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Selenium biochemistry and its role for human health
Cite this: DOI: 10.1039/c3mt00185g
Marco Roman,a Petru Jitarub and Carlo Barbante*a
Despite its very low level in humans, selenium plays an important and unique role among the
(semi)metal trace essential elements because it is the only one for which incorporation into proteins is
genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five
selenoproteins have been identified so far in the human proteome. The biological functions of some of
them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox
state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the
selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and
several forms of cancer. Comprehension of the selenium biochemical pathways under normal
physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic
effect for human diseases. This review summarizes the most recent findings on the biochemistry of
active selenium species in humans, and addresses the latest evidence on the link between selenium
intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the
Received 1st July 2013,
Accepted 4th October 2013
interpretation of biochemical mechanisms rather than epidemiological/observational data. In this
DOI: 10.1039/c3mt00185g
aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all
context, the review includes the following sections: (1) brief introduction; (2) general nutritional
human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of
www.rsc.org/metallomics
human diseases.
1. Introduction
Selenium (Se) is an essential trace element having biological
functions of utmost importance for human health. Differently
from the other (semi)metals, it is incorporated into proteins by a
co-translational mechanism as part of the amino acid selenocysteine (SeCys), the 21st amino acid used for proteins synthesis
in humans. Twenty-five Se-proteins have been identified so far in
humans, whereas only few of them have been functionally
characterized.1,2 Most Se-proteins participate in antioxidant
defence and redox state regulation, particularly the families of
glutathione peroxidases (GPxs) and thioredoxin reductases
(TrxRs). Some Se-proteins play more specific essential roles, such
as iodothyronine deiodinases (DIOs) which are involved in
thyroid hormones metabolism, GPx4 which is essential for
spermatogenesis, and selenophosphate synthetases 2 (SPS2)
participating in Se-proteins biosynthesis. Other Se-proteins
may also be involved in important biological processes, but their
exact mechanism of action is still not fully understood.
a
Institute for the Dynamics of Environmental Processes (IDPA-CNR),
Dorsoduro 2137, 30123 Venice, Italy. E-mail: marco.roman@unive.it,
barbante@unive.it; Fax: +39 041 234 8584; Tel: +39 041 234 8942
b
HydrISE, Institut Polytechnique LaSalle Beauvais, 19 rue Pierre Waguet,
BP 30313 F-60026 Beauvais Cedex, France. E-mail: petru.jitaru@lasalle-beauvais.fr
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Despite the scarce knowledge of the precise biochemical
functions, a very large number of studies have been carried out
in the last two decades showing that insufficient Se levels, and
particularly Se-proteins, are associated with several human diseases including cancer, diabetes, cardiovascular and immune
system disorders.3 In most cases, the link lies in the contrast to
the oxidative stress that may be both causing or caused by the
disease. In this context, it is important to decipher whether an
adequate Se status may contrast the risk factors for health
disorders, or Se supplementation may improve the therapy when
Se metabolism is altered. Additional attention was recently driven
by the finding that Se-proteins’ genes polymorphism is associated
to cancers and other diseases.4 Cancer research is one of the most
promising lines, in which Se has been used experimentally as a
key component of newly designed anti-cancer drugs.5
Even if still incomplete, the broad literature supporting the
importance of selenium for human health has yielded great
interest in Se supplementation. Despite many studies that have
suggested a beneficial effect from Se supplementation to general health protection, most of them have remarked that it is
limited to the initially inadequate Se status.6 Conversely, care
should be taken when using supplements because excessive Se
intake leads to toxic effects, and recent studies have shown that
even sub-toxic doses may be negatively impacting, for example
by increasing the risk of type 2 diabetes.7
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Deepening the knowledge of Se biochemistry in humans, as
well as its integration at clinical and epidemiological levels, is
important to extricate the relationship between Se status and
the efficiency of biological systems. This is particularly challenging when taking into account that such a link is expected to be
species-specific and system-specific, so that a given Se status
may be optimal for some functions but not for others.
2. Nutritional aspects
The comprehensive characterization of Se nutritional features
is beyond the aim of this work. Nevertheless, some key aspects
are important in terms of their bio-medical applications,
Dr Marco Roman studied
Environmental Sciences at the
University Ca’ Foscari of Venice
(Italy) where he obtained a
Master’s Degree in 2007. In
2011, he received a PhD in
Chemical Sciences from the
University of Venice, working on
the development of methods
for speciation analysis of
selenoproteins based on ICP-MS
and hyphenated techniques.
Since 2011, he has worked as a
Marco Roman
postdoctoral fellow at the
Institute for the Dynamics of Environmental Processes of the
Italian Research Council (CNR-IDPA) in Venice (Italy). His
current research is mainly focused on the speciation analysis of
metal(loid)s in human tissues under pathological conditions.
Dr Petru Jitaru graduated from
the University ‘‘Al. I. Cuza’’ of
Iasi (Romania) in 1997. He
obtained his PhD in Chemistry
at the University of Antwerp
(Belgium) in 2004 with a thesis
on ultra-trace speciation analysis
of mercury in the environment. In
2006–2008 he was Marie Curie
Fellow at the Institute for the
Dynamics of Environmental Processes of the Italian Research
Council (CNR-IDPA) in Venice
Petru Jitaru
(Italy), working on metallomics
of selenium. Further, he was a researcher (2008–2010) at the
National Metrological Institute (LNE) in Paris (France). He is
currently working at the Polytechnic Institute LaSalle of Beauvais
(France) as Associate Professor of Analytical Chemistry. His
research interests concern GC, HPLC, ICP-MS and hyphenated
techniques applied to speciation and fractionation of trace
metal(loid)s in the environment and biological systems.
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because any study aiming at the elucidation of Se biochemistry
must be contextualized within the nutritional status of the
subject. The main challenges in Se nutrition are: (i) the accurate assessment of the Se dose taken in by the subjects under
investigation; (ii) establishing the appropriate markers for the
assessment of Se status; (iii) identification of the confounding
factors allowing the conversion of Se intake into Se status. Such
challenges outline a complex scenario, which often clashes with
the need for simplicity of communication with the general
public and administrations.
2.1.
Selenium in food
The main route for Se intake is via the diet, whereas the
contribution from water and air is negligible.6 The total
amount of Se in the diet varies widely depending on the food
type and composition. The major contributors to Se intake is
typically provided by bread and cereals, meat, fish, eggs, and
milk/dairy products. An estimation of Se levels in different
types of food was recently reviewed.6,8
The level of Se in crops is related to that in the soil; the
bioavailability is regulated by physicochemical conditions of
the soils such as the pH, redox conditions, salinity, organic
matter, etc.9 Crops are an important source of Se taking into
account their consumption on a global scale. Nevertheless, Se
in crops is generally of low abundance because such plants do
not require Se for growth, and hence do not accumulate it
under normal physiological conditions. A level ranging between
10–550 mg kg 1 of Se (fresh wt) was reported in cereals,10 whereas
Se in bread is generally found at a level of B60–160 mg kg 1.9
Other vegetables such as those of the Allium family, including
garlic and onion, can accumulate significant amounts of Se,
reaching concentrations of Se up to 68 and 96 mg g 1, respectively.11 High amounts of Se can be accumulated also by
Prof. Carlo Barbante is director of
the Institute for the Dynamics of
Environmental Processes of the
Italian Research Council (CNRIDPA) in Venice (Italy). He is
also Full Professor of Analytical
Chemistry at the University Ca’
Foscari of Venice, being in 2011
Deputy
Director
of
the
Department of Environmental
Sciences,
Informatics
and
Statistics. Since 2013 he has
been the Italian National
Carlo Barbante
Delegate for the Horizon 2020
Program, WP Climate Action, Environment, Resource Efficiency
and Raw Materials. His research addresses the development of
mass spectrometry-based analytical methodologies for ultra-trace
determination of metals and organic pollutants in environmental
and biological matrices.
