Review
Selenium: Chemical Biology, Toxicology and
Radioprotection
Kavirayani Indira Priyadarsini*, Beena Govind Singh and Amit Kunwar
Radiation and Photochemistry Division, Bhabha Atomic Research Centre, Trombay, Mumbai – 400085, India
Selenium, a micronutrient and an active constituent of important redox enzymes like glutathione
peroxidase (GPx) and thioredoxin reductase (TrxR), has been investigated extensively by researchers
all over the world for the last four to five decades. Both inorganic and organic selenium compounds are
being evaluated as probable drugs or adjuvants for many viral infections and chronic diseases like
cancer. Several clinical trials in cancer patients have confirmed that selenium supplementation helps in
recovering from cancer therapy associated side effects and selenium itself does not interfere in cancer
therapy. Efforts are on to develop new selenium compounds with anti-cancer properties. These aspects
will be discussed in this article.
INTRODUCTION
Selenium, an element discovered in 1817
Tait et al., 2011; Lee and Jeong 2012;
by John Berzelius, belonging to the
Weekley and Harris, 2013). Several
group
reports
of
chalcogens,
was
initially
confirmed
selenium
to
increased
considered to be a highly toxic element
deficiency
for humans and animals. In the early
infection risks and is responsible for
nineteenth
was
diseases like Keshan disease – an
identified as the cause of livestock death
endemic cardio-myopathy, and Kashin-
in some parts of US due to its high levels
Beck disease – an endemic osteopathy,
in cereal grains. However, subsequent
primarily observed in China (Chen et al.,
research in early nineteenth century
1980; Yao et al., 2011). Consequently,
indicated that at small doses selenium
the deficiency has also been correlated
may be useful. Finally, Schwarz and
with the onset of many other disorders
Foltz
such
century,
(Schwarz
identified
selenium
and
selenium
as
Foltz,
an
1957),
essential
micronutrient for humans (Fairweather-
as
is
that
linked
neurodegeneration,
adverse
mood states, altered immune response,
cardiovascular
diseases
and
cancer
Key words: Selenium, redox reactions, selenoproteins, radioprotectors.
*Corresponding Author: Kavirayani Indira Priyadarsini, Radiation and Photochemistry Division, Bhabha Atomic
Research Centre, Trombay, Mumbai – 400085, India.
Email: [email protected]
Biomed Res J 2016;3(1):52–72
53
Priyadarsini et al.
(Fairweather-Tait et al., 2011; Weekley
relative abundance of selenium in earth
and Harris, 2013). Selenium, is now
crust is one-fourth of sulphur, while in
recognised as an important micronutrient,
humans it is ~105 times lesser. Selenium
and is an active centre of important
has
selenoproteins like glutathione peroxidise
ionisation energy and larger atomic
(GPx) and thioredoxin reductase (TrxR)
radius
which play a crucial role in maintaining
dissociation energies of C-Se, Se-H and
cellular redox homeostasis (Guo et al.,
Se-Se are less than that of C-S, S-H and
2007; Trachootam et al., 2008). Selenium
S-S bonds respectively. The selenol
compounds
as
(RSeH) is more acidic than thiol (RSH).
medicinal for treatment of cancer and
For example in selenocysteine, pKa of
other diseases, and also for minimising
Se-H is 5.43, while that of S-H in cystine
the side effects of cancer treatment. The
is 8.22. Thus at neutral pH, significant
current article provides a brief outline of
difference in the redox behaviour and
important aspects on chemical-biology,
chemical
toxicology and radio protective nature of
observed compared to sulfur (Jamier et
selenium.
al., 2010; Wessjohann et al., 2007).
are
being
explored
lower
electro-negativity
than
sulphur.
reactivity
of
The
and
bond
selenium
is
Tellurium, a heavier member of the same
of
group is a rare element on earth with
Selenium in Comparison with Sulphur
electronic configuration of [Kr] 4d 5s
and Tellurium
5p , atomic number is 52 and atomic
Selenium is a member of chalcogens and
weight
is present in Group 16 of the periodic
tellurium
table, between sulphur and tellurium,
organotellurium compounds. However
with outer electronic configuration of
due to its larger atomic size, the Te-C
[Ar] 3d104s24p4. The atomic number is 34
bond is weaker than Se-C bond and
and atomic weight is 78.96. As a
therefor no n tellurium containing amino
chalcogen, it shares many physical and
acids is found in nature (Cunha et al.,
chemical
2009).
Physico-chemical
properties
Properties
10
2
4
with
sulphur,
however being heavier than sulphur,
selenium shows distinct differences. The
is
127.60.
can
Like
form
selenium,
analogous
The redox behaviour of selenium
depends
on
molecular
form
and
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
54
localization with the neighboring groups
modulates the GPx like antioxidant
(Mugesh et al., 2001; Mukherjee, 2010).
activity and toxicity (Mugesh et al.,
In living beings selenium is present
2001). Similarly, selenomethionine is a
mainly in the form of selenocysteine and
better
selenomethionine
2002).
because of stabilization of intermediates
Selenocysteine, considered as the 21st
during oxidation through hemi-bonding
aminoacid, is more reactive than cystine
interactions between selenium centered
and is incorporated in proteins by the
radical and nitrogen atom (Priyadarsini et
specific UGA codons (Arnér, 2010;
al., 2013).
Behne
and
(Whanger,
Kyriakopoulos,
antioxidant
than
methionine,
2001;
Rahmanto and Davies, 2012). Selenium
Assimilation, Deficiency and Toxicity
has variable oxidation states between +6
of Selenium
and –2. In selenocysteine the element is
The entry point of selenium in animals is
fully reduced with oxidation state of –2,
via plants, which absorbs the element in
while that in diselenide selenocysteine
its inorganic form (sodium selenite and
the oxidation state is assigned to –1.
selenate) from the soil. In plants,
Selenium participates in electron transfer
selenium gets converted to organic forms
reactions in a similar way as sulfur,
such as methylated low molecular weight
however due to higher electropositivity
selenium compounds and the amino
selenium can be easily oxidized as
acids
compared to analogous sulfur compound
selenocysteine, methylselenocysteine and
(Iwaoka and Arai, 2013; Jacob et al.,
γ-glutamyl-Se-methylcysteine (Whanger,
2003). In organoselenium compounds
2002). Animals including humans obtain
selenium can interact with the suitable
selenium primarily in the form of
electron donor/acceptor, which results in
selenomethionine by consuming plant
non-bonding
products. This selenomethionine acts as a
interaction
between
such
selenomethionine,
selenium atom and heteroatoms like
precursor
nitrogen and oxygen (Bhabhak and
selenocysteine (Battin and Brumaghim,
Mugesh,
2009; Behne and Kyriakopoulos, 2001).
