The need of Selenium for our body and its importance, need, etc. is being explained here. Also care should be taken not to consume the same in excess, which results in Selenium toxicity. through this i am trying to throw some light on the various aspects of selenium and its various roles in human body.

1. SELENIUM
Dr.Arun Babu.N.B.
MD (Biochemistry)

2. Overview
… History & Chemistry
… physiological functions, dietary
reference intakes and sources
… absorption, metabolism & excretion
… interactions, Se deficiency &
toxicity, treatment
… analysis of tissue
levels and Se status
… its health benefits
2

3. HISTORY & CHEMISTRY
 Metal element present
naturally in large
quantities in earth’s crust &
in soil.
 Discovered by Jons Berzelius
in 1817 (Selene in Greek
means Moon)
 Located in same group as
Oxygen, Sulphur & Te in
periodic table.
 Exist in elemental, organic &
inorganic forms
3

4. CHEMISTRY
 Enzymes containing
Selenocysteine in their
active site are called
selenoproteins.
 Glutathione peroxidase
 Most familiar selenoprotein in
our body
 Using reduced glutathione (GSH)
as a substrate, it reduces H2O2
to water.
 Limits oxidative stress by
detoxifying Reactive Oxygen
Species (ROS).
 Iodothyronine deiodinase
 Important role in converting T4
to T3.
 Allows metabolic adaptation to
severe stress or injury.
4

5. Physiological Function of Selenoproteins
(Examples)
athione peroxidases (GPx)athione peroxidases (GPx)
othyronine deiodinasesothyronine deiodinases
oredoxin reductasesoredoxin reductases
selenoprotein Pselenoprotein P
selenoprotein Wselenoprotein W
DNA-bound spermatic selenoprDNA-bound spermatic selenopr
R-O-O-H
R-O-H
T4
T3 rT3
3,3’T2
NADPH NADP+
oxidized
thioredoxin
reduced
thioredoxin
 cell growth
and survival
oxidized
ascorbate
reduced
ascorbate
Antioxidant and transport function.
probably involved in Se-homeostasis
needed for muscle function
mitochondrial capsule selenopmitochondrial capsule selenop
antioxidants
may protect developing sperm
protects developing sperm from ox.
polymerizes into structural protein
for stability/motility of mature spe
selenophosphate synthetasselenophosphate synthetase
required for selenoprotein synthe
5

6. Dietary Reference Intakes and Sources
 Recommended daily intake of
30 μg found in:
6
lobster
tuna
mussels
kidney (calf)
codfish
oysters
liver (cow)
egg pasta
pork meat
eggs
whole grain
bread
In foods, Se is
usually present
as amino acid
derivatives –
selenomethionine
COMA set RNIs of
0.075 and 0.060 mg Se
per day for males &
females respectively
0.075 mg Se per day
for lactating women
(COMA,1991)
Lower limit of WHO
safe range of the
population mean
intake to meet
requirements - 0.040
mg Se per day
COMA – Committee On

7.  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)
7
Dietary Reference Intakes
 Safe upper limit (SGE)
adults 400 μg/d
(symptoms of chronic overload
above 800 μg/d)
narrow window between ingested
amounts resulting in deficiency
and those resulting in toxicity!

8. ABSORPTION & BIOAVAILABILITY
 Readily absorbed from
small intestine.
 Extent of absorption
depends on nature of
compound.
 Soluble selenate &
selenomethionine – Most
readily absorbed.
DISTRIBUTION & METABOLISM
 Widely distributed
throughout the body
 Can be detected in breast
milk 8

9. EXCRETION
 Largely excreted in urine
 Excreted in breath along with
some volatile metabolites
 Some faecal excretion
occurs, usually following
chronic administration.
INTERACTIONS
 Complex interaction between
selenium & iron
 Severe Se deficiency – May
Increase hypothyroid stress
caused by iodine deficiency
 Selenium supplementation 9