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mushrooms and broccoli. The richest natural source of Se
are Brazil nuts, which have a mean concentration of Se up to
83 mg g 1.12
In animal products, the level of Se reflects the levels used in
cattle feed. In meat, eggs, and particularly fish, which are
protein-rich, the Se content is relatively high, in the range of
B49–739 mg kg 1 (fresh wt).9 Additionally, specific organs, such
as liver and kidney, may contain a particularly high concentration of Se, up to 1500 mg kg 1.9
A number of approaches can be used to estimate the dietary
intake of Se, ranging from direct analysis of composite food
types, to indirect calculation using dietary or market basket
surveys and food composition tables.13 Notably, since the total
concentration of Se in food strongly reflects the soil conditions,
the dietary intake varies widely with geographical localization.14
An additional crucial aspect is that food types provide Se
in distinct combinations of chemical forms which in turn
entail a different bioavailability of the element.15 The main
Se-species in vegetables are selenomethionine (SeMet) and
selenate/selenite (SeO42 , SeO32 ); minor species are SeCys,
Se-methyl-selenocysteine (SeMCys) and g-glutamyl-Se-methylselenocysteine (GGSeMCys).15 Selenate/ite, SeMet and SeCys
are the main species in animal products, with widely variable
proportions depending on the animals’ diet. The distribution
of Se species in food varies considerably depending on the
plant/animal species, the environment and the growth conditions (natural or supplemented).15 As is discussed in the
following sections, each species is characterized by specific
absorption/assimilation routes and efficiency, and hence the
speciation analysis of Se in food is a key requisite to accurately
depict the relationship between intake and health status, especially where supplementation is concerned.
2.2.
Assessment of Se nutritional status
Selenium is an essential element presenting a very narrow
range between deficient, essential and toxic doses.10 The
assessment of optimum Se dietary requirements is still a matter
of debate. Until few years ago, most of the studies focusing on
Se status assessment investigated only the total level of the
element in tissues or body fluids. Plasma or serum Se concentration was generally considered a useful biomarker of both Se
status and dietary intake in the short-term, whereas erythrocyte
Se reflects better the long-term status.16 Other tissues were also
used to measure long-term Se status, including hair and toenails. Daily urinary excretion closely associates with plasma Se
level and dietary intake accounting for a stable value of 50–60%
of the total amount excreted, and thus was also used as shortterm intake measure.
Recently, it has been pointed out that total Se concentration
is not representative of the real functional activity of Se, because
the element is incorporated in a large variety of proteins with
different biological functions.16 The distribution of Se among
Se-proteins is strongly dependent on a precise hierarchy in its
incorporation, the average dietary intake, the speciation of Se in
food, the health state, age, lifestyle (smoking and exercise), and
also by genetic polymorphism of Se-proteins.16 Thus, the measure
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of individual Se-proteins activity is expected to constitute a more
accurate biomarker for the functional status of Se. In this respect,
the most frequently used parameter nowadays for the assessment
of Se status is the activity of the plasma Se-protein glutathione
peroxidase (GPx3), compared to its maximum. The activity of
GPx3, as well as erythrocyte GPx1, are well correlated with the total
level of Se in blood until a maximum is reached at B100 ng mL 1,
corresponding to approximately 70 mg per day intake.16 Plasma
selenoprotein P (SelP) has also been proposed as a biomarker,
reaching maximum expression at a slightly higher blood Se level,
namely B124 ng mL 1 corresponding to B105 mg per day
intake.17 The concentration of SelP reflects mostly the short-term
status of Se in the organism because it has a half-life in plasma of
few hours (3–4 h in rat plasma).18 This makes it a better marker
than GPx3 for the assessment of the Se nutritional status. Nevertheless, once the basal Se requirement is reached, additional
increase of the element does not lead to an increase in GPx3 or
SelP concentration, therefore such Se biomarkers have limited
validity.19
Plasma/serum selenoproteins, namely SelP and GPx3 are the
most commonly used markers for the assessment of Se status
also because they can be determined with a scarcely invasive
procedure compared to tissue Se-proteins, which requires a
biopsy. It is worth highlighting that the choice of Se-protein to
be used as a biomarker must consider its specific biological
function, which therefore provides partial information in terms
of Se bioactivity. In fact, the most efficient biomarker is
expected to be not a single protein, but rather a set of combined
parameters, being applied to a specific problem associated with
suboptimal Se status; an example could be the expression of
Se-proteins mRNA circulating leukocyte.20 The integration of
these biomarkers with the comprehensive analysis of health
parameters, endocrine and immunological status, Se-proteins
polymorphism and other variables is considered nowadays as
the most promising approach.20
An alternative approach for Se status assessment is the
comparison of dietary Se intake with the specific end-point of
a disease. The basal Se requirement should be the intake
allowing the prevention of pathologically and clinically relevant
signs of dietary inadequacy. This was the approach used in case
of Keshan disease, an endemic disorder found in Se-deficient
areas.21 More recently, the evolution towards recognition of an
‘optimal nutrition’ has moved interest to the possible health
effects of Se in larger than minimum intakes, considering the
alternative end-points of the promotion of growth, maintenance of good health and reduction of other diseases not
caused by nutritional deficiencies.6 Nevertheless, the causal
association between Se-proteins and specific diseases is still far
from being clarified, and its inclusion in the estimation of the
recommended Se intake dose appears to be premature.
2.3.
Recommended daily intake levels
Several institutions have proposed reference values for the daily
recommended dietary allowance (RDA) for Se, taking into
account the most reliable epidemiological studies. An intake of
B20 mg per day for adults is generally accepted as the minimum
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needed to prevent Keshan disease onset.21 Considering the more
general prevention of pathologically and clinically relevant signs
of dietary inadequacy, the World Health Organization (WHO)
corrected this basal requirement to an average of 19 mg per day,
corresponding to 21 mg per day for men and 16 mg per day for
women, taking into account body weight.22 Other criteria were
based on GPx3 activity maximization for the calculation of the
recommended level; in this respect, the RDAs provided by the U.S.
Department of Agriculture are mostly adopted as a general
reference.23 Most of the recommended daily intake levels range
between 50 and 60 mg per day, with small variations between
genders and for particular categories (i.e. pregnancy) or age groups.