2010).
Such
non-bonding
interactions in low molecular weight
Both
organoselenium compounds like ebselen
cysteine
Biomed Res J 2016;3(1):52–72
for
as
the
selenomethionine
are
analogs
synthesis
and
of
of
selenonaturally
55
Priyadarsini et al.
occurring amino acids, methionine and
per day, is recommended (Hou et al.,
cysteine respectively. The foods rich in
1993; Fairweather-Tait et al., 2011).
selenium are garlic, cabbage, Brazil nuts,
Investi-gations in China indicated that
broccoli,
and
750 μg per day is safe and did not
selenomthionine are added to nutritional
produce toxicity (Fairweather-Tait et al.,
supplements to increase selenium levels
2011).
etc.
Selenite
in the body (Fairweather-Tait et al., 2011;
Selenium
prevents
production
of
Whanger, 2002). Normal serum selenium
reactive oxygen species (ROS) and also
level differs with age and ranges from
scavenges
70–187 μg/dL. FDA has ranked selenium
decreasing the risk of diseases associated
th
some
of
these,
thereby
infant
with oxidative stress (Papp et al., 2007;
dietary
Priyadarsini et al., 2013). Selenium is
allowance for selenium is 55 μg per day
necessary for optimal immune response
for all healthy adults of both sexes. In
(Zwolak
domestic farm animals of both sexes, the
Selenium deficient individuals show
nutritional functionality of selenium
decreased IgM and IgG titres. Selenium
ranges from 40–4000 μg/kg (Dhillon and
plays an important role in affecting
Dhillon, 1997; Spallholz, 2001). In
prostacyclin and thromboxane ratio.
humans, up to 150 μg per day of
Selenium supplementation is considered
selenium is added to overcome selenium
as a therapeutic remedy to decrease
deficiency. As per US National Research
blood clotting.
as
30
nutrition.
mandatory
unit
for
Recommended
and
Zaporowska,
2011).
Council, it is safe to consume 50 to 200
Higher selenium also leads to severe
μg per day, although the upper limit is
toxicity, and self-supplementation with
considered to be more conservative.
frequent and higher selenium may retain
Individual
intakes
large quantities of selenium in the body
across the world vary significantly. The
and therefore all necessary precautions
highest levels of intake have been
must be undertaken while supplementing
reported in seleniferous regions of China
with selenium. Increased body selenium
and Venezuela. Additionally, in special
leads to selenosis, a condition of acute
conditions like treatment of viral infected
selenium
individuals, selenium as high as 2000 μg
characterized by loss of hair, nails and
dietary
selenium
poisoning
in
humans,
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
56
swelling at the fingertips. Although
Organoselenium compounds in general
Nelson et al. (1943) classified selenium
are less toxic compared to inorganic
as a carcinogen, there is no evidence that
selenium compounds because of the
selenium is carcinogen in humans. Since
oxidation state and its slow metabolism.
then a large number of reports on in vivo
However, organoselenium compounds
toxicology of selenium compounds has
undergoing
been reported (Fairweather-Tait et al.,
induces oxidative stress in cells through
2011; Nogueira and Rocha, 2011).
consuming glutathione (GSH). Further,
However, all the studies emphasized that
the metabolic intermediates of organo-
selenium becomes toxic only if its intake
selenium compounds depending on the
crosses the supplementation limit (> 200
chemical reactivities can oxidize the
μg/day).
vicinal
The
toxicity
of
selenium
reductive
thiol/sulfahydril
metabolism
groups
of
compounds not only depends on the
proteins involved in signal transduction
quantity of element consumed, but also
pathways leading to inactivation and
on its chemical form (Fairweather-Tait et
subsequent toxicities (McKenzie et al.,
al., 2011; Nagy et al., 2015; Painter
2002; Nogueira and Rocha, 2011). The
1941; Spallholz, 1994). Most of the
classical example of involvement of such
current knowledge on selenium toxicity
mechanisms in organoselenium induced
has been established by studying the
toxicity has been documented in case of
effects of supplementation with inorganic
diphenydiselenide. In this study, the
selenite at supra nutritional doses in
subcutaneous
animal
diphenydiselenide (250 µmol/kg body
models.
The
molecular
administration
mechanism underlying selenium toxicity
weight)
is not completely understood. In a few
oxidizing
reports, the toxicology of inorganic
aminolevulinic
selenium
has
been
related
ALA-D)
oxidation
of
thiols
of
to
the
induced
the
acid
involved
of
anemia
through
enzyme
delta-
dehydratase
in
(δ-
hemoglobin
biological
metabolism (Jacques-Silva et al., 2001).
importance, producing superoxide and
Apart from the above mechanisms,
hydrogen peroxide (Fairweather-Tait et
compounds
al., 2011; Kitahara et al., 1993; Nogueira
exhibit toxicity due to non-specific
et al., 2004; Wrobel et al., 2016).
incorporation in proteins leading to loss
Biomed Res J 2016;3(1):52–72
like
seleno-methionine
57
Priyadarsini et al.
Fig. 1: Structure of important selenium compounds.
of protein functions. Further, acute
proteins in place of methionine non-
selenium poisoning leads to cardio-
specifically.
circulatory failure and pulmonary edema
methionine and other organoselenium
(Fairweather-Tait et al., 2011). High
compounds are converted to seleno-
selenium levels increase the risk of type
cysteine via the intermediacy of seleno-
2 diabetes and amyotrophic lateral
cystathionine.
sclerosis (Brozmanová et al., 2010;
releases H2Se from selenocysteine. Some
Fairweather-Tait et al., 2011)
compounds
Alternately,
seleno-
Selenocysteine
are
converted
b-lyase
to
H2Se
through methylselenol (CH3SeH). H2Se is
Selenium Metabolism
incorporated in to selenoprotein P in the
Both inorganic and organic selenium
liver,
compounds are metabolised to hydrogen
selenoprotein synthesis. H2Se is excreted
selenide (H2Se). Inorganic selenite is
in the urine in the form selenosugars.
reduced to selenide through activation of
Some times H2Se may be converted to
TrxR
Alternately
CH3SeH and (CH3)2Se through methyl
selenite (SeO3 ) reacts with GSH to form
transfarases and (CH3)2Se is excreted in
selenodiglutathione,
a
the breath. Selenium metabolites and
substrate/intermediate for reduction of
compounds have been shown to be
selenoglutathione
glutathione
effective in the detoxification of heavy
reductase to selenol that reacts with GSH
metals such as Cd, Hg, Pb, As (Tapiero et
to yield H2Se (Fairweather-Tait et al.,
al., 2003). One of the mechanisms
2011;
suggests
and
thioredoxin.
