Selenium, Metamorphosis from Toxin to Essential Mineral Part One
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. T
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.
Above Left Image Photo courtesy of Vadim N. Gladyshev Selenium Expert
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, 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 University of 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?
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)
Left Image courtesy of Gerald Combs PhD, Selenium Expert
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.
Recruiting Patients from Dermatology Clinics
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)
The selenized yeast tablet used in the NPC trial was called
Seleno-Excel from Cypress Systems available at your local vitamin shop or health food store.
(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 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
Selenium and Cancer Prevention
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 increased
mortality with lower selenium levels, and reduced mortality with higher
selenium levels up to 150 ng/ml. (34)
Brazil Nuts are High in Selenium
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.
Articles with related interest:
For Part Two of Selenium, Click Here .
For Part Three Click Here
Click Here for: Selenium for Hashimoto’s Thyroiditis
Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.drdach.com
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.
(2)
http://extension.oregonstate.edu/yamhill/sites/default/files/documents/Selenium.pdf
WHAT’S NEW WITH SELENIUM …….FERTILIZING OREGON PASTURES By Gene Pirelli,
Jim Oldfield, Wayne Mosher and Ron Hathaway – white muscle disease in
Oregon
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 [10].
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
http://www.ars.usda.gov/pandp/people/people.htm?personid=31990
gerald combs
(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.
Vadim N. Gladyshev LAB , UGA, SECIS, selenium
(15)
http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1035&context=biochemgladyshev
Selenoproteins and selenoproteomes Vadim N. Gladyshev, University of Nebraska-Lincoln
15 kDa Selenoprotein (Sep15). Sep15 is a mammalian protein, but its homologs
are found in other eukaryotes (mostly in animals) (Chapter 13) [7]. It
resides in the endoplasmic reticulum where it binds UDP-glucose:glycoprotein
glucosyltransferase, a sensor of protein folding [35]. 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.
(16)
http://gladyshevlab.bwh.harvard.edu/research.html
Vadim Gladyshev Lab Selenium and Redox Biology
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.
(20)
http://nar.oxfordjournals.org/cgi/content/abstract/gkp788v1
Nucleic Acids Research Advance Access published online on September 25, 2009
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.
(22)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC372737/?page=1
Universal genetic code late 60s
(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
(24)
http://www.thorne.com/altmedrev/.fulltext/9/3/239.pdf
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
NPC Study JAMA -reduced cancer rate from selenium
(26)
http://jama.ama-assn.org/cgi/reprint/276/24/1957.pdf
link for full pdf file
(27)
http://jama.ama-assn.org/cgi/content/abstract/276/24/1957
Effects of Selenium Supplementation for Cancer Prevention in Patients
With Carcinoma of the Skin A Randomized Controlled Trial by Larry C.
Clark, MPH, PhD et al. JAMA. 1996;276(24):1957-1963.
(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
Paper by Clark and Combs
(28A)
http://jn.nutrition.org/cgi/reprint/118/2/237.pdf
Selenium and Cancer Prevention. CLARK,L. C. and.COMBS,G. F., JR. (1986)
Selenium compounds in the prevention of cancer: research needs and
public health
implications. Nutr. 116: 170-173.
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.
Select- Why Did It Fail ?
(30)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718722
http://molinterv.aspetjournals.org/content/9/1/18.full
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 thosecancers 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
(32)
http://www.time.com/time/health/article/0,8599,1865464,00.html
Vitamins Do Not Prevent Prostate Cancer, Study Finds
By Alice Park Wednesday, Dec. 10, 2008
(33)
http://well.blogs.nytimes.com/2008/10/28/disappointing-news-on-vitamin-e-and-selenium October 28, 2008 Disappointing News on Vitamin E and Selenium By TARA PARKER-POPE NY Times
(34)
http://www.ncbi.nlm.nih.gov/pubmed/18299496
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.
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.
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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472449/
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 i
6A
−/Tag mice demonstrated accelerated pathology associated with prostate cancer development
http://cancerprevention.aacrjournals.org/content/2/5/484.abstract
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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734116
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
http://archinte.ama-assn.org/cgi/content/abstract/170/3/256
Acute Selenium Toxicity Associated With a Dietary Supplement Jennifer K. MacFarquhar et al Arch Intern Med. 2010;170(3):256-261.