Providing upper limits for Se intake is difficult because there
are limited data regarding the Se toxicity for humans. So far,
acute toxic symptoms have been associated with extremely high
Se intakes ranging between 3200 and 6700 mg per day, but
symptoms such as fingernail changes have also been reported
for Se intakes of 1260 mg per day.24 Interestingly, some studies
did not report any observed adverse effect level (NOAEL) for an
intake o800 mg per day for adults, while others reported
selenosis in case of Se intakes Z850 mg per day.25 In this
context, the US Environmental Protection Agency has defined
an intake level of 1262 mg per day as the reference at which
clinical selenosis appears.
More difficult to estimate is the association between high
dietary Se intake and diseases which are not directly caused by
the element, such as cancer. For example, the Nutritional
Prevention of Cancer Trial found an increased risk of squamous cell carcinoma and total non-melanoma skin cancer in
individuals with a high basal risk supplemented with 200 mg per
day of Se,26 but there are still doubts about how this would relate
to risk for the general population. From a preventive perspective,
the National Health and Medical Research Council (NHMRC)
choose to apply to this latter estimate as a factor of 2 to protect
sensitive individuals from gaps in the data and incomplete
knowledge. The upper limit was therefore set at 400 mg per day
for all adults, as there are no data to suggest increased susceptibility during pregnancy and lactation.27
2.4.
Se supplementation
Because of the low abundance of soil Se in some areas around
the globe, a wide variety of Se-enriched materials have been
produced in order to supply the population with Se to meet the
levels adequate to the RDAs. Several strategies have been
followed to obtain such products. The use of fertilizers
enriched in sodium selenite is one of the most commonly used
techniques to obtain vegetables with high Se concentration, a
strategy which has been used in Finland since 1984.28 The use
of fertilizers supplemented with Se is very effective and is easily
controlled to favour accumulation by plants, and plant growth
itself is generally enhanced by this element; however, plant
growth may be reduced by feedback mechanisms when the Se
concentration is too high.28 Plants having the ability to accumulate high concentrations of Se such as broccoli,29 garlic,30
green onions,31 green tea32 and mushrooms,33 are particularly
adapt at obtaining natural dietary supplements following a
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fertilization strategy. As a consequence of Se fertilization, an
increase of Se levels in milk, meat, eggs and the whole food
chain has been observed.28 The total Se intake in Japan,
Australia, Finland, and the USA, as well as Keshan areas in
China has been significantly increased in the last decades by
the diffusion of Se-enriched fertilizers.9 However, Se speciation
in these fertilizing products plays a differential role which has
not yet been clearly elucidated.
The use of Se-enriched fertilizers has been effective, but Se is
partially lost during harvesting and manipulation prior to
uptake by the plants.10 An alternative is supplementation of
animal feed to become enriched in Se. This strategy includes: (i)
direct application of Se to pastures to increase Se uptake by
plants for animal feed; (ii) supply of sodium selenite or selenate
incorporated into salt blocks or licks; (iii) direct administration
of Se to animals by yeast-based supplements or by drenching
the feed with Se salt solutions such as sodium selenite; and (iv)
use of Se pellets that is slowly released into the gut of the
animal.9 Recently, a technological process to produce Se-enriched
eggs, meat and milk has been developed and successfully introduced in various countries worldwide.34 Nevertheless, detailed
investigations into the possible interactions with other nutrients
in Se-enriched food are still missing.
Direct intake of Se supplements by humans has also
received considerable attention in recent years. Two types of
multimicronutrients are commonly used such as: (i) multivitamins and multi-mineral preparations containing inorganic
Se, other trace elements and vitamins, and (ii) supplements
based on Saccharomyces cerevisiae yeast (Baker’s yeast).9 The
selenized yeast is particularly attractive due to its low cost,
facility to grow under different conditions, and its ability to
assimilate up to 3000 mg g 1 of Se starting from sodium selenite
added to the growth medium. Se-enriched yeast is currently the
primary Se dietary supplement, where Se is present mostly as
SeMet.35 Several minor organic species have been reported,
such as methylselenol, SeCys, selenohomocysteine, selenoadenosine and others at trace levels.35
3. Metabolic routes of Se in humans
3.1.
Absorption and metabolism
The global metabolism of Se in mammals is schematically
represented in Fig. 1. The main pathway for the assimilation
of Se intake was first proposed by Ip36 and consists of the
reduction of the different species to hydrogen selenide (HSe ).
This species plays the role of a central gateway for both utilization and excretion of Se. Selenium excess detoxification occurs
through a mechanism of sequential methylation into dimethylselenide (DMSe), excreted into the breath, and selenosugars and
trimethylselenide (TMSe), which are excreted into the urine.
The absorption of Se-species occurs mainly in the lower part
of the small intestine by different routes and mechanisms, in
many cases shared with their sulphur analogues. Almost all
forms of Se, inorganic as well as organic, are readily absorbed
with an overall efficiency close to be complete (70–90%) under
normal physiological and intake conditions.37 Selenite is an
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Fig. 1
Critical Review
Global view of Se metabolism in mammals.
exception because its direct absorption does not exceed 60%.
However, in the presence of reduced glutathione (GSH), as occurs
in the gastrointestinal fluid, the absorption of selenite is increased
up to quantitative proportions.38 In these conditions, selenite
reacts non-enzymatically with thiol groups of GSH to form
selenodiglutathione (GS-Se-SG, Fig. 1 path a), as follows:39
2H+ + 4GSH + SeO32 - GSSG + Gs-Se-SG + 3H2O
GS-Se-SG is subsequently decomposed by glutathione reductase into selenide following the steps (Fig. 1 path b):
GS-Se-SG + NADPH - GS-Se + GSH + NADP*
GS-Se + H2O - Se0 + GSH + OH
GS-Se + NADPH + H2O - HSe + GSH + NADP+ + OH
GS-Se + GSH - HSe + GSSG
HSe (O) - Se0 + OH
HSe + (O) + 2GSH - HSe + GSSG + H2O
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The GS-Se-SG should remain stable in the stomach due to
the low pH conditions, but it is expected to become unstable
and reactive in the intestine.40 The transport proteins involved
in the direct or indirect absorption of selenite are not yet
known. The fraction of selenite which is directly absorbed
undergoes the same reduction in red blood cells (RBCs), so
that the overall pool of the species is converted into selenide.41
Alternatively, selenite can be a substrate for the thioredoxin
system (thioredoxin, NADH and thioredoxin reductase, itself a
Se-protein) and directly reduced to selenide (Fig. 1 path c)
following a reaction path similar to that reported above for
glutathione reductase.39 The diglutathione (GSSG) is not a
substrate for thioredoxin reductase and is a poor disulfide
substrate for reduced thioredoxin. Nevertheless, the insertion
of a Se atom makes this compound a highly reactive substrate
for the thioredoxin system, capable of redox cycling in the
presence of oxygen.
Selenate is absorbed paracellularly, with elevated efficiency, via
a passive diffusional process.38 After absorption, it is reduced to
selenite (Fig. 1 path d), as in sulfate reduction, by ATP sulfurylase
via the still unidentified Se-isologue of 3-phosphoadenosine
5-phosphosulfate (Se-PAPS).
