Transcript Selenium in Nutrition and Toxicology

Selenium in Nutrition and Toxicity
Dr. Karin Hotz
Jeannine Baumgartner
ETH Laboratory of Human Nutrition
Institute of Food, Nutrition and Health
Overview
… deficiency and overload
… dietary reference intakes and sources
… species: inorganic and organic compounds
… absorption, metabolism & excretion
… and its functions in selenoproteins
… importance to human health
Picture: www.buzzle.com
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Selenium as an essential trace element:
symptoms of deficiency and overload
 Selenium deficiency
 Selenium overload
 Impaired muscle function
 Keshan disease
(Se as causative cofactor)
cardiomyopathy
 Acute overdosing:
 garlic odor on the breath
 nausea
 stomach ache
 liver damage
 chronic overdosing:
 hair loss
 brittle fingernails
 neurological damage
 Kashin-Beck disease
(Se as causative cofactor)
deforming
arthritis
pictures: www.wikipedia.org
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Dietary Reference Intakes
 Recommended daily intakes (SGE)
children
25-60 μg/d
adolescents 30-70 μg/d
adults
30-70 μg/d
(U.S. RDA: 55 μg/d)
 Safe upper limit (SGE)
adults
400 μg/d
(symptoms of chronic overload above 800 μg/d)
narrow window between ingested amounts resulting in deficiency
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and those resulting in toxicity!
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Dietary Reference Intakes and Sources
 Recommended daily intake of 30 μg found in:
lobster
tuna
mussels
kidney (calf)
codfish
oysters
liver (cow)
egg pasta
pork meat
eggs
whole grain bread
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SGE
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Dietary Reference Intakes and Sources
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Soil concentration, dietary intake and serum levels
recommended
intake 30-70 μg/d
Dumont E. (2006)
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Dietary Reference Intakes and Sources
Soil concentration, dietary intake and serum levels
Upper safe limit
400 μg/l
Dumont E. (2006)
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Selenium metabolism in plants
Se2-
(CH3)-Se-Cys
accumulated
in certain plants
(CH3)-Se-Met
phytovolatilization (detoxification)
(CH3)2Se
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Dumont E. (2006)
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Selenium metabolism in plants
Se-accumulating plants
normal:
< 100
Se-accumulators: > 1000
garlic
(allium sativum)
pictures: www.wikipedia.org
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μg/g Se (dry weight)
μg/g Se (dry weight)
broccoli
(brassica oleracea)
common mushroom
(agaricus bisporus)
Dumont E. (2006)
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Se species: inorganic and organic Se compounds
Se2-
selenide (Se-II)
S
selenite (SeIV)
selenocysteine
H
selenoproteins
(Se-Cys in active site)
methylselenide
Me-selenocysteine
selenate (SeVI)
Se-containing
proteins
dimethylselenide
selenomethionine
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(e.g. Met replaced
by Se-Met, no specific
function for Se)
Dumont E. (2006)
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Se species: inorganic and organic Se compounds
Bioavailability
organic selenium species have a higher bioavailability
than inorganic species
picture: www.magen-darm-grippe.de
Targeting
depending on the species,
Se is specifically targeted to functional compartments or unspecifically distributed
between tissues
picture: www.monetized.co.za
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Selenium metabolism in humans
A) low Se intake
SeO4
2-
SeO32-
Selenoproteins
GSH
(Se-Cys in
active site)
H2Se
Se-Cys
Se-Met
Se-Met
methyl-transferase
Se-Cys
demethylase
SeO32-
human body
CH3SeH
Yanghorbani 1999
Ip 1998
Brozmanova 2010
Wolffram 1989
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urine
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Selenium metabolism in humans
B) high Se intake
SeO32-
SeO32-
2-
Selenoproteins
GSH
(Se-Cys in
active site)
H2Se
Se-Cys
Se-Met
Se-Met
methyl-transferase
Se-Cys
demethylase
SeO4
human body
Se-sugars
CH3SeH
Se-Met-containing
proteins (Se stores)
(Se-Met incorporated instead of
Met)
Yanghorbani 1999
Ip 1998
Brozmanova 2010
Wolffram 1989
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(CH3)2Se
(CH3)3Se+
breath
urine
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Physiological Function of Selenoproteins (Examples)
R-O-H
selenoprotein P
glutathione peroxidases (GPx)
antioxidants
antioxidant,
probably involved in Se-homeostasis