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.
http://www.mdpi.com/1420-3049/14/10/3975/pdf
Molecules 2009, 14, 3975-3988
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.
http://diss.kib.ki.se/2009/978-91-7409-732-0/thesis.pdf
CYTOTOXIC MECHANISMS OF SELENIUM IN CANCERki.se [PDF]
E Olm – 2009 – Karolinska Institutet, Stockholm, Sweden
http://www.raysahelian.com/selenium.html
Selenium by Ray Sahelian
Harold Foster on Selenium
http://jn.nutrition.org/cgi/reprint/118/2/237.pdf
FOSTER, H. D. (1986) Reducing Cancer Mortality: A Geo graphical
Perspective, Western Geographical Series, vol. 23, University of
Victoria, Victoria, B.C.
http://www.orthomolecular.org/library/jom/1998/articles/1998-v13n01-p008.shtml
The Journal of Orthomolecular Medicine Vol. 13, 1st Quarter 1998
Selenium and Cancer: A Geographical Perspective Harold D. Foster, Ph.D
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.
The higher blood Se concentrations of Japanese healthy subjects as
compared to healthy Americans can be attributed to differences in the
dietary Se intakes; low blood Se concentration may be indicative of
increased breast cancer risk.
http://www.ncbi.nlm.nih.gov/pubmed/2484517
Biol Trace Elem Res. 1988 Jan-Apr;15:205-12.
The distribution of selenium in human blood samples of Israeli
population–comparison between normal and breast cancer cases. Chaitchik
S, Shenberg C, Nir-El Y, Mantel M. Elias Sourasky Medical Center
Tel-Aviv, Israel.
A preliminary study was carried out in order to compare the selenium
concentration in breast cancer patients and healthy subjects (controls)
in Israel. Blood serum samples were obtained from 32 breast cancer
patients and 36 controls and were analyzed for selenium by the XRF
method. A weighted mean of 0.076 +/- 0.014 ppm Se in the blood serum of
breast cancer patients, as compared to 0.119 +/- 0.023 ppm Se for
controls, was obtained. These results indicate that the concentration of
selenium in breast cancer patients is significantly lower than in
controls. The relationship between selenium concentration and malignancy
stage shows an inverse dependence, i.e., the concentration decreases
with stage number.
Selenium Supplementation in BRCA Gene carriers
http://www.ncbi.nlm.nih.gov/pubmed/20063075
Cancer Causes Control. 2010 Jan 9. Toenail selenium status and DNA
repair capacity among female BRCA1 mutation carriers. Kotsopoulos J et
al.
Women’s College Research Institute, 790 Bay Street, Toronto, ON, Canada,
Selenium is an important cofactor of various antioxidant enzymes and
has been shown to enhance DNA repair in normal human fibroblasts. Oral
selenium supplementation has also been shown to decrease the number of
chromosome breaks in BRCA1 mutation carriers. Because the predisposition
to cancer among BRCA1 mutation carriers may be linked to high rates of
DNA damage and chromosome breakage, we evaluated the association between
toenail selenium concentrations and three measures of DNA repair
capacity (the single-cell alkaline gel electrophoresis (comet) assay,
the micronucleus test, and the enumeration of gamma-H2AX nuclear foci)
in female BRCA1 mutation carriers and in non-carriers.
Toenail selenium levels were inversely associated with levels of
chromosomal damage following exposure to gamma-irradiation, as assessed
by the micronucleus test. This association was limited to women with a
BRCA1 mutation (p = 0.03). These results provide evidence for a possible
protective effect of selenium against BRCA1-associated breast cancers.
http://www.ncbi.nlm.nih.gov/pubmed/19843683
Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):2923-8. Selenium
supplementation reduced oxidative DNA damage in adnexectomized BRCA1
mutations carriers. by Dziaman T et al. Poland.
Some experimental evidence suggests that BRCA1 plays a role in repair
of oxidative DNA damage. Selenium has anticancer properties that are
linked with protection against oxidative stress. To assess whether
supplementation of BRCA1 mutation carriers with selenium have a
beneficial effect concerning oxidative stress/DNA damage in the present
double-blinded placebo control study. Altogether, these results suggest
that BRCA1 deficiency contributes to (Oxidative Damage and Breaks )
accumulation in cellular DNA, which in turn may be a factor responsible
for cancer development in women with mutations, and that the risk to
developed breast cancer in BRCA1 mutation carriers may be reduced in
selenium-supplemented patients who underwent adnexectomy.
http://cebp.aacrjournals.org/content/14/5/1302.long
Cancer Epidemiology, Biomarkers & Prevention May 2005 14; 1302
Increased Rates of Chromosome Breakage in BRCA1 Carriers Are Normalized
by Oral Selenium Supplementation by Elzbieta Kowalska1, Steven A.