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The Se-amino acids SeMet and SeCys are absorbed through
transcellular pathways mediated by transporters which are
basically shared with their sulphur-containing analogues.42
SeMet is absorbed through a Na+-dependent process, but
the identity and affinity of the transport proteins is still to
be established.
SeMet can also be incorporated non-specifically into proteins such as serum albumin and haemoglobin, by randomly
replacing the (sulphur) methionine (Fig. 1 path e).43 Alternatively, it can be transformed into SeCys (Fig. 1 path f) and then
into selenide (Fig. 1 path g) via the trans-selenation pathway,
analogous to the trans-sulfuration pathway,44 schematized in
Fig. 2. The SeMet released through protein catabolic processes
enters the trans-selenation pathway in the same way. Excess of
SeMet has been also proposed to undergo direct methylation by
g-lyase (Fig. 1 path h).45
The absorption of SeMCys may share with SeMet part of the
transport mechanism, but some distinctions are still not clearly
understood.42 The Se-dipeptide GGSeMCys is assumed to play
the role of a carrier of SeMCys. After ingestion as a dietary
constituent, the bulk (not necessarily the entire amount) of
GGSeMCys is hydrolyzed by g-glutamyl transpeptidase in the
gastrointestinal tract (Fig. 1 path i), releasing SeMCys for absorption and systemic delivery to the other tissues.46 GGSeMCys is
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quantitatively absorbed from the gastrointestinal tract like
SeMCys. SeMCys and GGSeMCys are directly methylated by
b-lyase to MSe (Fig. 1 path j) so that urinary excretion is the
major route for eliminating the excess of Se from these species.45
3.2.
Utilization
The utilization of selenium requires the generation of Se-donor
selenophosphate (SePhp) from selenide and ATP (Fig. 1 path k)
that is mediated by selenophosphate synthetase 2 (SPS2).
Different from all the other amino acids that are synthesized
before being aminoacylated onto their tRNAs, SeCys is directly
synthesized on its tRNA, designated tRNA[Ser]Sec, by the mechanism represented in Fig. 3.47 The tRNA[Ser]Sec is initially aminoacylated with serine by seryl-tRNA synthetase (SerRS). The
hydroxyl moiety of Ser is then replaced by a phosphate group
to form O-phosphoseryl-tRNA[Ser]Sec by a specific kinase (PSTK).
Finally, SeCys synthase (SeCysS) exchanges the phosphate
group with activated SePhp to form selenocysteyl-tRNA[Ser]Sec.
The tRNA[Ser]Sec reads the UGA codon and is used for the
integration of SeCys into the amino acidic sequence to form
Se-proteins (Fig. 1 path l).47 Thus, SeCys is recognised as the
21st amino acid because its synthesis is genetically encoded in
the ribosome-mediated system. Interestingly, in mice Cys can
replace SeCys in Se-proteins such as thioredoxin reductases in
Fig. 2 Se-compounds generated within the trans-selenation pathway. The involved enzymes are: 1, SAM synthetase; 2, methyl transferase; 3, SAH hydrolase; 4,
methionine synthase; 5, cystathionine b-synthase; 6, cystathionine g-lyase; 7, cysteine lyase; 8, cysteine synthase; 9, cystathionine g-synthase; 10, b-cystathionase.
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Fig. 3
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Scheme of the Se-proteins biosynthesis pathway.
proportions that depend on the Se status.47 The catabolism of
Se-proteins releases SeCys (Fig. 1 path m) which is cyclically
reconverted into selenide.
3.3.
Systemic distribution
The Se-species absorbed into the gastro-intestinal tract are
firstly transported into the liver: SeMet is usually transported
in the form of Se-albumin (SeAlb)44 while selenate and the
other organic species may be transported intact or through
mechanisms which are still not elucidated. The liver is the
foremost organ in Se metabolism, since it synthesizes most of
the Se-proteins and regulates the excretion of Se metabolites.48
The SelP produced into the liver is released into the bloodstream and is responsible for the distribution of Se to the other
organs, where other Se-proteins can be synthesized. The local
uptake of Se from plasma has been shown to occur by endocytosis mediated by receptors of the apolipoprotein family such
as apoER2 in testis and brain,49 and megalin (Lrp2) in kidney.50
Thus, the liver regulates the whole-body Se distribution by sorting
the metabolically available Se between the two pathways of
Se-proteins synthesis and the excretory metabolite synthesis.51
Such regulation might be passive, so that the fraction of Se that
cannot be utilized for Se-proteins synthesis enters the excretory
pathway. Active regulation of the excretory metabolites has
been also hypothesized,51 but not yet investigated.
3.4.
Excretion
The excretion of Se in humans follows two possible routes,
leading in both cases to methylated products. The proportion
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among the main metabolites depends on the source species
and the Se status. Under supplemented or toxic Se status, TMSe
is well established as the main metabolite.52 Its production
starts from Se sources which are already mono-methylated
species, such as SeMCys and selenobetaine (SeBet), and is
subsequently transformed following a stepwise methylation
pathway mediated by methyltransferases (Fig. 1 path n).53
The formation of the intermediate species, DMSe, excreted
trough the breath, seems to be kinetically favoured with respect
to TMSe.
Under low-toxic Se status the metabolism of Se follows
another route, where selenide is converted into an intermediate
selenosugar-GS conjugated (GS-Se-N-acetyl-galactosamine,
GS-SeGal) and then into SeMethyl-N-acetyl-galactosamine
(MSeGalNAc), excreted into the urine (Fig. 1 path o).41 Minor
selenosugars have been also detected in urine, including
SeMethyl-N-acetyl-glucosamine (MSeGluNAc)54 and the deacylated analogue of SeGalNAc, SeMethyl-N-amino-galactosamine
(MSeGalNH2).55 It has been also hypothesized that in case of Se
excess, HSe can be metabolized entering into the stepwise
methylation pathway (Fig. 1 path p).53
4. Selenoproteins
Selenium is the key component of the active site of several
Se-proteins having essential biological functions. Twenty-five
Se-proteins have been identified in the human proteome2 and
24 in rat and mouse proteome.56 The main characteristics of
human Se-proteins are summarized in Table 1. Most Se-proteins
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Table 1
Human Se-proteins
Protein
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Tissue distribution
Subcellular location
Mw (kDa)
Glutathione peroxidases (GPxs) family
GPx1 (cGPx)
Ubiquitous, highly expressed in erythrocytes, liver, kidney, lung
GPx2 (GPx-GI)
Liver, epithelium of the gastrointestinal tract
GPx3 (pGPx)
Plasma
GPx4 (PHGPx)
Testes
GPx6
Olfactory epithelium, embryos
Cytoplasm
Cytoplasm
Secreted
Cytoplasm, mitochondria, nucleus
Secreted
87 (tetramer)
93 (tetramer)
93 (tetramer)
22
23
Thioredoxin reductases (TrxRs) family
TrxR1 (TxnRd1)
Ubiquitous
Cytoplasm, nucleus
TrxR2 (TxnRd2)
Ubiquitous; highly expressed in the prostate, ovary, liver, testes,
uterus, colon, small intestine
TrxR3 (TxnRd2, TGR) Testes
Iodothyronine deiodinases (DIOs) family
DIO1
Liver, kidney, thyroid, pituitary gland, ovary
DIO2
Thyroid, heart, brain, spinal cord, skeletal muscle, placenta,
kidney, pancreas
DIO3
Placenta, fetal tissues, skin
Se-proteins 15 and M family
SelM
Mainly brain; kidney, lung and other tissues
Sep15 (15 kDa
High levels in prostate and thyroid gland; lung, brain, kidney,
Se-protein)
H9 T cells
60–108 (dimer,
4 isoforms)
Mitochondria
60–106 (dimer,
4 isoforms)
Cytoplasm, nucleus, ER, microsome 75
ER and plasma, membrane
ER membrane
4–29 (9 isoforms)
30, 34 (2 isoforms)
Cell and endosome membrane
31
Perinuclear region, ER lumen, Golgi 14
ER lumen
15, 13 (2 isoforms)
Se-protein S and K family
SelS (VIMP)
Plasma, various tissues
SelK
Various tissues; abundant in heart
ER membrane
ER membrane
21
10
Rdx proteins family
SelW (SEPW1)
SelH
SelT
SelV
Various tissues, abundant in muscles
Various tissues, mainly expressed in embryonic and tumor cells
Ubiquitous
Testes
Cytoplasm
Nucleus
ER, Golgi
Unknown
9
13
20
17
Secreted
SPS2
SelR (MrsB1, SelX)
SelN
Expressed in the liver, heart and brain, secreted into the plasma.
