Chapter 30. Selenium from Toxin to Essential Mineral - Part One

 Chapter 30. Selenium, from Toxin to Essential Mineral - Part One

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.  One hundred and forty 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 giving selenium to Vitamin E deficient mice protected them from liver degeneration.(1)

Left Image : Selenium Soil Content by Counties, with darker counties having higher selenium soil content. Courtesy of the United States Geological Survey (62)

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”, causing 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)  A soil selenium map of the United States shows selenium rich areas in the plains states and deficient areas in Oregon, the West coast and the South East.(62-63) 

Finland Has Low Selenium Soil

Finland is a 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)

Keshan Disease in China Caused by Selenium Deficiency

In the 1960's and 1970's in China, government sponsored research discovered a form of cardiac muscle degeneration in humans called Keshan disease occurring in the Keshan province noted for low selenium levels in its soil.  Similar to "white muscle disease" in cattle,  Keshan disease caused the heart muscle to degenerate.  Afflicted children of the Keshan province succumbed to cardiac failure with a dilated, nonfunctional heart,  also called cardiomyopathy.  Selenium supplements were found to be preventive of the disease.(3-4)

Sudden Death From Selenium Deficient Cardiomyopathy

In the early 1980's, selenium deficiency was recognized in the United States when patients on long term artificial feeding died suddenly from cardiomyopathy (a form of heart failure) induced by selenium deficiency.  Apparently, the artificial feeding solution had not included selenium, resulting in selenium deficiency and sudden death from heart muscle degeneration. (8-10)

It's Not the Selenium, It's the Seleno-Protein

Selenium is an essential trace mineral because of the selenoproteins critical for antioxidant defense, fertility, thyroid hormone metabolism, immune responses, 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 in that geographic area. (5-7)

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 atom is replaced by selenium, cysteine becomes seleno-cysteine. Subsequent incorporation of seleno-cysteine into a protein amino acid sequence is called a seleno-protein.

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 can also translate as seleno-cysteine, the 21st amino acid. This was an unexpected twist which nobody expected, and biochemists were quite surprised by this new information.  Notice the translation table below has a code for START and STOP which instructs the cell when to start and stop the amino acid chain under construction. However, there is no code for seleno-cysteine which is incorporated into a seleno-protein.  This is because the STOP codon, (UGA) also serves to code for the amino acid, seleno-cysteine, whenever there is a “SECIS” instruction set present in the DNA code.

Dr. Vadim Gladyshev and Selenium, Correcting the Human Genome Project

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. The UGA Stop Codon also codes for seleno-cysteine, depending 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)

Selenoproteins- What Do They Do? Here are a Few Selenoproteins and Their Function

1) Glutathione Peroxidase – This is a major antioxidant which works in harmony with vitamin E converting (reducing)  hydrogen peroxide to water, and preventing lipid peroxidation and oxidative cellular damage. (24)

2) Iodothyronine De-iodinase Enzyme – This is involved in thyroid function, converts thyroid hormone T4 to T3. (24).   See the Iodine Book by David Brownstein MD for an excellent summary of selenium and thyroid function.(64)

3) Thioredoxin reductase – This is an antioxidant responsible for degrading peroxides and hydroperoxides which cause cell death, DNA damage, and tissue atrophy.(24)

4) Sept 15 Selenoprotein- This is a candidate for cancer prevention. (15)

There are about 40 families of selenoproteins. Most still have unknown functions.

Selenium Deficiency and 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 for its effect on cancer prevention.  Clark chose selenized yeast containing 200 mcg 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 1,300 patients, with a mean age of 63 years.  All had a history of basal and/or squamous cell carcinoma (skin cancer). 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)

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)

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 4.0 ng/mL or less, to determine if the vitamins reduced risk of prostate cancer. The vitamins used were 200 µg L-selenomethionine and 400 IU of synthetic vitamin E. The results showed the vitamins did not prevent prostate cancer in this group. (29)

SELECT - Why Did It Fail ?

Hatfield and 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)  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 Screening programs rapidly remove 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), which is clearly inferior to natural vitamin E. Results may have been different for natural vitamin E.

Blood Selenium Levels below 130 ng/ml benefit from supplementation

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 both cancer mortality, and all cause mortality.   They found that selenium supplementation was beneficial up to a serum selenium level of 130 ng/ml. (34) Above 130 ng/ml, they found no further benefit.  (34)

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-seleno-methionine in the amount of 200 -300 mcg per day.

References for Chapter 30. Selenium, From Toxin to Essential Mineral, Part One

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(64) Iodine, Why You Need It , Why You Can't Live Without It, by David Brownstein MD, Fourth Edition 2009, Medical Alternatives Press.

Author Dr Dach

Jeffrey Dach MD