial).68
The NPC Trial is the only prospective double-blind, placebo-controlled, randomized trial in the Western world to test a selenium supplement on a large population and measure cancer incidence.
The study originally attempted to assess the ability of selenized yeast containing 200 mcg of elemental selenium to prevent recurrences of nonmelanoma skin cancer in 1,312 residents of the southeastern United States, where soil selenium levels are the lowest in the nation. Because of unexpected results, the trial was unblinded early; i.e., selenium supplementation significantly decreased the total cancer incidence by 50 percent, and specifically dropped the incidence of lung cancer by 48 percent, prostate cancer by 63 percent, and colorectal cancer by 58 percent.69
Analysis of more extended data from the original trial found the protective effect of selenium, although still impressive, decreased to a statistically significant 25-percent reduction in total cancer incidence, a 42-percent reduction in prostate cancer incidence, and a 51-percent reduction in total cancer mortality.
In this follow-up report the decrease in lung cancer incidence was no longer statistically significant, while a 54-percent reduction in colorectal cancer incidence was marginally significant (p=0.057).70 Because 75 percent of the trial group was male, the effects were confined to males and were most prominent in smokers and those with baseline plasma selenium levels below 121.6 ng/mL. Those who entered the trial with plasma selenium levels less than 106 ng/mL showed both the greatest protection from selenium and the highest rates of subsequent cancer in the control group
(25) http://www.gpmcf.org/JAMA2009.pdf JAMA. 2009;301(18):1876 (doi:10.1001/jama.2009.625) Margaret P. Rayman; Gerald F. Combs, Jr; David J. Waters Selenium and Vitamin E Supplementation for Cancer Prevention
(28) http://www.healthyodds.com/selenium.html Larry C. Clark, Ph.D., M.P.H., died March 20, 2000 from prostate cancer. He was 51. Dr. Clark joined the faculty of the U. Arizona College of Medicine in 1987. Until his death, he directed the Nutritional Prevention of Cancer Projects in Selenium at the Arizona Cancer Center. Dr. Clark began his research work alongside Gerald F. Combs, Jr. Ph.D. while at Cornell University in the early 1980’s. Often referred to as the "Clark and Combs Trial" the Nutritional Prevention of Cancer Trial (NPC) was deemed a "landmark" trial following the 1996 publication in JAMA
SELECT - Selenium DID NOT PREVENT Cancer (29) http://jama.ama-assn.org/cgi/content/full/301/1/39 Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers The Selenium and Vitamin E Cancer Prevention Trial (SELECT) BY Scott M. Lippman, MD et al JAMA. 2009;301(1):39-51
A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35 533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.
Oral selenium (200 µg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac--tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.
Conclusion Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.
Mol Interv. 2009 February; 9(1): 18–21. The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) Reveals the Need for Better Understanding of Selenium Biology Dolph L. Hatfield1 and Vadim N. Gladyshev
Why are SELECT’s findings different from those of earlier trials (3–8) and numerous animal studies (9, 10) that also employed selenium, but showed dramatic reductions in certain forms of cancer. For example, the Nutritional Prevention of Cancer (NPC) trial found dramatic reductions in various forms of cancer, as well as in cancer mortality.
NPC initially reported that prostate cancers were reduced 63%, colorectal cancers 58%, and lung cancers 48% (5). A subsequent analysis of the complete NPC trial data reported that selenium supplementation reduced total and prostate cancer incidence but did not reduce lung or colorectal cancer incidence significantly (6).
SELECT used pure L-selenomethionine as the intervention agent (1, 2), whereas other human trials and animal studies have demonstrated anti-tumorigenic efficacy for selenite and selenium-enriched baker’s yeast.
SELECT - problems with design of trial.
1) How can an selenium be shown to prevent prostate cancer when PSA testing may be rapidly removing those cancers from the population at risk before they progress?
2) The subjects enrolled in SELECT had higher initial plasma levels of selenium than those in the NPC trial (135 ng/ml and 113 ng/ml, respectively). The subjects in the NPC trial were selected, in part, on the basis of their having relatively low serum selenium levels it was in this cohort that selenium supplementation was effective in reducing cancer risks.