R-O-O-H
T4
iodothyronine deiodinases
T3
NADP+
thioredoxin reductases
oxidized
thioredoxin
reduced
thioredoxin
 cell growth
and survival
needed for muscle function
rT3
3,3’T2
NADPH
selenoprotein W
oxidized
ascorbate
reduced
ascorbate
DNA-bound spermatic selenoprotein
may protect developing sperm
mitochondrial capsule selenoprotein
protects developing sperm from ox. damage,
polymerizes into structural protein required
for stability/motility of mature sperm
selenophosphate synthetase
required for selenoprotein synthesis
Rayman 2000
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The importance of selenium to human health
Immune function
Viral infection
Thyroid function
Cardiovascular disease
Cancer and chemoprevention
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Role of selenium in immune function
Immune system
Innate “nonadaptive” immunity
humoral
cellular
Acquired ”adaptive” immunity
humoral
cellular
Cytokines
Macrophages
Antibodies
Lymphocytes
- Interferon
Granulocytes
- Immunoglobulin
- T-cell
- Interleukins (eg. IL-3, IL-2, etc)
- Neutrophils
(eg. IgG, IgA, etc)
- B-cell
- Basophils
- Eosinophils
Natural-Killer (NK) cells
Involvement of Se in immune system:
• Increased activity of NK cells
• Proliferation of T-cells
• Increased interferon production
• Increased interleukin receptors
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Figure: Modified from http://www.ndt-educational.org/muellerslide
• Stimulation of vaccine-induced immunity
• More antibody-producing B-cells
• Macrophage and neutrophil activity
Tinggi, 2007
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….proposed mechanisms
Selenoproteins influence three broad areas of cell function an therefore affect immune function through:
• Antioxidant activities
• Thyroid hormone metabolism
• Regulation of the activity of redox-active proteins
Example: Neutrophil function
-
Neutrophils produce peroxi-derived radicals to kill invading microbes, but also the neutrophils themselves need to be
protected from the radicals by the system.
-
Radical production and protection depends on GPx activity in neutrophils, which is impaired in Se-deficiency.
Arthur, 2003
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Role of selenium in viral infection
 In Se-deficient mice harmless viruses can become virulent.
( e.g. coxsackie virus causing cardiomyopathy in Keshan disease)
Se +
Infection with virus
Se -
GPx Adequate
GPx deficient
↑ Oxidative stress
↑↑↑ Oxidative stress
Normal immune
response
Mild to no tissue
damage
Altered immune
response
Viral mutation
Moderate to severe
tissue damage
Figure: Beck, 2001
 Subjects supplemented with Se showed less mutations in poliovirus compared to placebo group.
 HIV patients are nearly 20 times more likely to die from HIV-related causes than those with adequate levels.
And low Se levels in HIV-infected children are related to faster disease progression.
Rayman, 2000
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Role of selenium in thyroid function
 Deiodinases are Se-containing enzymes playing important
roles in thyroid hormone metabolism.
 Low plasma T3:T4 ratios found in people with low Se intake.
 A combined deficiency of iodine and selenium is associated with severe endemic myxedematous cretinism (in
Democratic Republic of Congo).
 Se supplementation in elderly subjects decreased plasma thyroxine (T4) concentrations , increased
deiodinase activity and improved conversion of the active hormone T3.
 Se
function.
Impaired thyroid hormone metabolism has adverse effects on
Figure: Myxedematous endemic cretinism in
the Democratic Republic of Congo
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immune
Tinggi, 2008; Rayman, 2000
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Role of selenium in cardiovascular disease (CVD)
Increased production of ROS can cause oxidative stress and cause
damage to cellular lipids, proteins and DNA, leading to CVD.
 Selenoproteins may help to combat oxidative modification of lipids and to reduce platelet aggregation.
 Epidemiological studies produced mixed findings (examples):
 2 to 3-fold increase in CV morbidity and mortality in subjects with serum Se conc. below 45 µg/L compared to subjects above at
baseline.
 Increased risk of ischaemic heart disease in Danish men with serum Se below 79 μg/L.
 Inverse association between toenail Se and risk of myocaridal infarction only in areas with the lowest Se status. Thus, effect maybe only
apparent in populations of low Se status.

Ebselen, a synthetic mimic of glutathione reductase showed cardio- protective effects in mice.