Narod2, Tomasz Huzarski1, Stanislaw Zajaczek1, Jowita Huzarska1, Bohdan
Gorski1 and Jan Lubinski1
Women who carry a mutation of the BRCA1 gene face a lifetime risk of
breast cancer of ∼80% and a lifetime risk of ovarian cancer of ∼40% (1).
Men who carry a BRCA1 mutation seem at elevated risk for breast and
prostate cancer (2). The BRCA1 gene product is involved in the
maintenance of the integrity of the human genome and functions in
conjunction with BRCA2 and RAD51 to repair double-stranded DNA breaks
through the mechanism of homologous recombination (3).
One of the most commonly used cytogenetic tests for the assessment of
chromosome instability is the in vitro bleomycin assay (9). This is a
simple and reproducible assay that measures induced chromosome breaks.
Patient lymphocytes are cultured in the presence of bleomycin, a known
mutagenic agent that typically induces double-strand breaks (similar to
those induced by ionizing radiation). The mean number of chromosomal
breaks per cell is then measured after bleomycin exposure. The assay has
been used to study susceptibility to various types of cancer (9, 10).
Using this technique, we explored the possibility that oral selenium
supplementation may reduce the formation of induced chromosome breaks in
female BRCA1 carriers.
An oral selenium solution was provided to the study subjects which
contained 690 μg of pure selenium, in the form of sodium selenite
(Na2SeO3) per mL of 70% ethanol. Subjects were requested to consume 0.2
mL of the solution twice daily. Among the BRCA1 carriers (n = 32), this
level of supplementation resulted in an increase in the mean serum
selenium from 56.7 ± 12.7 to 90.2 ± 17.6 ng/mL (P < 0.001). Selenium
levels were not measured in the noncarrier controls.
In the first phase of this two-part study, we observed that the
lymphocytes from heterozygous carriers of deleterious mutations of the
BRCA1 gene show an elevated frequency of chromosome breaks after
exposure to bleomycin in vitro compared with noncarriers. In the second
part of the study, we have shown that in most cases, these elevated
levels can be reduced to normal with oral selenium supplementation.
Although our sample size was small, our results were highly significant;
in every case, selenium supplementation resulted in a reduced frequency
of chromosome breaks.
http://www.hccpjournal.com/content/4/1/58
A Lowering of Breast and Ovarian Cancer Risk in Women with a BRCA1 Mutation by Selenium Supplementation of Diet
Tomasz Huzarski1 , Tomasz Byrski1, Jacek Gronwald1, Elżbieta
Kowalska1, Stanisław Zajączek1, Bohdan Górski1, Jowita Huzarska1, Cezary
Cybulski1, Steven A Narod2 and Jan Lubiński International Hereditary
Cancer Center – Department of Genetics and Pathology, Pomeranian Medical
University, Szczecin, Poland, Women’s College Hospital, Toronto,
Canada, Hereditary Cancer in Clinical Practice 2006, 4:58
It has been shown that individuals with inherited predisposition to
cancer (including colon, breast and ovary) have increased sensitivity to
bleomycin. We published that bleomycin-induced chromosomal instability
in BRCA1 carriers is inhibited by selenium supplementation in
physiologic (according to WHO) doses.
Selenium was shown to reduce the risk of several cancers.
The aim of our study is to verify the idea that selenium
supplementation of diet reduces the risk of cancer in women with a BRCA1
mutation. We performed two pilot studies involving 200 healthy BRCA1
mutation carriers (100 matched pairs – cases and controls). After two
years of oral selenium administration the frequency of BRCA1-associated
tumours was two times lower in women who supplemented their diet with
selenium, as compared to women without supplementation.
Sep 15 selenoprotein genome and breast cancer
http://www.cancer-therapy.org/CT1A/HTML/34%20%20Diamond%20et%20al,%20293-29%20c.htm
Cancer Therapy Vol 1, 293-298, 2003. Allelic loss at the SEP15 locus in
breast cancer by Mohamed A. Nasr, Ya Jun Hu, and Alan M. Diamond
Department of Human Nutrition, University of Illinois at Chicago,
Chicago, IL
Sep15 is a selenium-containing protein whose gene is mapped on human
chromosome 1 at position 117-123 cM on the human transcript map,
corresponding approximately to 1p31, a common position of chromosomal
loss in breast cancer and other solid tumors. These observations, the
studies reported here for breast cancer, and the likelihood that Sep15
protein levels might be reduced in individuals with sub-optimal selenium
intake, raise the possibility that the Sep15 gene product provides an
anti-cancer protective role and may mediate some of the protective
effects associated with selenium adequate or supplemental intake.