Also found in the kidney.
Liver
Heart, liver, muscle, kidney
Ubiquitous; abundant in skeletal muscle, brain, lung, placenta
Cytoplasm
Cytoplasm, nucleus
ER membrane
SelI (hEPTI)
SelO
Various tissues; abundant in brain
Various tissues
ER membrane
Unknown
45–57 (3 isoforms,
glycosylated)
47
5–14 (2 isoforms)
61–62 (2 isoforms,
glycosylated)
45
73
Other Se-proteins
SelP (SEPP1)
exhibit antioxidant activities, but other specific processes have
been linked with Se-proteins, including biosynthesis of deoxyribonucleoside triphosphates (dNTPs) for DNA, reduction of
oxidized proteins and membranes, redox regulation of transcription factors, regulation of apoptosis, immunomodulation, regulation of thyroid hormones, selenium transport and storage,
protein folding and degradation of misfolded proteins in the
endoplasmatic reticulum (ER). It is worth noting that for many
Se-proteins the biochemical role is still partially unknown.11
Except for SelP, all Se-proteins contain one SeCys residue
solely which plays a central role in defining their biochemical
activity. Based on the location of the SeCys residue, the Se-proteins
can be divided into two groups.57 One group comprises of thioredoxin reductases, SelK, SelS, SelR, SelO, and SelI, where SeCys is
located in the C-terminal region. The second group includes
all the other Se-proteins, having the SeCys residue in the
N-terminal region. All Se-proteins are sensitive to the overall
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intake of Se according to a hierarchy, which depends on the
specific tissue and the biological functions under examination.58
This section presents the main and most recently discovered
characteristics of Se-proteins, with particular emphasis on their
biochemistry.
4.1.
Glutathione peroxidases
Glutathione peroxidases (GPxs) are a family of enzymes with
antioxidant functions. The GPxs family comprises of eight
isoforms, but only five members have a SeCys residue and
can catalyze the reduction of hydrogen peroxide (H2O2) and
lipid hydroperoxides using GSH as a reducing cofactor.59 This
group comprises of the ubiquitous cytosolic GPx (cGPX, GPx1),
gastrointestinal GPx (GI-GPx, GPx2), plasma GPx (pGPX, GPx3),
phospholipid hydroperoxide GPx (PHGPx, GPx4) and the olfactory epithelium GPx (GPx6). The SeCys residue is oxidized by
the peroxide with the formation of selenenic acid, which is then
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Scheme of the catalytic activity of GPxs (left) and active site of the protein showing the catalytic triad (right).
reduced back to the selenolate by thiols according to the
scheme in Fig. 4.60 The selenolic group of GPx active site is
included into a catalytic triad of SeCys-Trp-Gln residues where
it is both stabilized and activated by hydrogen bounding.60 A
specific ranking characterizes GPxs in terms of Se incorporation, which is supposed to be representative of their relative
biological importance, namely GPx2 > GPx4 c GPx3 = GPx1.61
GPx1 is a ubiquitous homotetrameric protein localized in
the cytosol and mitochondria. This enzyme utilizes exclusively
GSH as a substrate for the reduction of H2O2 and a limited
number of organic hydroperoxides including cumene hydroperoxide and tert-butyl hydroperoxide.59 The reactions mediated
by GPx1 mean this enzyme is implicated in the cellular processes
modulated by hydroperoxides, including cytokine signalling and
apoptosis. Among its family members, GPx1 is one of the most
highly sensitive to changes in both Se status and oxidative stress
conditions,62 but it appears that global protein synthesis is
reduced under conditions of stress as a means of reserving
cellular resources, and that GPx1 recovers rapidly compared to
the other Se-proteins.2
GPx2 is a secreted homotetrameric enzyme mainly expressed
in the gastrointestinal system mucosa, including the squamous epithelium of the esophagus; and in humans, it is also
detectable in the liver. Its expression in the intestine is not
uniform, but it is higher in the crypt grounds and decreases
gradually toward the luminal surface, suggesting a role in cell
proliferation.63 The function of GPx2 is mainly to protect
intestinal epithelium from oxidative stress and to guarantee
mucosal homeostasis. GPx2 exhibits substrate specificity
similar to that of GPx1, which includes H2O2, tert-butyl hydroperoxide, cumene hydroperoxide, and linoleic acid hydroperoxide, but not phosphatidylcholine hydroperoxide.64 The
expression of GPx2 is much more resistant than GPx1 or
GPx3 to dietary Se deficiency.61 GPx2 location and resistance
suggest that this Se-protein may serve as a first line of defence
in exposure to oxidative stress induced by ingested prooxidants
or gut microbiota.