–2
Weekley
which
by
and
Harris,
is
2013).
Selenomethionine is incorporated in
which
is
a
formation
source
of
of
all
biologically
inactive selenides which accumulate as
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
58
granules
in
some
organs
(García-
an antioxidant enzyme that detoxifies
Sevillano et al., 2015; Dauplais et al.,
peroxides and protects against oxidative
2013). Chemical structures of important
stress, and was essential for life in a
selenium compounds are given in Fig. 1.
knockout mouse model. GPx protects
biomembranes
and
other
cellular
Selenoproteins
components from oxidative damage by
The groups of proteins that contain
catalyzing reduction of a variety of
selenium as an integral part of the
hydroperoxides, using glutathione (GSH)
polypeptide
as
as the reducing substrate. Four distinct
selenoproteins and these proteins are
isoforms of GPx have been reported to
responsible for most of the physiological
be expressed in mammals, the classical
functions mediated by selenium such as
cytosolic GPx (cGPx), phospholipid
role in cellular antioxidative protection,
hydroperoxide GPx (PHGPx), plasma
redox regulation, male fertility, thyroid
GPx (pGPx) and gastrointestinal GPx
function and immune function. Seleno-
(GI-GPx) (Brigelius-Flohé and Maiorino,
proteins are present in all lineages of life
2013). cGPx catalyses reduction of
(i.e., bacteria, archaea and eukarya)
hydrogen peroxide and a limited number
(Arner, 2010; Weekley and Harris, 2013;
of organic hydroperoxides such as
Papp et al., 2007). In prokaryotes,
cumene hydroperoxide and tert-butyl
formate dehydrogenase, hydrogenases
hydro-peroxide. The PHGPx is active on
and glycine reductase are important
all phospholipid hydroperoxides, fatty
selenoproteins in which selenocysteine is
acid hydroperoxides, cumene hydro-
present as the selenium moiety. In
peroxide,
eukaryotes at least 25 selenoproteins
cholesterol hydroperoxides and hydrogen
have been identified, and important
peroxide (Ursini et al., 1985). Although
antioxidant selenoproteins, GPx, TrxR
pGPx and GI-GPx reduce hydrogen
and Selenoprotein P (SelP) are discussed
peroxide and organic hydroperoxides,
in the following sections.
these are less active than the cGPx. The
chain
are
defined
tert-butyl
hydroperoxide,
four GPx isoforms require selenium in
Gpx
form of selenocysteine in the active sites
The most important and well-studied
of GPx enzyme and are directly involved
selenoprotein in eukaryotes is GPx. It is
in catalytic reactions.
Biomed Res J 2016;3(1):52–72
59
Priyadarsini et al.
TRxR1 and TRxR2 suggest that deletion
TRxR
important
of these enzymes cannot be compensated
selenoprotein, known for its role in DNA
by any other selenoproteins (Horstkotte
synthesis and protecting cells from
et al., 2011; Jakupoglu et al., 2005).
Human
TRxR
is
an
oxidative stress (Arner, 2010). It is the
only enzyme that catalyses the reduction
SelP
of oxidized thioredoxin (TRx) using
SelP is a plasma protein, which contains
NADPH
ten
as
a
source
of
reducing
selenocysteine
residues
per
equivalents. Trx is a ubiquitously present
polypeptide chain (Burk and Hill, 2005)
redox-active
major
accounting more than 50% of the
reducing
selenium content present in mammalian
function
peptide,
is
to
whose
supply
as
plasma. The physiological roles of SelP
ribonucleotide reductase involved in
is not completely understood, however
nucleotide
its
equivalents
to
enzymes
synthesis
such
(Nordberg
and
function
as
an
extracellular
Arner, 2001). During the process, TRx is
antioxidant seems most probable. The
oxidized and therefore needs to be
protective role of SelP in human plasma
reduced by TRxR. In addition to TRx,
against
several other endogenous compounds
phospholipid
such as lipoic acid, lipid hydroperoxides,
activity are well documented in literature
cytotoxic peptide NK-lysin, vitamin K,
(Rock and Moss, 2010). Some studies
dehydroascorbic
free
suggest a probable role of SelP in
radical and tumour-suppressor protein
intracellular transport and storage of
p53 have been reported as the substrate
selenium (Renko et al., 2008). Although,
for TRxR. In mammals, two isoforms of
SelP has been shown to be expressed in
TRxR namely TRxR1 and TRxR2 have
various tissues, the plasma level of SelP
been reported. The TRxR1 is localized in
is mainly contributed by liver (Renko et
the
al., 2008).
cytoplasm,
acid,
ascorbyl
whereas
TRxR2
is
localized in the mitochondria. Both
the
peroxynitrite
hydroperoxide
and
its
reducing
Apart from selenoproteins some low-
possess
molecular weight selenium compounds,
selenocysteine at the C-terminal end,
such as methylselenic acid, methyl-
which is required for the catalytic
selenol,
activities. The knockout mice model of
selenomethionine synthesized in the
TRxR1
and
TRxR2
methylselenocysteine,
and
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
60
body
as
byproduct
of
metabolism
also
physiological
functions
selenium
contribute
to
similarity of some of viral proteins with
mammalian
GPx
(Ramanathan
and
the
Taylor, 1997; Taylor et al., 1997). The
antioxidant mechanisms (Fairweather-
high versus low selenium content within
Tait et al., 2011)..
cells acts as a signal for HIV viruses to
through
differentiate between a healthy and a
Selenium and Viral Diseases
dying cell (Taylor et al., 1997). During
Selenium deficiency has been linked with
selenium deficiency, the ROS generation
the progression of several viral diseases
within the host cells is increased leading
like Human immunodeficiency virus
to oxidative stress, signaling HIV viruses
(HIV) and Coxsackie virus (Fairweather-
to replicate and leave the dying cell to
Tait et al., 2011; Rayman, 2012). Recent
infect another healthy cell (Taylor et al.,
outbreak of Ebola virus in West Africa
1997; 2016). The supplementation of
has also been linked with selenium
selenium in AIDS patients induces
deficiency (Abd-ElMoemen et al., 2015).
expression of host as well as viral
Epidemio-logical
selenoprotein.