10. SELENIUM DEFICIENCY
 3 diseases associated with it
namely:
 Keshan’s Disease
 Kashin – Beck disease.
 Myxoedematous Endemic Cretinism.
 KESHAN’S DISEASE
 Found out in China
 Affect children (2 to 10yrs) and
women of child bearing age.
 Fatigue (even after mild
exercise)
 Cardiac arrythmia
 Palpitation
 Loss of appetite
 Cardiac insufficiency
 Cardiomegaly
 Congestive cardiac failure 10
Cardio
myopa
thy

11.  Mitochondrial dysfunction
 Sarcolema Earliest
affected.
 Multifocal myocardial necrosis
 Fibrosis
 Periacinar Pancreatic fibrosis
 KASHIN-BECK DISEASE
 In China, Russia & Korea
 Selenium responsive bone & joint
disease
 Severe joint pain
 Short stature
 Joint Necrosis (Epiphyseal
degeneration of the arm and leg
joints – Result in structural
shortening of the fingers & long
bones with consequent growth
retardation and stunting).
11

12.  MYXOEDEMATOUS ENDEMIC
CRETINISM
 Seen in Africa
 Partially related to selenium
deficiency
 Iodine deficiency also occur in
this area of Africa.
 Decreased function of
Iodothyronine deiodinases
decreased T3 production
 Selenium dependent Glutathione
peroxidase detoxifies injurious
H2O2, which abounds in Thyroid.
 Manifest symptoms of Mental
Retardation & Hypothyroidism.
 Prolonged use of Total
Parenteral Nutrition (TPN) –
Assoc. with Se & other
nutritional deficiencies.
 Severe Crohn’s disease & 12
Myxoedematous
endemic cretinism in
the Democratic
Republic of Congo

13. SELENIUM TOXICITY / SELENOSIS
 ACUTE SELENIUM TOXICITY
 Appear to occur at doses of 0.5≥
mg/kg body wt.
 Hypersalivation
 Nausea
 Emesis
 Stomach Ache
 Garlic aroma on the breath (due
to excretion of volatile
selenium metabolites)
 GI effects (severe vomiting &
diarrhoea)
 Hair Loss (Due to disruption of
structural proteins in Keratin)
 Fatigue
 Irritability
 Neurological Disturbances
(Restlessness, Spasms, 13

14.  CHRONIC SELENIUM TOXICITY /
SELENOSIS
 Changes to hair & nails
 Skin lesions
 Numbness
 Convulsions
 Paralysis
 Clinical Neurological effects
 Peripheral hypoaesthesia
 Acroparesthesiae
 Pain
 Hyperreflexia
 As a consequence of
inadequate human cases of
Selenosis, much of our
knowledge is based on animal
models. As per that, selenium
toxicity is a dose dependent
process. 14

15. TREATMENT
 CHELATION THERAPY
 To identify a compound that will
bind to the toxic substance and
enhance elimination without
redistributing the substance to
other vital areas in the body
(like CNS).
 No proven chelators for
selenium so far.
 Animal data with BAL, edentate
calcium disodium & succimer –
demonstrate the formation of
nephrotoxic complexes with
selenium that likely worsen
toxicity.
 Proposed that Vit-C will compete
with selenium absorption and
uptake into vital enzymatic
processes, thereby limiting
15

16. RISK ASSESSMENT
 ENDEMIC SELENOSIS
 In parts of Venezuala & China
 Symptoms – Typical
Integumentary Findings
 Hair Loss
 Nail Changes
 Selenium has a variety of
toxic endpoints in both
animals & humans
 In man, 1st
sign of chronic
toxicity appear to be
pathological changes in hair
and nails,
 Followed by adverse
effects on the nervous
16

17. CARCINOGENECITY &
GENOTOXICITY Selenium sulphide –
carcinogenic in rats & mice.
 Other selenium compounds
are not carcinogenic
 Increase in chromosomal
aberrations in Hamster bone
marrow occurred, but at
lethal doses of sodium
selenite.
 Selenium compounds are not
mutagenic in vivo
MECHANISM OF TOXICITY
 No specific mechanisms yet
identified 17

