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
Left Image : Selenium Soil Content by Counties, with darker counties
having higher selenium soil content. Courtesy of the United States Geological
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)
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)
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)
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)
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)
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.
Codon Translation Table For Amino Acids
GCC, GCA, GCG
UUG, CUU, CUC, CUA, CUG
CGC, CGA, CGG, AGA, AGG
CCC, CCA, CCG
UCC, UCA, UCG, AGU, AGC
ACC, ACA, ACG
GGC, GGA, GGG
GUC, GUA, GUG
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)
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
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.
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)
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)
- 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
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.
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)
Selenium constitutes a health risk with increased risk for cancer, and immune
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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