studies
linked
the
These
seleno-proteins
outbreak of life threatening viral diseases
protect the host cells from oxidative
like AIDS and hemorrhagic fever caused
stress leading to inhibition of viral
by HIV and Ebola viruses with selenium
replication and spread of infection
deficiency.
that
(Taylor et al., 1997; 2016). Since the
retroviruses may incorporate selenium of
viral replication is inhibited, the chance
the host cells into viral proteins or “viral
of viral genome to undergo mutation and
selenoprotein theory” has emerged in the
to
last decade. Till date there is no absolute
resistance is also reduced. In contrast to
direct proof that a virus can make a
HIV, Ebola viruses have been postulated
selenoprotein. However, computational
to
analysis
selenocysteine
However
have
the
not
only
idea
confirmed
acquire
contain
characteristics
genes
of
drug
with
several
insertion
sites
presence of several of UGA codons along
(Ramanathan and Taylor, 1997; Taylor et
with
insertion
al., 2016). Therefore, the growth of
sequence in the genome of HIV and
Ebola virus in the host cells is expected
Ebola
to
the
virus,
selenocysteine
but
also
Biomed Res J 2016;3(1):52–72
established
compete
with
the
host
for
61
Priyadarsini et al.
incorporation
of
selenoprotein.
This
condition
called
selenium
may
in
peroxide and hydroperoxides and also
a
reacts with peroxynitrite. It inhibits
selenium
enzymes such as lipoxygenases, NO
cause
“induced
deficiency” in the host cell and can
synthases,
contribute
clotting
kinase C and H+/K+-ATPase. Ebselen
characteristics of hemorrhagic fever. The
exhibits anti-inflammatory and anti-
above assumption is justified considering
oxidant properties and protects against
that the biochemical basis for an anti-
oxidative challenge, which has been
clotting effect of selenium is well
demonstrated in a variety of in vivo
established. Clinical data supporting the
models (Schewe, 1995). It is a modest
use of selenium for treatment of Ebola-
immunostimulant and induces several
like hemorrhagic fever, demonstrated the
interleukins including IL-1, IL-6, IL-10
remarkable
study,
and IL-18. Ebselen is less toxic than
administration of a very high oral dose of
many other compounds, as metabolism
2 mg selenium per day as sodium
produces compounds in which selenium
selenite, for 9 days reduced the death rate
is retained within the ring structure.
from 100% (untreated) to 37% (treated)
Ebselen
in very severe cases, and from 22% to
permeability
zero in the less severe cases (Hou et al.,
following oral administration (Singh et
1993).
al.,
to
the
results.
blood
In
the
NADPH
oxidase,
demonstrates
and
2013).
A
blood-brain
rapid
variety
protein
absorption
of
studies
demonstrated that ebselen attenuates
Ebselen,
an
Important
Synthetic
neuronal
cell
death
induced
by
Selenium Antioxidant
ischemia/reperfusion. It has been shown
Ebselen, 2-phenyl-1,2-benzisoselenazol-
to be a safer alternative for lithium, for
3(2H)-one (PZ 51, DR3305), is an
treatment of bipolar disorder. It shows
organoselenium
antidiabetic
compound
(Fig.
1),
properties
and
prevents
extensively studied and considered as a
associated heart complications in diabetic
standard synthetic selenium antioxidant
rats (Saad et al., 2006).
(Azad and Tomar, 2014; Muller et al.,
Experimental studies in rats and dogs
1984). It exhibits promising GPx like
revealed
activity
vasospasm and tissue damage in stroke
by
scavenging
hydrogen
that
ebselen
inhibits
both
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
62
models,
which
the
table, selenium compounds both in
inhibitory effects on oxidative processes.
inorganic and organic forms have been
Results
placebo
tested for radioprotection. It has been
controlled, double blind clinical studies
reported that radiotherapy significantly
on the neurological consequences of
reduces selenium levels (Eroglu et al.,
acute ischaemic stroke patients treated
2012). Sodium selenite was the first
with ebselen showed encouraging results.
selenium
Safety and tolerability were good and no
radioprotection
adverse effects were observed. High
administered
concentrations of ebselen caused cellular
(–24 h and –1 h) or shortly after (+15
toxicity (Singh et al., 2013).
min) irradiation, it increased the thirty-
from
correlates
randomised,
with
compound
tested
in
for
mice.
intraperitoneally
When
before
day survival of mice irradiated at a lethal
Selenium in Radiotherapy
dose of 9 Gy (Weiss et al., 1992).
Radiotherapy is one of the common
Selenite
treatment modalities for cancer. The
administered
approach of radiation therapy is to
vitamin
minimize radiation damage to normal
prevented radiation induced reduction in
tissue,
radiation
levels of antioxidant enzymes in mice
exposure to tumor tissue (Weiss et al.,
model. In these models, sodium selenite
1992). However in practice, normal
supplementation increased the activity of
tissue damage occurs during radiation
serum GPx and reduced the therapy
therapy and therefore it is necessary to
induced oxidative stress. Selenite has
protect normal tissue with the help of
also
external
are
radioprotection in normal fibroblast cells,
therefore developed and even after
but not in head and neck carcinoma cells.
several years of research, the only
Effect of selenite supplementation in
clinically acceptable radioprotector till
cancer patients undergoing radiotherapy
date is amifostine, an aminothiol, with
for gastrointestinal, breast, lung, larynx,
the active group of RSH (Andreassen et
head and neck, non-Hodgkin lymphoma,
al., 2008). Since selenium belongs to the
brain,
same group as sulphur in the periodic
cancers was studied (Lippman et al.,
while
agents.
maximising
Radioprotectors
Biomed Res J 2016;3(1):52–72
was
E
been
also
in
before
effective
when
combination
with
γ-irradiation
reported
prostrate
and
to
and
exhibit
gynaecological
63
Priyadarsini et al.
2009; Klein et al., 2011). Sodium selenite
former exhibiting better activity. Ebselen
was administered orally in the dose range
has also been tested for radioprotection
of 200–500 μg daily or 1000 μg daily by
in mice. The results indicated that
infusion. Based on the results from 16
ebselen administration for 14 days at a
clinical trials, it was concluded that
daily dosage of 10 mg/kg body weight
selenium supplementation improved the
before whole body irradiation at 8 Gy
general condition of the patients and at
provided substantial protection (60%)
the doses employed, selenium toxicity
against mortality and oxidative damage
was not observed, and did not decrease
(Tak and Park, 2009). Thus results
effectiveness of radiotherapy (Puspitasari
reported
et al., 2014).
support that selenium compounds have a
A few organoselenium compounds
potential
from
as
various
laboratories
radioprotectors.