18. ANALYSIS OF TISSUE LEVELS &
SELENIUM STATUS Can be measured directly
from plasma, serum, red
cells, nails and hair.
 Can also be determined
indirectly by measuring
tissue glutathione
peroxidase activity,
although a plateau activity
may occur with higher
levels of selenium intake
not producing a
corresponding increase in
activity.
18

19. 19

20. 20

21. Selenium metabolism in plants
Se-accumulating plants
21
rmal: < 100 μg/g Se (dry weight)
accumulators: > 1000 μg/g Se (dry weight)
garlic
(allium sativum)
broccoli
(brassica oleracea)
common mushroom
(agaricus bisporus)

22. Selenium metabolism in humans
SeO3
2-
SeO4
2-
Se-Met
SeO3
2-
human body
H2Se
Se-Cys
Se-Met
CH3Se
H
GSH
(glutathione)
β-lyase
γ-lyase
Se-Cys
methyl-
transferas
e
demethyla
se
GSH
A) low Se intake
Seleno-
proteins
(Se-
Cys
in
activ
e
site)
urine
22

23. Selenium metabolism in humans
SeO3
2-
SeO4
2-
Se-Met
SeO3
2-
human body
H2Se
Se-Cys
Se-Met
CH3Se
H
(CH3)2Se
(CH3)3Se+
breath
urine
GSH
(glutathione)
Seleno-
proteins
β-lyase
γ-lyase
Se-Met-containing
proteins (Se stores)
Se-sugars
Se-Cys
methyl-
transferas
e
demethyla
se
GSH
B) high Se intake
(Se-
Cys
in
activ
e
site)
(Se-Met
incorporat
ed instead
of Met)
23

24. 24

25. 25

26. Immune function
Viral infection
Thyroid function
Cardiovascular disease
Cancer and
chemoprevention
26
The importance of selenium to human health

27. Role of selenium in immune function
27
Innate “nonadaptive” immunityInnate “nonadaptive” immunity Acquired “adaptive” immunityAcquired “adaptive” immunity
Immune systemImmune system
HumoralHumoral CellularCellular HumoralHumoral CellularCellular
Cytokines
- Interferon
- Interleukins (eg. IL-3, IL-2,
etc)
Macrophages
Granulocytes
- Neutrophils
- Basophils
-Eosinophils
-Natural-Killer (NK) cells
Antibodies
- Immunoglobulin
(eg: IgG, IgA, etc)
Lymphocytes
- T-cell
- B-cell
Involvement of Se in immune
system:
• Increased
activity of NK
cells
•
• Stimulation of
vaccine-induced
immunity
• More antibody-

28. ….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 28

29. Role of selenium in viral
infection In Se-deficient mice harmless
viruses can become virulent.
( e.g. coxsackie virus causing
cardiomyopathy in Keshan disease)
 Subjects supplemented with Se
showed less mutations in
poliovirus compared to placebo
group.
Infection with virus
GPx Adequate
↑ Oxidative stress
Normal immune
response
Mild to no tissue
damage
Se + Se -
GPx deficient
↑↑↑ Oxidative stress
Altered immune
response
Viral mutation
Moderate to severe
tissue damage
29

30. 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 ,
30
Myxedematous
endemic cretinism in
the Democratic
Republic of Congo

31. 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. 31

32. Role of selenium in cancer prevention
Possible mechanisms of cancer preventionPossible mechanisms of cancer prevention
by seleniumby selenium
32

33. …history of selenium in cancer prevention
• 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.
33

34. Se in cancer prevention
• 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 cancer
preventive mechanisms.
• Inorganic forms, such as
selenite/selenate, were more 34

35. 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.
H2Se
CH3Se
H
(CH3)2Se
breath urine
methyl
-
transf
erase
demethy
lase
SeMC
MSA
β-l
y
a
s
e
GSH
Monomethylated Se
compounds, SeMC and
methylselenic acid
(MSA), were shown to
be more effective
than other Se
compounds in
chemoprevention.
to
xic
MSA
35

36. 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
36

37. Literature
37
 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
 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);