3) the form of Vitamin E used was SYNTHETIC (all racemic)
SELECT Study Explained by Dr Combs in JAMA letter
(31) http://www.gpmcf.org/JAMA2009.pdf JAMA. 2009;301(18):1876 (doi:10.1001/jama.2009.625) Margaret P. Rayman; Gerald F. Combs, Jr; David J. Waters Selenium and Vitamin E Supplementation for Cancer Prevention Select and NPC are consistent - with U shaped response curve. Men with high baseline selenium levels have no benefit from selenium supplementation.
Prostate Cancer and Selenium Epidemiology Reduced risk above 135 mcg/L, worse risk with low vit E level
We evaluated the association between selenium levels and all-cause and cause-specific mortality in a representative sample of US adults.
Methods Serum selenium levels were measured in 13,887 adult participants in the Third National Health and Nutrition Examination Survey. Study participants were recruited from 1988 to 1994 and followed up for mortality for up to 12 years.
Results The mean serum selenium level was 125.6 ng/mL. The multivariate adjusted hazard ratios comparing the highest ( 130.39 ng/mL) with the lowest (< 117.31 ng/mL) serum selenium level tertile were 0.83 (95% confidence interval [CI], 0.72-0.96) for all-cause mortality, 0.69 (95% CI, 0.53-0.90) for cancer mortality, and 0.94 (95% CI, 0.77-1.16) for cardiovascular mortality. However, based on spline regression models, the association between serum selenium levels and all-cause and cancer mortality was nonlinear, with an inverse association at low selenium levels (< 130 ng/mL) and a modest increase in mortality at high selenium levels (> 150 ng/mL).
Conclusions In a representative sample of the US population, we found a nonlinear association between serum selenium levels and all-cause and cancer mortality. Increasing serum selenium levels were associated with decreased mortality up to 130 ng/mL. Our study, however, raises the concern that higher serum selenium levels may be associated with increased mortality.
Selenium and Prostate Cancer
http://www.ncbi.nlm.nih.gov/pubmed/12494476 Int J Cancer. 2003 Feb 20;103(5):664-70. Serum selenium and risk of prostate cancer in U.S. blacks and whites. Vogt TM, Ziegler RG, Graubard BI, Swanson CA, Greenberg RS, Schoenberg JB, Swanson GM, Hayes RB, Mayne ST. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7246, USA.
We measured serum selenium in 212 cases and 233 controls participating in a multicenter, population-based case-control study that included comparable numbers of U.S. black and white men aged 40-79 years.
Serum selenium was inversely associated with risk of prostate cancer (comparing highest to lowest quartiles, OR = 0.71, 95% CI 0.39-1.28; p for trend = 0.11), with similar patterns seen in both blacks and whites.
Analysis of serum selenium data indicated a reduced risk of prostate cancer above concentrations of 0.135 microg/ml (median among controls) Because both the selenoenzyme GPX and vitamin E can function as antioxidants, we also explored their joint effect. Consistent with other studies, the inverse association with selenium was strongest among men with low serum alpha-tocopherol concentrations. In conclusion, our results suggest a moderately reduced risk of prostate cancer at higher serum selenium concentrations, a finding that can now be extended to include U.S. blacks.
Mouse Model Transgenic - increased prostate CA, selenium deficiency
Proc Natl Acad Sci U S A. 2006 May 23; 103(21): 8179–8184. Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model Veda Diwadkar-Navsariwala,*† Gail S. Prins,†‡ Steven M. Swanson,§ Lynn A. Birch,‡ Vera H. Ray,¶ Samad Hedayat,? Daniel L. Lantvit,** and Alan M. Diamond*††
Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals:
mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i6A-) and
mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [C3(1)/Tag]. The resulting bigenic animals (i6A-/Tag) and control WT/Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia.
The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.