Since
like selenourea, selenocysteine, seleno-
selenium in organic form exhibits lower
xanthene, and selenomethionine, have
toxicity,
also been examined for radioprotection
extensive research on modulation of
using in vitro and in vivo models.
radiation
However these agents did not show
organoselenium compounds is required.
promising
activity,
in
induced
inorganic
changes
by
form,
new
seleno-
Our group has also contributed in this
significantly
research area. After evaluating a number
increased the 30-day survival of mice
of in-house synthesized organoselenium
irradiated at lethal doses of 9 and 10 Gy
compounds like selenoethers, diselenides
(Weiss et al., 1992). It was equally
and cyclic selnolanes, 3′-3′ diseleno-
protective when administered at 24 h, 1 h
dipropionic acid (DSePA (Fig. 1) was
and 15 min prior to γ-irradiation.
identified as a lead radioprotector. It is a
However, when selenomethionine was
water soluble derivative of seleno-
provided in the diet as selenous yeast
cysteine, synthesized in our laboratory. It
protection against acute or chronic
was shown as an effective free radical
radiation exposure was not observed.
scavenger,
Both
selenomethionine
mimic (Kunwar et al., 2007). The
showed remarkable chemo-preventive
compound was also nontoxic in normal
activities in human clinical trials, the
cells
methionine,
selenite
which
and
except
than
and
anti-hemolytic
maximum
and
tolerable
GPx
dose
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
64
Figure 2: Potential biological activities of DSePA.
(MTD) in mice was estimated as ~88
evaluation is a prerequisite for any
mg/kg body weight for intraperitoneal
compound to be proposed for clinical
mode of administration (Kunwar et al.,
application, DSePA was investigated in
2010). The radio-protective ability of
detail for the same in Chinese Hamster
DSePA was evaluated in BALB/c mice,
Ovary cells. The results of this study
wherein the administration of DSePA (2
indicated that DSePA treatment on its
mg/kg/day for 5 consecutive days) prior
own
to whole body irradiation (10 Gy) led to
prevented radiation induced genotoxicity
35% increase in the number of mice
and subsequent cytotoxicity in model
surviving up to 30 days. Our results
cellular systems (Chaurasia et al., 2014).
demonstrated
DSePA
DSePA
treatment
to
did
not
also
induce
toxicity,
protected
against
but
the
prevent oxidative damage (such as lipid
depletion of endogenous antioxidants in
peroxidation
hepatic tissue of irradiated mice. In line
and
DNA
damage),
apoptosis and inflammatory response in
with
radiosensitive organs like hematopoietic
improved the 30-day survival of the
and gastrointestinal system (Kunwar et
irradiated mice by 35%.
al., 2010; 2011). Since toxicological
Biomed Res J 2016;3(1):52–72
Late
these
lung
observations,
tissue
DSePA
responses
like
65
Priyadarsini et al.
pneumonitis and fibrosis are the serious
Pro-oxidant Effects of Selenium and
dose-limiting side effects of thoracic
Use in Cancer Therapy
radiotherapy
Similar
used
in
several
to
several
trace
elements,
malignancies affecting organs in the
selenium also plays a dual role. It is an
thorax
the
antioxidant at low concentrations (< 200
we
µg/per day) and acts as a pro-oxidant at
showed that administration of DSePA
higher concentrations (> 200 µg/per day)
during the post irradiation period at a
(Fairweather-Tait et al., 2011; Lee and
similar dosage (2 mg/kg/three days in a
Jeong, 2012). The antioxidant function is
week) delayed the thoracic radiation (18
mainly through selenoproteins, which
Gy) induced pneumonitis response in
maintain
C3H/HeJ mice (Kunwar et al., 2013).
homeostasis and thereby preserve the
The
had
normal physiological processes in the
significantly reduced levels of lipid
cell; while at high concentrations, it
peroxidation
cell
becomes a source of ROS. The pro-
influx in the lungs and increased GPx,
oxidant behaviour at high concentration
compared
only
suggested selenium as a probable anti-
pharmacokinetic
cancer drug. Several researchers studied
area.
preliminary
results
DSePA
irradiation.
Encouraged
treated
and
to
on
DSePA,
mice
inflammatory
mice
Further
by
receiving
the
anticancer
intracellular
studies of orally administered DSePA in
the
different organ systems of tumor bearing
compounds. The pro-oxidant effect of
mice showed maximum bioavailability of
selenium was correlated with well-
DSePA in lungs followed by kidney, liver
established
and intestine; while, that in the tumors
cytotoxic
was significantly low (Gota et al., 2015).
proteins like AP-1, NF-kB, P53 and
Hence, the preclinical investigations are
protein kinase C under in vivo conditions
extended to develop DSePA as oral
(Brozmanová et al., 2010; McKenzie et
supplemented lung radioprotector for
al.,
thoracic radiotherapy. The studies related
pronounced in malignant cells than
to DSePA are summarized in Fig. 2.
normal
growth
activities
2002).
candidates
effects
The
cells,
for
of
redox
selenium
inhibiting
through
effects
cellular
are
indicating
anticancer
and
more
potential
agents
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
66
(Fernandes and Gandin, 2015; Orian and
combination with other chemotherapy
Toppo, 2014).
drugs, or as a remedy for chemotherapy
Both inorganic and organic selenium
compounds have been evaluated for
anticancer
showed
activity.
Sodium
Organic selenium compounds have
been examined for anticancer activity
micromolar concentrations in a variety of
(Fernandes and Gandin, 2015). These
cancers cells from different organs such
include selenomethionine, methylseleno-
as lung, prostrate, cervix, ovary and
cysteine,
(Brozmanová
cytotoxicity
2015).
in
colon
significant
selenite
toxicity (Micke et al., 2009; Misra et al.,
et
al.,
selenoglutathione,
seleno-
2010;
cysteine, aromatic selnides, quinozoline
Fairweather-Tait et al., 2011). It was also
derivatives, diphenyl diselenide, ebselen,
effective against drug resistant cells and
etc. However most of the studies were
enhanced efficacy of other cancer drugs
limited to in vitro studies and examined
like
and
in different cancer cell lines. Several of
irinotican in in vivo models. However
them showed encouraging results but a
there were some reports indicating
lot more studies under in vivo conditions
genotoxicity of selenite (Nogueira and
are necessary to explore their ability
Rocha, 2011). A recent clinical study in
against cancer. Selenocysteine is the only
34 cancer patients was reported. The
compound which has been extensively
patients received first line chemotherapy,
studied and evaluated. It is a diselenide
followed by selenite treatment daily for
of the amino acid, selnocysteine (Chen
five days over two or four weeks. The
and Wang, 2008). It has been shown to
results concluded that sodium selenite is
be effective against human melanoma,
safe and tolerable when administered up
cervical and lung cancer cells. It also
5-fluorouracil,
oxaliplatin
2
to 10.2 mg/m , no major systemic
showed selectivity between cancer and
toxicity was reported and the most
normal
common adverse effects were fatigue,
selenocystiene potentiated the efficacy of
nausea, and cramps in fingers. The study
5-fluorouracil
indicated that the drug was an effective
However, it has limitation due to low
chemotherapeutic agent which works in
water solubility and instability.
three ways, either by itself, or in
Biomed Res J 2016;3(1):52–72
cells,
in
(Fan
melanoma
et
al.,
cells,
2013).
