Selenium, From Toxin to Essential Mineral by Jeffrey Dach MD
Selenium, Metamorphosis from Toxin to Essential Mineral
by Jeffrey Dach MD
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)
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 CancerRisk
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 prostatecancers 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)
Conclusion
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.
Seleno-Proteins: When Stop Doesn't Really Mean Stop