Animals expressing reduced selenoprotein levels exhibit accelerated development of PIN lesions with microinvasive carcinoma. At all time points examined, prostates obtained from i6A−/Tag mice demonstrated accelerated pathology associated with prostate cancer development
Methyl-Selenium Compounds Inhibit Prostate Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model with Survival Benefit Lei Wang et al Hormel Institute, University of Minnesota, Austin, Minnesota Cancer Prevention Research May 2009 2; 484
Here we used the transgenic adenocarcinoma mouse prostate (TRAMP) model to establish the efficacy of methylseleninic acid (MSeA) and methylselenocysteine (MSeC) against prostate carcinogenesis and to characterize potential mechanisms. Eight-week-old male TRAMP mice (C57B/6 background) were given a daily oral dose of water, MSeA, or MSeC at 3 mg Se/kg body weight and were euthanized at either 18 or 26 weeks of age. By 18 weeks of age, the genitourinary tract and dorsolateral prostate weights for the MSeA- and MSeC-treated groups were lower than for the control (P < 0.01). At 26 weeks, 4 of 10 control mice had genitourinary weight >2 g, and only 1 of 10 in each of the Se groups did.
The efficacy was accompanied by delayed lesion progression, increased apoptosis, and decreased proliferation without appreciable changes of T-antigen expression in the dorsolateral prostate of Se-treated mice and decreased serum insulin-like growth factor I when compared with control mice.
In another experiment, giving MSeA to TRAMP mice from 10 or 16 weeks of age increased their survival to 50 weeks of age, and delayed the death due to synaptophysin-positive neuroendocrine carcinomas and synaptophysin-negative prostate lesions and seminal vesicle hypertrophy. Wild-type mice receiving MSeA from 10 weeks did not exhibit decreased body weight or genitourinary weight or increased serum alanine aminotransferase compared with the control mice. Therefore, these selenium compounds may effectively inhibit this model of prostate cancer carcinogenesis.
Molecular Biology of Prostate Cancer Biopsy Tissue - Selenium and Gene expression
Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer by Dimitra Tsavachidou et al JNCI Journal of the National Cancer Institute 2009 101(5):306-320; This study provided a proof-of-principle that prostate biopsy specimens can serve as a source of tissue for molecular interrogation. Differential gene expression related to selenium and/or vitamin E treatments was identified that was cell type specific and tissue zone specific and that may have clinical implications. Transgenic mouse model colon cancer - selenium effectively reduced cancer risk.
http://www.ncbi.nlm.nih.gov/pubmed/16614422 J Nutr. 2006 May;136(5):1311-7. Both selenoproteins and low molecular weight selenocompounds reduce colon cancer risk in mice with genetically impaired selenoprotein expression. Irons R, Carlson BA, Hatfield DL, Davis CD. Nutritional Science Research Group, National Cancer Institute, Rockville, MD 20852, USA.
Selenium has cancer protective effects in a variety of experimental systems. Currently, it is not known whether selenoproteins or low molecular weight selenocompounds are responsible for this activity. To evaluate the contribution of selenoproteins to the cancer protective effects of selenium, we used transgenic mice that carry a mutant selenocysteine transfer RNA gene, which causes reduced selenoprotein synthesis. Selenium homeostasis was characterized in liver and colon of wild-type and transgenic mice fed selenium-deficient diets supplemented with 0, 0.1, or 2.0 microg selenium (as selenite)/g diet. (75)Se-labeling, Western blot analysis, and enzymatic activities revealed that transgenic mice have reduced (P < 0.05) liver and colon glutathione peroxidase expression, but conserved thioredoxin reductase expression compared with wild-type mice, regardless of selenium status. Transgenic mice had more (P < 0.05) selenium in the nonprotein fraction of the liver and colon than wild-type mice, indicating a greater amount of low molecular weight selenocompounds. Compared with wild-type mice, transgenic mice had more (P < 0.05) azoxymethane-induced aberrant crypt formation (a preneoplastic lesion for colon cancer). Supplemental selenium decreased (P < 0.05) the number of aberrant crypts and aberrant crypt foci in both wild-type and transgenic mice. These results provide evidence that a lack of selenoprotein activity increases colon cancer susceptibility. Furthermore, low molecular weight selenocompounds reduced preneoplastic lesions independent of the selenoprotein genotype. These results are, to our knowledge, the first to provide evidence that both selenoproteins and low molecular weight selenocompounds are important for the cancer-protective effects of selenium
Selenium Prevents Cancer Reviews
Review by Gerald Combs
http://www.cypsystems.com/media/anticarcinogenesis.pdf Selenium and anticarcinogenesis: underlying mechanisms by Matthew I. Jackson and Gerald F. Combs Jr Current Opinion in Clinical Nutrition and Metabolic Care 2008, 11:718–726 , Conclusion - Se compounds, particularly at supranutritional levels, can reduce cancer risk. The efficacious use of Se for reducing cancer risk will demand knowing who can benefit from increased Se intake and what forms/levels are necessary.