It is also interesting to note that
67
Priyadarsini et al.
DSePA (Kunwar et al., 2010) which
where oxidative stress plays an important
shows
in
role. Selenium exerts its effects through
normal cells can also be used in chemo-
modulation of redox regulating seleno-
sensitization of melanoma cancer cells
proteins. Many selenium compounds,
(Cao
significant
et
al.,
radioprotection
2014).
Combinatorial
both inorganic and organic forms, show
treatment of DSePA with tumor necrosis
excellent antioxidant effects, and several
factor related apoptosis inducing ligand
exhibiting promising effects as radio-
(TRAIL), a promising targeted cancer
protectors. Excessive selenium leads to
drug, not only enhanced the apoptotic
toxicity, a property to be considered for
inducing efficacy of TRAIL but also
design of new selenium based anticancer
overcame resistance of melanoma cells.
drugs. With increasing understanding of
The ability of DSePA to chemo-sensitize
the chemistry and biology of selenium, it
melanoma
is feasible that new selenium compounds
cells
was
through
the
induction of ROS, DNA damage and P53
may be used as therapeutic agents.
activation. The fact that DSePA shows
antioxidant activity in normal cells and
ACKNOWLEDGEMENTS
pro-oxidant activity in tumor cells,
The authors wish to express sincere
makes it an ideal candidate for future
thanks to Department of Atomic Energy,
evaluation as a cancer adjuvant drug.
Government of India and acknowledge
the contributions of many co-authors and
CONCLUSIONS
students whose names appeared in the
Selenium, an element considered to be
publications listed from our group.
highly toxic, is now considered as an
essential nutrient. Selenium deficiency
CONFLICT OF INTEREST
has been linked with several diseases
The authors claim no conflict of interest.
REFERENCES
Abd-ElMoemen A, Menshawy A, Negida A, El-
Chemical radioprotection: A critical review of
Din MA, Kamel A, Farouk AE. Ebola
amifostine as a cytoprotector in radiotherapy.
Outbreak in west Africa: Is selenium
Semin Radiat Oncol 2008;13:62–72.
involved. Int J Pept Res Ther 2015;22(1):
135–141.
Andreassen CN, Grau, C, Lindegaard, JC.
Arnér ESJ. Selenoproteins – What unique
properties can arise with selenocysteine in
place of cysteine? Exp Cell Res 2010;316:
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
68
1296–1303.
Cyto-genotoxicity assessment of potential
Azad GK, Tomar RS. Ebselen, a promising
radioprotector, 3,3′-diselenodipropionic acid
antixodiant drug: mechanism of action and
(DSePA) in Chinese Hamster Ovary (CHO)
targets of biological pathways. Mol Biol Rep
cells
2014;41:4865–4879.
lymphocytes. Mutat Res 2014;774:8–16.
and
human
peripheral
blood
Battin EE, Brumaghim JL. Antioxidant activity of
Chen T, Wong YS. Selenocysteine induces
sulphur and selenium: A review of reactive
apoptosis of A375 human melanoma cells by
oxygen
activating
species
scavenging,
glutathione
ROS-mediated
mitochondrial
peroxidae and metal binding antioxidant
pathway and p53 phosphorylation. Cell Mol
mechanisms. Cell Biochem Biophys 2009;55:
Life Sci 2008;65:2763–2775.
1–23.
Behne
Chen X, Yang G, Chen J, Chen X, Wen Z, Ge K.
D,
Kyriakopoulos
A.
Mammalian
Studies on the relations of selenium and
selenium-containing proteins. Annu Rev Nutr
Keshan disease. Biol Trace Elem Res 1980;2:
2001;21:453–473.
91–107
Bhabhak KP, Mugesh G. Functional mimics of
Cunha RLOR, Gouvea I, Juliano L. A glimpse on
glutathione peroxidase: bioinspired synthetic
biological activities of tellurium compounds,
antioxidants. Acc Chem Res 2010;43:1408–
Annals Brazilian Acad Sci 2009;81:393–407.
1419
Dauplais M, Lazard M, Blanquet S, Plateau P,
Brigelius-Flohé R, Maiorino M, Glutathione
Neutralization by Metal Ions of the Toxicity
peroxidases. Biochim Biophys Acta 2013;
of Sodium Selenide. PLoS ONE 2013;8:
1830:3289–3303.
e54353.
Brozmanová
J,
Mániková
D, Vlčková V,
Dhillon
KS,
Dhillon
SK,
Distribution
of
Chovanec M. Selenium: a double-edged
seleniferous sois in north-west India and
sword for defense and offence in cancer. Arch
associated toxicity problems in the soil-plant-
Toxicol 2010;84(12):919–938.
animal-human
Burk
RF,
Hill
KE.
Selenoprotein
P:
an
extracellular protein with unique physical
characteristics
and
a
role
in
selenium
continuum.
Land
Contam
Reclam 1997;5:313–323.
Eroglu C, Unal D, Cetin A, Orhan O, Sivgin S,
Oztürk A. Effect of serum selenium levels on
homeostasis. Annu Rev Nutr 2005;25:215–
radiotherapy-related
235.
undergoing radiotherapy for head and neck
Cao W, Li X, Zheng S, Zheng W, Wong YS, Chen
T
Selenocysteine
TRAIL
resistance
derivative
in
overcomes
melanoma
toxicity
in
patients
cancer. Anticancer Res 2012;32:3587–3590.
Fairweather-Tait SJ, Bao Y, Broadley MR,
cells:
Collings R, Ford D, Hesketh JE, Hurst R.
evidence for ROS-dependent synergism and
Selenium in human health and disease. Antiox
signaling crosstalk. Oncotarget 2014;5(17):
Redox Signal 2011;14(7):1337–1383.
7431–7445.