GPx3 is the only extracellular enzyme of the GPxs family. It is
a glycosylated homotetrameric protein produced into the cells
of the proximal tubular epithelium and in the parietal cells of
Bowman’s capsule of the kidney.65 Part of GPx3 is then secreted
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into the plasma, where it constitutes approximately 15–20% of
the total Se, but a major fraction remains bound to the basement membranes in kidneys.65 Such membrane binding-ability
has been demonstrated also in the gastrointestinal tract, the
lung, and the male reproductive system.66 Both GPx3 protein
and mRNA have been also detected in several tissues, particularly the heart and thyroid gland, where this enzyme may play
a role in a local source of extracellular antioxidant capacity.58
Unlike GPx1, GPx3 presents a more restricted hydroperoxide
substrate specificity. Although it can reduce H2O2 and the same
organic hydroperoxides, its activity is B10 fold lower than the
activity of GPx1. Considering that GSH is a poor reducing
substrate for GPx3 and the low concentration of reduced thiol
groups in human plasma, it has been proposed that binding of
GPx3 to the basement membrane exposes the enzyme to higher
levels of secreted GSH, thus increasing the activity of GPx3 at
the basal extracellular aspect of epithelial cells.66
GPx4 is a monomeric intracellular enzyme presenting three
isoforms: cytosolic, mitochondrial, and nuclear. The expression
and activity of this protein has been documented in many
tissues, particularly of endocrine organs and in the mitochondria
in the midpiece of spermatozoa, and is hormone-regulated.67
Unlike the other GPxs, it can directly use phospholipid hydroperoxide as substrate, and reduces H2O2, cholesterol-, cholesteryl
ester- and thymin-hydroperoxides, by using electrons from protein
thiols as well as from GSH.68 GPx4 plays essential role of antioxidant defence during cellular differentiation in embryonic
development and in spermatogenesis and is involved in the condensation of chromatin during spermatogenesis.69 It is also a
structural protein in spermatozoa: the nuclear isoform contributes
to posttesticular chromatin condensation via disulfide bridging
in thiol-containing protamines, while the mitochondrial isoform participates to the structural organization of mitochondria
in the sperm midpiece.70 A recent study has shown that GPx4
plays an important protective role for photoreceptor cells against
oxidative stress.71
GPx6 is a close homolog of plasma GPx3. Compared to other
GPx proteins, GPx6 was identified rather late because its mouse
and rat orthologs had Cys in place of SeCys. This enzyme is only
expressed in embryos and olfactory epithelium,1 and its specific
function remains unknown.
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4.2.
Thioredoxin reductases
The thioredoxin reductases (TrxRs) are homodimeric enzymes
belonging to the flavoprotein family of pyridine nucleotidedisulphide oxidoreductases, which includes lipoamide hydrogenase, glutathione reductase and mercuric ion reductases.
Three isoforms were identified in mammals: cytosolic (TrxR1,),
mitochondrial (TrxR2), and thioredoxin glutathione reductase
(TGR, TrxR3).72
As is the case in other enzymes of the flavoproteins family, each
monomer of TrxRs includes a FAD prosthetic group, a NADPH
binding site and an active site containing a redox-active disulphide. The two subunits participate in the activity of the enzyme in
a coordinated way.72 Electrons are transferred from NADPH via
FAD to the active site disulphide of TrxR, which then reduces the
substrate as represented in Fig. 5. TrxRs specifically reduces
oxidized thioredoxins (Trxs), a group of small (10 12 kDa)
ubiquitous redoxactive peptides that supply reducing equivalents
to the disulphide bonds in enzymes such as ribonucleotide
reductase, thioredoxin peroxidase, and some transcription factors,
resulting in their increased binding to DNA and altered gene
transcription.72 Mammalian Trxs have also been shown to act
as cell growth factors and to inhibit apoptosis. Since TrxRs are
the only class of enzymes known to reduce oxidized Trx, it is
possible that alterations in TrxR activity may regulate some of the
activities of Trxs.
In addition to Trxs, many other endogenous substrates have
been identified for TrxRs, including lipoic acid, lipid hydroperoxides, the cytotoxic peptide NK-lysin, dehydroascorbic acid,
the ascorbyl free radical, Ca-binding proteins, glutaredoxin 2,
and the tumour-suppressor protein p53.73 However, the physiological role that TrxRs play in the reduction of most of these
substrates is still unknown. Some of the most likely functions for
TrxRs are summarized in Fig. 5. The ability of TrxR to reduce the
ascorbyl free radical suggests that TrxR may play an additional
action through the recycling of ascorbate.74 Humans lack the
Fig. 5
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ability to synthesize ascorbic acid, an important antioxidant in
the protection of cells from oxidative stress; therefore dietary
intake and the recycling of ascorbate from its oxidized forms
(dehydroascorbic acid and the ascorbyl free radical) are essential
for maintenance of ascorbate levels. The relation between TrxR
level and ascorbate cycle has been demonstrated by the observation that maintenance of rats on a Se-deficient diet results in
decreased liver ascorbate, GPx and TrxR levels.74 Interestingly,
Se-containing compounds including selenite, GS-Se-SG and
SeCystine are also substrates for the TrxRs, so that these Seenzymes are themselves implicated in Se-proteins synthesis by
generating selenide for assimilation.75
Despite the wide variety of essential biological functions
characterizing TrxRs, the relatively recent discovery of the isoforms TrxR2 and TrxR3 limits the knowledge of their specific
role with respect to TrxR1. TrxR1 and TrxR2 are known to be
essential for embryogenesis through mechanisms that appear to
be non redundant.76 The function of mitochondrial TrxR2
involves the protection from mitochondrial-mediated oxidative
stress and apoptosis during embryogenesis. TrxR3 is composed
of two 65 kDa subunits with an additional glutaredoxin domain.
This enzyme is mainly expressed in the male germ cells and has
been suggested to play a role in sperm maturation by influencing
the formation of disulfide bonds in structural proteins.73
4.3.
Iodothyronine deiodinases
The iodothyronine deiodinases (DIOs) are a family of three
integral membrane proteins with similar structure. DIO1 and
DIO3 are plasma membrane proteins, whereas DIO2 is localized
in the ER membrane.77,78 All DIOs are oxido-reductases with
SeCys residue in the active site, that participate in thyroid
hormone metabolism by catalyzing the activation (DIO1, DIO2)
or inactivation (DIO3) of tetraiodothyroxine (T4), triiodothyronine (T3), and reverse-triiodothyronine (rT3) as schematized in
Fig. 6.79 These thyroid hormones regulate various metabolic
Scheme of the catalytic activity and biological functions of TrxRs.
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Fig. 6 Scheme of the metabolism of thyroid hormones mediated by DIOs. DIO2 catalyzes the monodeiodination of the outer ring of the iodothyronine nucleus (from
T4 to T3, and from rT3 to T2), whereas DIO3 catalyzes the monodeiodination of the inner ring (from T4 to rT3, and from T3 to T2). DIO1 catalyses monodeiodinations
unspecifically.
processes, such as lipid metabolism, thermogenesis, growth and
hearing, that are essential for homeostasis but also for the
normal development of the fetal brain.80
Like other Se-proteins families, the functional differences
amongst individual isoforms are not yet well elucidated. The
three DIOs exhibit differentiated expression patterns and tissue
distribution. DIO1 is expressed mostly in the liver, kidney,
thyroid, and pituitary gland; DIO2 in the thyroid, the central
nervous system, the pituitary gland, and skeletal muscle.81 DIO3
presents a more specific expression pattern as it is mainly
present in the embryonic and neonatal tissues. Its privation
entails an abnormal developmental pattern, so that DIO3 is
considered a fetal enzyme.81 It is assumed that DIO1 is responsible mainly for the control of circulating T3 levels, whereas
DIO2 and DIO3 are involved in the local regulation of deiodination
processes. However, their relative role in these mechanisms is still
not well understood and seems to vary depending on the Se
status and development stage.82 DIOs occupy a high rank in the
hierarchy of Se-proteins for incorporation of the element under
deficiency conditions, particularly concerning the accumulation
and/or redistribution of DIO1 in the thyroid gland, and DIO2
and DIO3 in brain and placenta.81
4.4.