http://www.ncbi.nlm.nih.gov/pubmed/16313696 Proc Nutr Soc. 2005 Nov;64(4):527-42. Selenium in cancer prevention: a review of the evidence and mechanism of action. Rayman MP. Division of Nutrition, Dietetics and Food, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UK.
Se is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (SeCys), by means of a mechanism requiring a large SeCys-insertion complex. This exacting insertion machinery for selenoprotein production has implications for the Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins.
The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence, which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colo-rectal and lung cancers. The effect seems to be strongest in those individuals with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from gamma-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and Se-enriched yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA, including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) relating to prostate cancer, although a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.
http://carcin.oxfordjournals.org/cgi/content/full/20/9/1657 Carcinogenesis, Vol. 20, No. 9, 1657-1666, September 1999 Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase Howard E. Ganther Department of Nutritional Sciences, University of Wisconsin, 1415 Linden Drive, Madison, WI 53706, USA Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se.
Selenium Toxicity from supplement containing 200x times labeled concentration
The source of the outbreak was identified as a liquid dietary supplement that contained 200 times the labeled concentration of selenium. Of 201 cases identified in 10 states, 1 person was hospitalized. The median estimated dose of selenium consumed was 41, 749 µg/d (recommended dietary allowance is 55 µg/d).
Frequently reported symptoms included diarrhea (78%), fatigue (75%), hair loss (72%), joint pain (70%), nail discoloration or brittleness (61%), and nausea (58%). Symptoms persisting 90 days or longer included fingernail discoloration and loss (52%), fatigue (35%), and hair loss (29%). The mean initial serum selenium concentration of 8 patients was 751 µg/L (reference range, 125 µg/L). The mean initial urine selenium concentration of 7 patients was 166 µg/24 h (reference range, 55 µg/24 h). Conclusions Toxic concentrations of selenium in a liquid dietary supplement resulted in a widespread outbreak.
Brazil Nuts- High in Selenium - 2 Brasil nuts per day same as 100 mcg selomethionine
http://www.ajcn.org/cgi/content/abstract/87/2/379 Brazil nuts: an effective way to improve selenium status. Am J Clin Nutr. 2008 Feb. Thomson CD, Chisholm A, McLachlan SK, Campbell JM. Department of Human Nutrition, University of Otago, Dunedin, New Zealand.
We investigated the efficacy of Brazil nuts in increasing selenium status in comparison with selenomethionine. Participants consumed 2 Brazil nuts thought to provide approximately 100 mug Selenium, 100 mug Selenium as selenomethionine, or placebo daily for 12 wk. Actual intake from nuts averaged 53 mug Selenium /d (possible range: 20-84 mug Se). Plasma selenium and plasma and whole blood glutathione peroxidase activities were measured at baseline and at 2, 4, 8, and 12 wk, and effects of treatments were compared. Plasma selenium increased by 64%, 61%, and 7%; plasma glutathione peroxidase by 8%, 3%, and -1%; and whole blood glutathione peroxidase by 13%, 5%, and 1.9% in the Brazil nut, selenomethionine, and placebo groups, respectively. Consumption of 2 Brazil nuts daily is as effective for increasing selenium status and enhancing glutathione peroxidase activity as 100 mug Se as selenomethionine.
www.mdpi.com/journal/molecules Review - Selenium in Oncology: From Chemistry to Clinics, Oliver Micke et al. Through this study, the significant benefits of sodium selenite supplementation with regards to selenium deficiency and radiotherapy induced diarrhea in patients with cervical and uterine cancer has been shown for the first time in a prospective randomized trial. Survival data imply that supplementation with selenium does not interfere with the positive biological effects of radiation treatment and might constitute a valuable adjuvant therapy option especially in marginally supplied individuals.