Selenium inhibits breast cancer in mouse model
http://cancerres.aacrjournals.org/cgi/content/abstract/51/17/4613
[Cancer Research 51, 4613-4617, September 1, 1991]
Inhibition of 7,12-Dimethylbenz(a)anthracene-induced Mammary Tumors and
DNA Adducts by Dietary Selenite by Jinzhou Liu et al. University of
Illinois
The present studies were designed to examine the influence of dietary
selenite supplementation on the initiation phase of
7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis and
to correlate selenite-induced changes in the binding of DMBA
metabolites to rat mammary cell DNA with the ultimate tumor incidence.
Diets formulated to contain selenium, as sodium selenite at 0.1, 0.5, 1,
2, or 4 µg/g were fed for 2 weeks prior to and 2 weeks following
treatment with DMBA (5 mg/kg body weight). Food intake and weight gain
did not differ among treatments. Tumor incidence correlated inversely to
the quantity of selenium consumed (r = -0.99). Final tumor incidences
were 52, 32, 24, 14, and 10% for rats fed 0.1, 0.5, 1, 2, and 4 µg
selenium/g, respectively.
In a separate group of rats fed a diet containing 4 µg selenium/g
during both the initiation and promotion stages the final tumor
incidence was 4.8%. Selenite supplementation for 2 weeks markedly
depressed the occurrence of individual and total DMBA-DNA adducts. The
final mammary tumor incidence correlated positively with total DMBA-DNA
adducts (r = 0.99). These studies clearly demonstrate that selenite can
inhibit the initiation stage of mammary carcinogenesis. This reduction
in tumor incidence is likely due to a reduction in carcinogen metabolism
and ultimately adduct formation.
Selenium Prevents Colon Cancer in Mouse Model
http://www.wjgnet.com/1948-5204/pdf/v1/i1/74.pdf
Selenium as a chemopreventive agent in experimentally induced colon carcinogenesis
World J Gastrointest Oncol 2009 October 15; 1(1): 74-81 by Fereshteh Ezzati Ghadi et al. Panjab University, India
RESULTS: 100% of the DMH treated rats developed tumors, which was reduced to 60% upon simultaneous selenium supplementation.
Histopathological studies on DMH treated rats revealed dysplasia of the colonic
histoarchitecture, which showed signs of improvement following selenium treatment.
CONCLUSION: The study suggests the antioxidative potential of
selenium is a major factor in providing protection from development of
experimentally induced colon carcinogenesis.
Bladder cancer associated with low serum selenium
70% greater incidence of bladder cancer below 96 mcg/L
http://www.ncbi.nlm.nih.gov/pubmed/16984549
Int J Urol. 2006 Sep;13(9):1180-4. Selenium is inversely associated with
bladder cancer risk: a report from the Belgian case-control study on
bladder cancer. Kellen E, Zeegers M, Buntinx F. Belgium.
Selenium is an essential trace element with suspected
anticarcinogenic properties in humans. To date, eight epidemiological
studies have examined the association between serum selenium
concentration and bladder cancer risk.
METHODS: The authors carried out a population case-control study in
178 cases and 362 controls to assess the relationship between bladder
cancer risk and selenium serum concentrations. Unconditional logistic
regression was calculated to determine odds ratios (OR) for bladder
cancer occurrence with corresponding 95% confidence intervals (95% CI).
Effect modification by smoking status, low fruit and vegetable intake,
retinol equivalent, vitamin C, vitamin E and total antioxidant status
were also assessed.
RESULTS: Serum selenium level was negatively associated with bladder
cancer risk. After adjustment for sex, age, smoking and occupational
exposure, the OR was 0.48 (95% CI 0.29-0.79) comparing the second with
the lowest tertile (serum selenium concentration >82.40 microg/L).
The adjusted OR for the highest tertile (serum selenium concentration
>96.00 microg/L), was 0.30 (95% CI 0.17-0.52) (P-trend <0.001). An
increase of 10 microg/L in serum selenium concentration was associated
with a significant decreased bladder cancer risk (OR: 0.76; 95% CI
0.67-0.85). CONCLUSION: This case-control study suggests an inverse
association between serum selenium concentration and bladder cancer
risk.
Selenium in Lymphoma – induces apoptosis, beneficial with chemo
http://www.ncbi.nlm.nih.gov/pubmed/18953506
Biol Trace Elem Res. 2009 Mar;127(3):200-10. Epub 2008 Oct 25.