Chaurasia RK, Balakrishnan S, Kunwar A, et al.,
Biomed Res J 2016;3(1):52–72
Fan C, Chen J, Wang Y, Wong YS, Zhang Y,
Zheng W, Cao W, et al. Selenocysteine
69
Priyadarsini et al.
potentiates cancer cell apoptosis induced by
and Biological Chemistry. Curr Chem Biol
5-fluorouracil by triggering reactive oxygen
2013;7:2–24.
species-mediated
DNA
damage
and
Jacob C, Giles GI, Giles NM, Sies H, Sulfur and
inactivation of the ERK pathway. Free Radic
selenium: the role of oxidation state in protein
Biol Med 2013;65:305– 316.
structure and function. Angew Chem 2003;42:
Fernandes AP, Gandin V. Selenium compounds as
therapeutic agents in cancer. Biochim Biophys
Acta 2015;1850:1642–1660
García-Sevillano
MA,
4742–4758.
Jacques-Silva MC, Nogueira CW, Broch LC,
Flores EM, Rocha JB. Diphenyl diselenide
G,
and ascorbic acid changes deposition of
García-Barrera T, Navarro F, Gómez-Ariza
selenium and ascorbic acid in liver and brain
JL. Biological interactions between mercury
of mice. Pharmacol Toxicol 2001;88(3):
and
119–125.
selenium
detoxification
Rodríguez-Moro
in
distribution
processes
in
and
mice
under
Jakupoglu C, Przemeck GK, Schneider M,
controlled exposure. Effects on selenoprotein.
Moreno SG, Mayr N, Hatzopoulos AK, et al.,
Chem Biol Interact 2015;229:82–90.
Cytoplasmic thioredoxin reductase is essential
Gota V, Goda JS, Doshi K, Patil A, Sunderajan S,
Kumar
K,
et
al.,
Biodistribution
and
pharmacokinetic study of 3,3' Diseleno
dipropionic
acid
(DSePA),
a
for embryogenesis but dispensable for cardiac
development. Mol Cell Biol 2005;25(5):1980–
1988.
synthetic
Jamier V, Ba LA, Jacob C. Selenium and
radioprotector, in mice. Eur J Drug Metab
tellurium containing multifunctional redox
Pharmacokinet 2015;Epub ahead of print.
agents as biochemical redox modulators and
Guo S, Wharton W, Moseley P, Shi H, Heat shock
selective toxicity. Chem Eur J 2010;16:
protein 70 regulates cellular redox status by
modulating
glutathione-related
enzyme
10920–10928
Kitahara
J,
Seko
Y,
Imura
N.
Possible
activities. Cell Stress Chaperones 2007;12:
involvement of active oxygen species in
245–254.
selenite toxicity in isolated rat hepatocytes.
Horstkotte J, Perisic T, Schneider M, Lange P,
Arch Toxicol 1993; 67(7):497–501.
Schroeder M, Kiermayer C. Mitochondrial
Klein EA1, Thompson IM Jr, Tangen CM,
thioredoxin reductase is essential for early
Crowley JJ, Lucia MS, Goodman PJ, et al.
postischemic
Vitamin E and the risk of prostate cancer: the
myocardial
protection.
Circulation 2011;124:2892–2902.
Hou JC, Jiang ZY, He ZF. Inhibitory effect of
selenium on complement activation and its
clinical significance. Zhonghua Yi Xue Za Zhi
1993;73:645–646, 699.
Iwaoka M, Arai K. From Sulfur to Selenium. A
New Research Arena in Chemical Biology
Selenium and Vitamin E Cancer Prevention
Trial (SELECT). J Am Med Assoc 2011;306:
1549–1556.
Kunwar A, Bag PP, Chattopadhyay S, Jain VK,
Priyadarsini
inflammatory
KI.
and
Anti-apoptotic,
anti-
immunomodulatory
activities of 3,3'-diselenodipropionic acid in
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
70
mice exposed to whole body γ-radiation. Arch
Toxicol 2011; 85:1395–1405.
Misra S, Boylan M, Selvam A, Spallholz JE,
Bjornstedt
M.
Redox
active
selenium
Kunwar A, Bansal P, Kumar SJ, Bag PP, Paul P,
compounds- From toxicity and cell death to
Reddy ND, et al., In vivo radioprotection
cancer treatment. Nutrients 2015;7:3536–
studies
3556.
of
3,3'-Diselenodipropionic
acid
(DSePA), a selenocysteine derivative. Free
Radic Biol Med 2010;48:399–410.
Kunwar A, Jain VK, Priyadarsini KI, Haston CK.
A selenocysteine derivative therapy delays
and reduces radiation-induced neutrophilia
Mugesh G, du Mont WW, Sies H. Chemistry of
biologically
important
synthetic
organo-
selenium compounds. Chem Rev 2001;101:
2125–2180.
Mukherjee AJ, Zade SS, Singh HB, Sunoj RB.
and pneumonitis in the mouse. Am J Respir
Organoselenium
Cell Mol Biol 2013;49:654–661.
intramolecular interactions. Chem Rev 2010;
Kunwar A, Mishra B, Barik A, Kumbhare LB,
chemistry:
role
of
110:4537–4416.
Pandey R, Jain VK, Priyadarsini KI. 3,3'-
Muller A , Cadenas E, Graf P, Sies H. A novel
Diselenodipropionic acid, an efficient peroxyl
biologically active seleno-organic compound
radical scavenger and a GPx mimic, protects
as glutathione peroxidase mimic. Glutathione
erythrocytes from AAPH induced haemolysis.
peroxidase like activity of ebselen. Biochem
Chem Res Toxicol 2007;20:1482–1487.
Pharmacol 1984;33(20):3235–3239.
Lee KH, Jeong D, Biomedical actions of
Nagy G, Benko I, Kiraly G, Voros O, Tanczos B,
selenium essential for antioxidant and toxic
Sztrik A, et al. Cellular and nephrotoxicity of
pro-oxidant activities: The selenium paradox
selenium species. J Trace Elem Med Biol
(review). Mol Med Reports 2012; 5: 299–304.
2015; 30:160–170.