Selenoproteins 15 and M
Se-proteins 15 (Sep15) and M (SelM) are thiol-disulfide oxidoreductases which constitute a distinct family of Se-proteins.
In mammals, the two proteins are expressed with similar tissue
distribution, Sep15 with highest levels in prostate, liver, kidney,
testis, and brain, whereas SelM is mainly expressed in the brain.83,84
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Sep15 and SelM localize in the ER; both proteins encode a
N-terminal peptide which is cleaved after translocation in the
ER. In addition, the native Sep15 has shown migration properties in SDS-PAGE that are consistent with a 150–240 kDa
complex, whose constituents have not yet been established.85
Sep15 contains a Cys-rich domain in the N-terminal part of
the protein, but lacks of an ER retention sequence.86 Through
its N-terminal Cys-rich domain, Sep15 has been shown to form
a complex with UDP-glucose:glycoprotein glucosyltransferase
(UGGT).87 The UGGT acts as a folding sensor by initiating the
association of unfolded glycoproteins with calnexin (CNX) and
protein disulfide isomerase ERp57, and may also directly assist
folding of a specific group of glycoproteins. The complex
formed by Sep15 with UGGT is responsible for its retention
by the ER and suggests a possible implication in the folding or
secretion of glycoproteins.87 Sep15 presents a thiodedoxin-like
domain with a surface accessible redox-active motif, Cys-XSeCys, in which SeCys and Cys form a reversible Se–S bond.86
In relation to its redox potential, this suggests for Sep15 a
possible additional function of catalyzing the isomerization or
reducing disulfide bonds.88 Sep15 may also play a role in
regulation of apoptosis, as shown in malignant mesothelioma
and NIH3T3 cell lines,89,90 but insufficient data exists to
provide the evidence.
SelM shares 31% of sequence with Sep15. Differently from
the latter, SelM lacks the UGGT-binding domain and presents
an ER-retention signal, whereas its redox-active motif is in the
form Cys-X-X-SeCys.83 The binding partners and the specific
role of SelM remain to be established.
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4.5.
Selenoproteins S and K
The Se-proteins S (VIMP, SelS) and K (SelK) belong to the same
family whose members share a short N-terminal ER luminal
sequence, an N-terminal single pass transmembrane helix, and a
C-terminal active site (with SeCys in the case of Se-proteins). SelS
and SelK share similar structural characteristics, binding proteins, and reaction processes involved in the regulation of ER
stress, because both are transmembrane ER-resident proteins.
SelK is a ubiquitous protein, highly expressed in the spleen,
immune cells, brain and heart.91,92 Unlike the other Se-proteins,
its catalytic site is part of a motif where SeCys is not paired with a
nearby Cys, Ser or Thr.93 This means that a possible hydrogen
bond donor for the protection of SeCys approaches the residue
only as a consequence of the 3D structure of the protein, or is
provided by an unknown partner. SelS presents the same motif,
whose SeCys in position 188 has been recently shown to form a
Se–S bond with a Cys residue in position 174.94 The structural
and redox properties of SelS and SelK suggest that they function
as reductases adapted for a wide range of substrates.
SelS and SelK are involved in the ER-associated degradation
(ERAD) of unfolded and misfolded proteins, a multi-step process involving many proteins whose specific roles have not been
clearly elucidated.95 Derlin-1 and -2 are strong candidates to
play the role of channel proteins responsible for the retrotranslocation of unfolded proteins from the ER to the cytosol,
the early stage of ERAD. Recent studies have shown that both
SelS and SelK are associated with Derlins and p97 ATPase, with
which may form an ER-membrane associate complex.95 SelS
may mediate the interaction of cytosolic p97 and Derlin-1,96 but
such an assumption still needs to be confirmed. Additional
partners of SelS in the complex may be required to exploit its
function, and SelK seems to be a potential candidate. The role
of SelS and SelK in ERAD is confirmed by their upregulation
under glucose deprivation,97 and Ca2+ depletion,98 both being
processes inducing the aggregation of improperly folded proteins in the ER. While SelS expression is induced by ER stress,
its depletion increases the release of inflammatory cytokines.
SelS was also shown to interact with serum amyloid A, suggesting a potential role in type 2 diabetes which is linked to the
regulation of the inflammatory response.99
4.6.
Selenoprotein W
Se-protein W (Sepw1, SelW) is a small protein with the SeCys
residue as part of a Cys-X-X-SeCys redox motif localized in an
exposed loop.100 The analogy with the motif Cys-X-X-Cys of Trx,
high affinity for GSH, and overexpression against oxidative
stress in muscle tissues suggest an antioxidant function.101
However, the precise molecular pathways are not yet elucidated, so the specific functions remain unknown.
Recent studies have shown that SelW interacts with specific
isoforms of 14-3-3 proteins.102,103 Such proteins participate in
several cellular processes, including the regulation of the cell
cycle, metabolic control, apoptosis, protein trafficking, and gene
transcription. For example, SelW may play an important role in
the recovery from G2 arrest, an interruption of progression into
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mitosis, by determining the dissociation of 14-3-3 from the
phosphatase CDC25B by a redox-regulated mechanism.102
SelW is ubiquitously expressed in tissues, with a particular
preservation into the brain under Se deficiency.104 In glial cells,
SelW expression is specifically induced in response to a radical
generator, suggesting a potential specific function in the
brain.105 It is also expressed in early embryonic development,
during implantation and gastrulation, and subsequently,
within the nervous system, limbs, and heart.106 The early
developmental expression pattern of SelW in muscle progenitor
cells and its high expression levels in proliferating myoblasts,
suggest a specific role of SelW in muscle development and
diseases.
Overexpression of SeW markedly reduces the sensitivity of
Chinese hamster ovary (CHO) and lung cancer cells to H2O2
cytotoxicity.101 The SeCys residues 13 and 37 have been shown
to be necessary for the antioxidant activity of SelW, which is
downregulated by GSH, but seem to be not correlated with
intracellular levels of reactive oxygen species (ROS). SelW was
also found to be a specific molecular target of methylmercury in
human neuronal cells, whereas other Se-proteins were not
affected.107
4.7.
Selenoprotein H
Se-protein H (SelH) is a nucleolar thioredoxin-like protein with
DNA-binding properties.108 It is moderately expressed in various
mouse tissues, whereas elevated expression levels were found in
brain during early development, but also in the thyroid, lung,
stomach, and liver human tumors.109 These data suggest a
possible role of SelH in cellular proliferation during development or cancer growth. SelH is also involved in up-regulating the
levels of GSH, the activity of GPx and the total antioxidant
capacity in response to the redox state, with protective effects
against superoxide and cell damage induced by ultraviolet B
(UVB) irradiation.108,110 A recent study has shown that SelH may
exert its protective function through the activation of mitochondrial biogenesis signalling pathway by increasing the level of the
nuclear encoded regulators PGC-1a, NRF1 and Tfam.111
4.8.