In 1966, Dr. Raymond Shamberger discovered that cancer patients displayed depressed selenium blood levels. Together with Dr. Douglas Frost,3 he then established that, in the United States, there was an inverse relationship between cancer incidence and mortality and selenium levels in soils and crops. Furthermore in 1977, Schrauzer and his colleagues4 discovered that, in the 27 countries they surveyed, cancer mortality was inversely proportional to the amount of selenium in the typical national diet Obviously an editorial is not the place to review the massive literature that so clearly establishes selenium as a significant cancer prophylactic
Between 1983 and 1991, seven dermatology clinics recruited a total of 1312 patients, with a mean age of 63 years, who had a history of basal and/or squamous cell carcinoma. These took part in a randomized, double-blind, placebo controlled prevention trial, that utilized 200 micrograms of selenium in brewer’s yeast tablets. It was discovered that, after a total following of 8271 person-years, selenium treatment did not significantly affect the incidence of basal or squamous cell skin cancer. However, patients in the group receiving selenium had a significant reduction in their total cancer mortality. In addition, this trace element was found to have produced significant reductions, in comparison to gender-matched controls, in the incidences of total cancer (41 percent), total carcinomas (46 percent) and in cancers of the prostate (69 percent), colon-rectum (64 percent) and lung (46 percent). These beneficial effects were consistent over time and between study clinics, clearly supporting the hypotheses that supplemental selenium had reduced cancer risk.
Gerhard Schrauzer10 reported to a Workshop in Chemoprevention of Cancer, held at the National Cancer Institute, that “the key to cancer prevention lies in assuring the adequate intake of selenium, as well as other essential trace elements”. Elsewhere,11 in 1978 he argued that selenium’s use as a supplement could cut cancer mortality in the USA by 80 to 90 percent, saving 200,000 to 225,000 lives annually. Nor was Schrauzer alone in his views, a poll of bioinorganic scientists attending an international meeting in San Diego, in the Spring of 1979, showed that a majority believed that available data was sufficient to show that supplementation of diet with 100 to 200 micrograms of selenium would reduce cancer incidence.12
it took me only a few weeks to reach the conclusion that selenium was a key cancer prophylactic and I immediately began to take a daily selenium yeast supplement (100-400 micrograms).
Selenium Levels and Breast Cancer Risk -
http://www.ncbi.nlm.nih.gov/pubmed/3924710 Jpn J Cancer Res. 1985 May;76(5):374-7. Selenium in the blood of Japanese and American women with and without breast cancer and fibrocystic disease. Schrauzer GN, Molenaar T, Mead S, Kuehn K, Yamamoto H, Araki E.
Selenium concentrations in whole blood of Japanese and American women with and without breast cancer and benign fibrocystic breast disease were determined. The observed blood Se levels of healthy Japanese women (0.286 +/- 0.021 micrograms/ml) were similar to previously reported values for healthy Japanese adults.
The Japanese patients with benign breast disease and with breast cancer exhibited blood selenium concentrations of 0.200 +/- 0.045 and 0.195 +/- 0.057 micrograms/ml, respectively.
The mean blood Se concentration of Japanese breast cancer patients with recurrence was 0.188 +/- 0.061 micrograms/ml.
The mean blood Se concentrations of healthy American women from San Diego, Calif., were 0.191 +/- 0.023 micrograms/ml; of women with benign fibrocystic disease, 0.142 +/- 0.010 micrograms/ml; and of breast cancer patients, 0.167 +/- 0.032 micrograms/ml.