Tinggi, 2008, Rayman 2000
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Role of selenium in chemoprevention
Possible mechanisms of cancer prevention by selenium
Mechanisms of Se
From homepage of German Cancer Research Center
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…history of selenium in chemoprevention
• In 1969 Shamberger found that his cancer patients had selenium blood levels only 60 to 80 % as high as
non-cancer patients.
•
In 1977, Schrauzer reported that selenium intake in 27 countries was inversely correlated with breast cancer
death rates.
• Several human epidemiological studies found a statistically significant inverse relationship between Se level
and risk of cancer overall, particularly in men.
• Also early animal studies have shown that selenium added to the diet reduced cancer incidence.
Tinggi, 2008, Rayman 2000
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Se in chemoprevention
• In the first RCT, supplementation with selenized yeast (200 µg/day), predominantly in the form of
selenomethionine (Se-Met) for 4 years, led to a reduction of nearly 50% in overall cancer morbidity (Clark, 1996).
 Average selenium intake of the study subjects 90 µg/day, well above levels needed for optimal selenoprotein activity.
 This suggests additional chemopreventive mechanisms.
• Inorganic forms, such as selenite/selenate, were more effective than commonly used organic form Se-Met in
fighting cancer.
• Because cells can not distinguish Se-Met from essential amino acid methionine, it is incorporated into general
body proteins.
• However, inorganic Se is more toxic compared to organic Se forms.
Brozmanova, 2010, Rayman 2000, Ip, 1998
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Methylselenocystein (Met-Se-Cys): Less toxic alternative
• Is formed naturally in various plants grown on high selenium soil.
• Met-Se-Cys rich foods have shown good anticancer activity, without
excess tissue accumulation or toxicity.
• Met-Se-Cys is converted into methylselenol (CH3SeH), which has been shown to be an active anticancer form
of Se.
 Mechanism of action: Apoptosis and inhibition of angiogenesis.
toxic
methyl-transferase
H2Se
SeMC
CH3SeH
demethylase
MSA
And it is less toxic!
(CH3)2Se
breath
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Monomethylated Se compounds, SeMC and methylselenic acid
(MSA), were shown to be more effective than other Se compounds
in chemoprevention.
MSA
urine
Brozmanova, 2010, Rayman 2000, Ip, 1998
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Selenium in human health – A double-edged sword
• Several organic and inorganic Se compounds have been investigated as Se supplements. Their safety and
efficacy differ markedly because of their differential metabolic processing by the body.
• The inorganic Se compound, sodium selenite, due to its prooxidant character, represents a promising
alternative for cancer therapy.
• However, this Se compound is highly toxic compared to organic Se forms.
• To achieve chemopreventive effects, Se had to be given at Se levels 5-10 fold higher than what would be
required for normal nutritional need.
• Due to a broad interest in the positive effects of Se on human health and cancer therapy, studies
investigating the negative effects such as toxicity and DNA damage are highly required.
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Literature
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Rayman M.P. (2000); The importance of selenium to human health. Lancet 356: 233-41
Dumont E., Vanhaecke F., Cornelis R. (2006); Selenium speciation from food source to metabolites: a critical review. Anal. Bioanal.
Chem. 385: 1304-1323
www.sge-ssn.ch (homepage of SGE, “Schweizerische Gesellschaft für Ernährung”)
Brozmanova J., Manikova D., Vlckova V., Chovanec M. (2010); Selenium: a double-edged sword for defense and offence in cancer.
Arch. Toxicol. 84: 919-938
Ip, C. (1998); Lessons from Basic Research in Selenium and Cancer Prevention. J. Nutr. 128(11): 1845-1854
Janghorbani M., Xia Y., et. al. (1999); Metabolism of Selenite in Men with Widely Varying Selenium Status. J. Am. Coll. Nutr. 18(5),
462-469
Tinngi U (2008); Selenium: its role as antioxidant in human health. Environ Health Prev Med. 13:102-108
Arthur J.R, McKenzie RC, Beckett J (2003); Selenium in the Immune System. J. Nutr 133: 1457S-1459S
Beck MA (2001); Antioxidants and Viral Infections: Host Immune Response and Viral Pathogenicity. J. Am College of Nutrition. 20(5),
384S-388S
http://www.dkfz.de/en/tox/c010-2_projects/list_assays.html (homepage of German Cancer research Center)
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