Lippman SM, Klein EA, Goodman PJ, Lucia MS,
Nelson AA, Fitzhugh OG, Calvery HO. Liver
Thompson IM, Ford LG et al., Effect of
tumors
selenium and vitamin E on risk of prostrate
selenium in rats. Cancer Res 1943;3:230–236.
cancer and other cancers: the selenium and
Nogueira CW, Rocha JT. Toxicology and
vitamin E cancer prevention trial (SELECT).
pharmacology of selenium: emphasis on
J Am Med Assoc 2009; 301: 39–50.
synthetic organoselenium compounds. Arch
McKenzie RC, Arthur JR, Beckett GJ. Selenium
following
cirrhosis
caused
by
Toxicol 2011;85:1313–1359.
and the regulation of cell signaling, growth,
Nogueira CW, Zeni G, Rocha JB. Organo-
and survival: molecular and mechanistic
selenium and organotellurium compounds:
aspects. Antiox Redox Signal 2002;4(2):339–
toxicology and pharmacology, Chem Rev
351.
2004;104:6255– 6285.
Micke O, Schomburg L, Buentzel J, Kisters K,
Nordberg J, Arnér ES. Reactive oxygen species,
Muecke R. Selenium in oncology: from
antioxidants, and the mammalian thioredoxin
chemistry to clinics. Molecules 2009;14:
system. Free Radic Biol Med 2001;31:1287–
3975–3988.
312.
Biomed Res J 2016;3(1):52–72
71
Priyadarsini et al.
Orian L, Toppo S. Organochalcogen peroxidise
Rock C, Moos PJ. Selenoprotein P protects cells
mimetics as potential drugs: a long story of
from lipid hydroperoxides generated by 15-
promise still unfulfilled. Free Radic Biol Med
LOX-1. Prostaglandins Leukot Essent Fatty
2014;66:65–74.
Acids 2010;83(4–6):203–210.
Painter FP. The chemistry and toxicity of
Saad SY, Najjar TA, Arafah MM. Cardio-
selenium compounds, with special reference
protective effects of subcutaneous ebselen
to the selenium problem. Chem Rev 1941;
against
28(2):179– 213.
myopathy in rats. Basic Clin Pharmacol
Papp L V, Lu J, Holmgren A, Khanna KK. From
daunorubicin-induced
cardio-
Toxicol 2006;99:412– 417.
selenium to selenoproteins: synthesis, identity,
Schewe T. Molecular actions of ebselen – an anti-
and their role in human health. Antioxid
inflammatory antioxidant. Gen Pharmacol
Redox Signal 2007;9(7):775–806.
1995;26(6):1153–1169.
Priyadarsini KI, Singh BG, Kunwar A. Current
Schwarz K, Foltz CM Selenium as an integral
developments on synthesis, redox reactions
part of factor 3 against dietary necrotic liver
and
degeneration, J Am Chem Soc 1957;79:3292–
biochemical
studies
of
selenium
antioxidants. Curr Chem Biol 2013;7:37–46.
3293.
Puspitasari IM, Abdulah R, Yamazaki C, Kameo
Singh N, Halliday AC, Thomas JM, Kuznetsova
S, Nakano T, Koyama H. Updates on clinical
OV, Baldwin R, Woon EC. A safe lithium
studies
mimetic for bipolar disorder. Nat Commun
of
selenium
supplementation
in
radiotherapy. Radiat Oncol 2014;9(125):1–9.
Rahmanto AS, Davies MJ. Selenium-containing
Amino
Acids
as
Direct
and
2013;4:1332.
Spallholz JE. Selenium and the Prevention of
Indirect
Cancer. Part 1I - Mechanism for the
Antioxidants. IUBMB Life 2012;64(11):863–
Carcinostatic Activity of Se Compounds. Bull
871.
Selenium Tellurium Dev Assoc 2001;1–12.
Ramanathan CS, Taylor EW. Computational
genomic
analysis
of
hemorrhagic
fever
viruses. Viral selenoproteins as potential
factor in pathogenesis. Biol Trace Elem Res
1997;56:93–106.
Rayman MP. Selenium and human health. Lancet
2012;379:1256–1268.
Spallholz JE. On the nature of selenium toxicity
and carcinostatic activity. Free Radic Biol
Med 1994;17(1):45–64.
Tak JK, Park JW. The use of ebselen for
radioprotection in cultured cells and mice.
Free Radic Biol Med 2009;46(8):1177–1185.
Tapiero H, Townsend DM, Tew KD. The
Renko K, Werner M, Renner-Müller I, Cooper
antioxidant role of selenium and seleno-
TG, Yeung CH, Hollenbach B, et al. Hepatic
compounds. Biomed Pharmacother 2003;57:
selenoprotein P (SePP) expression restores
134–144.
selenium transport and prevents infertility and
Taylor EW, Bhat A, Nadimpalli RG, Zhang W,
motor-incoordination in Sepp-knockout mice.
Kececioglu J. HIV-1 encodes a sequence
Biochem J 2008;409(3):741–749.
overlapping env gp41 with highly significant
Biomed Res J 2016;3(1):52–72
Selenium: Toxicology and radioprotection
72
similarity to selenium-dependent glutathione
disease. Chem Soc Rev 2013;42:8870–8897.
peroxidases. J Acq Immune Defic Syndr Hum
Weiss JF, Srinivasan V, Kumar KS, Landauer
Retrovirol 1997;15(5):393–394.
MR. Radioprotection by metals: selenium.
Taylor EW, Ruzicka JA, Premadasa L, Zhao L.
Adv Space Res 1992;12:223–231.
Cellular Selenoprotein mRNA Tethering via
Wessjohann LA, Schneider A, Abbas M, Brandt
Antisense Interactions with Ebola and HIV-1
W. Selenium in chemistry and biochemistry in
mRNAs
comparison to sulfur. Biol Chem 2007;388:
May
Impact
Host
Selenium
Biochemistry. Curr Top Med Chem 2016;
16(13):1530–1535.
Trachootam D, Lu W, Ogasawara MA, RiveraDel Valle N, Huang P. Redox regulation of
cell survival. Antioxid Redox Signal 2008;10:
1343–1374.
Ursini F, Maiorino M, Gregolin C. The
997–1006.
Whanger PD. Selenocompounds in plants and
animals and their biological significance. J
Am Coll Nutr 2002;21:223–232.
Wrobel JK, Power R. Toborek M. Biological
activity of selenium: Revisited. IUBMB Life
2016;68:97–105.
selenoenzyme phospholipid hydroperoxide
Yao Y, Pei F, Kang P. Selenium, iodine, and the
glutathione peroxidase. Biochim Biophys Acta
relation with Kashin-Beck disease. Nutrition
1985;839:62–70.
2011;27:1095–1100.
Weekley C.M, Harris HH. Which form is that?
Zwolak I, Zaporowska H. Selenium interactions
The importance of selenium speciation and
and toxicity: A review. Cell Biol Toxicol 2012;
metabolism in the prevention and treatment of
28:31–46.
Biomed Res J 2016;3(1):52–72