High-dose sodium selenite can induce apoptosis of lymphoma cells in
adult patients with non-Hodgkin’s lymphoma. by Asfour IA, El-Tehewi MM,
Ahmed MH, Abdel-Sattar MA, Moustafa NN, Hegab HM, Fathey OM. Department
of Internal Medicine and Clinical Hematology, Clinical Hematology Unit,
Ain-Shams Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
The present study was undertaken to explore the effect of
administration of high doses of sodium selenite on the apoptosis of
lymphoma cells in patients with non-Hodgkin’s lymphoma (NHL). Forty
patients with newly diagnosed NHL were randomly divided into two groups.
Group I received standard chemotherapy, whereas group II received
adjuvant sodium selenite 0.2 mg kg(-1) day(-1) for 7 days in addition to
chemotherapy. Flow cytometry was used for monitoring of lymphoma cells
apoptosis at the time of diagnosis and after therapy in the two groups.
Sodium selenite administration resulted in significant increase in
percentage of apoptotic lymphoma cells after therapy in group II (78.9
+/- 13.3% versus 58.9 +/- 18.9%, p < 0.05). In addition, patients who
received sodium selenite treatment demonstrated statistically
significant increase in percentage of reduction of cervical and axillary
lymphadenopathy, decrease in splenic size, and decreased percentage of
bone marrow infiltration. Also, we found a statistically significant
decrease in cardiac ejection fraction (CEF) in group I and no reduction
in CEF in patients who received sodium selenite ‘group II’, denoting the
cardioprotective effect of selenium. It is concluded that sodium
selenite administration at the dosage and duration chosen has
synergistic effect to chemotherapy in inducing apoptosis and,
consequently, could improve clinical outcome.
Selenium Health Claim – FDA
http://www.emord.com/media/press-releases/emord-sues-fda.htm
Emord Sues FDA: Selenium Claim Suppression Violates First Amendment
Emord asked the Court to hold FDA’s June 19, 2009 decision to suppress
selenium/cancer risk reduction claims unconstitutional under the First
Amendment and to enjoin FDA from censoring the claims.
http://jn.nutrition.org/cgi/content/full/135/2/354
2005 The American Society for Nutritional Sciences J. Nutr. 135:354-356, February 2005
The Level of Evidence for Permitting a Qualified Health Claim:
FDA’s Review of the Evidence for Selenium and Cancer and Vitamin E and
Heart Disease1 Paula R. Trumbo2 Center for Food Safety and Applied
Nutrition, Food and Drug Administration, College Park, MD 20740
Selenium and cancer
In 2002, a petition was submitted to the FDA requesting a health
claim on selenium and certain cancers. Five intervention cancer
prevention trials were reviewed. Two of these trials provided
multinutrient supplements; therefore, it was not possible to determine
the independent effect of selenium on risk reduction of cancers (23,24).
Of the remaining 3 trials, 2 were conducted in China and included
malnourished individuals (25,26). Although these 2 studies are not
relevant to the U.S. population, 1 study showed a reduced incidence of
liver cancer (25) and the other showed a lower incidence of stomach
cancer mortality (26).
The remaining intervention trial, the Nutritional Prevention Cancer
Trial, was placebo-controlled, conducted in the United States, and was
designed to evaluate the effect of supplemental selenium on the risk of
basal and squamous cell carcinomas of the skin (27). This study found no
beneficial effects of selenium supplementation on the incidence on
nonmelanoma skin cancer. A post-hoc analysis of this trial on effects of
selenium on secondary cancer endpoints suggested that selenium
supplementation may reduce the risk of total, prostate, lung, and
colorectal cancers, especially for men with low plasma selenium
concentrations. A 7.9-y follow-up of this trial evaluated the relative
risk of these secondary cancer endpoints and found that the significant
reductions in lung and colorectal cancer were no longer observed.
Of the 36 observational studies that were reviewed, approximately
half supported an association with total cancers and half did not. It
was noted, however, that the greatest consistency was observed for
breast and prostate cancer. It was concluded that although the limited
number of intervention studies had significant flaws for evaluating a
selenium/cancer relationship and the findings were not conclusive, there
was some basis for a qualified health claim. Therefore a qualified
health claim was permitted,
Jeffrey Dach MD
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Yet another transgenic mouse prostate cancer study published in May 2009 AACR by Wang et al showed inhibition of prostate cancer and increased survival in mice treated with selenium compounds.(3)