Selenoprotein T
Se-protein T (SelT) is a member of the thioredoxin-like family
that has been predicted to be a glycosylated transmembrane
protein.112 In mouse and rat cells it localizes in Golgi, ER and
possibly in the plasma membrane.100,113 It is ubiquitously
distributed, with high expression in the testes.58 The expression
of SelT is regulated by the trophic neuropeptide pituitary
adenylate cyclase-activating polypeptide (PACAP).113,114
Elevated expression was found in embryonic tissues, followed
by a decrease in most adult tissues, excluding the pituitary
gland, thyroid and testis.114 SelT was found to be highly
expressed also in the brain of hypoxia-induced mice115 and in
regenerating liver cells after partial hepatectomy.114 Altogether
these observations suggest an important role for SelT in ontogenesis, tissue maturation/regeneration, and cellular metabolism of nervous and endocrine tissue, with a possible redox
action in Ca2+ homeostasis.113 Structural analogies characterize
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SelT and SelW, indicating a potential functional relation, supported
by the observation that knockdown of SelT in mouse fibroblasts
may be compensated by increased expression of SelW.116
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4.9.
Selenoprotein V
Selenoprotein V (SelV) is a member of thioredoxin-like family
exclusively expressed in spermatocytes.1 It has a proline-rich
N-terminal domain and SeCys located in a hydrophobic
domain. Possible partners for SelV have been recently
proposed, including the proteins O-acetylglucosamine transferase (OGT), Asb-9 and Asb-17; the Asb-family proteins present
the SOCS domain, a suppressor of cytokine signalling.117,118
4.10.
Selenoprotein P
Se-protein P (SEPP1, SelP) is the only Se-protein containing ten
SeCys residues in rats, mice, and humans.2 It is a glycosylated
protein since it presents 3 occupied N-glycosylation sites and 1
occupied O-glycosylation site.119 Several disulfide and selenenylsulfide bonds have also been identified in purified rat SelP.
These bonds might have structural functions and might serve
in the protection of the reactivity of selenolic groups.119 SelP
purified from rat plasma is present as 4 isoforms containing a
lower number of 6 SeCys residues.120 A recent study reported
the separation and characterization of three distinct SelP isoforms also in human plasma, with Mw of 45, 49 and 57 kDa, the
first being a truncated isoform lacking in Se.121,122 SelP is
mainly produced in the liver and then secreted into the plasma,
where it incorporates the major part of Se, but it is expressed
and probably secreted also by other tissues including the brain
and the heart. As mentioned in Section 3.3, evidence supports
functions of SelP in Se transport and homeostasis throughout
the whole body.18 SelP knockout mice present very low Se
concentrations in brain, testis and foetus, with severe pathophysiological consequences in each tissue.123 In addition, these
mice excrete moderate amounts of Se in the urine. On the other
hand, dietary Se deficiency causes a profound decrease in liver
Se concentration, presumably because the liver exports a fraction of its metabolically available Se as SelP, even when the
element supply to the organ is drastically decreased. Under
dietary Se deficiency, SelP appears to be responsible for maintaining preferentially Se in the brain and testis by a mechanism
that is distinct from its effect on the other organs.124,125 In the
kidney and in the muscle, Se concentration falls approximately
to the same extent as does whole-body Se with the deletion of
SelP and with dietary deficiency. Since Se is covalently bound,
its release requires disruption of SelP to exploit its transport
function.126
The specific biochemical activity of SelP remains still
unclear. Indications exist about the possible role of the protein
in antioxidant defence. The SelP plasma level correlates with
prevention of lipid and low density lipoproteins peroxidation
and hepatic endothelial cell injury, and an association has also
been reported between SelP and protection against oxidant
injury from GSH depletion in Se-deficient rats.18,127 In addition,
SelP binds to endothelial cells in the rat, probably through its
heparine-binding site.18,128 Endothelial cells release primary
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free radicals NO and O2 from which peroxynitrite (ONOO )
and H2O2 secondary products are formed. Thus, endothelial
cells and their environment have been hypothesized to be sites
of oxidative stress. Localization of SelP in proximity of endothelial cells is consistent with its having an antioxidant defence
function related to the protection of membranes.
4.11.
Selenophosphate synthetase
As mentioned earlier, selenophosphate synthetase 2 (SPS2)
catalyzes the synthesis of SePhp, the key Se-donor for Se-proteins
biosynthesis, by transferring the g-phosphoryl group of ATP to
selenide.47 Two isoforms of SPS (1 and 2) are encoded in higher
eukaryotes, but SPS1 is not a Se-protein since the SeCys residue
is replaced by Arg. Despite a study has shown that SPS1 catalyzes
SePhp biosynthesis very weakly and using only SeCys as substrate, suggesting a role in recycling process of SeCys,129 a
further work did not confirm this hypothesis.130 SPS1 seems to
be unnecessary for the assimilation of Se in Se-proteins, but may
play another role in Se metabolism as shown by its potential
to complex with a number of proteins involved in SeCys biosynthesis.131 The Se-protein SPS2 remains the only responsible
for the generation of SePhp, but the exact mechanism driving
this reaction has yet to be determined.
4.12.
Selenoprotein R
Se-protein R (MsrB1, SelX, SelR) belongs to the methioninesulfoxide reductases family. These proteins are responsible for
the reconversion of Met residues from their oxidized form
methionine sulfoxide (MetSO), which can negatively affect a
number of biological functions.132 Methionine sulfoxide forms
by the action of ROS as a mixture of two diastereomeric forms
(Met-S-SO and Met-R-SO), in which reduction is specifically
mediated by distinct enzyme families, respectively named MsrA
and MsrB. At least four different MsrB products, encoded by
specific genes, have been identified in humans, each with a
proper subcellular location: MsrB1 in the cytoplasm and
nucleus, MsrB2 and MsrB3B in mitochondria, MsrB3A in the
ER.133 However, only MsrB1 is a Se-protein, whereas a Cys
residue substitutes SeCys in the active site of the other three
products. The catalytic activity of MsrB1 proceeds through the
steps which are schematized in Fig. 7.134 Firstly, the SeCys
attacks the substrate to form methionine and is converted into
a selenenic acid intermediate. In the following step the recycling Cys attacks the selenenic acid to form a Se–S bond, which
is further reduced by Trx. Interestingly, SelR is also a zinccontaining enzyme.135 The metal is bound through four Cys
residues, and has been suggested to play a structural function.136
4.13.
Selenoprotein N
Se-protein N (SelN) is a ubiquitous glycoprotein highly expressed
in fetal tissues, muscle, brain and lung.137 The catalytic site
consists of the motif Ser-Cys-SeCys-Gly, similar to that of
TrxR (Gly-Cys-SeCys-Gly), so that a reductase-function may be
hypothesized. However, limited access to the site, located in the
centre of the protein, and the absence of typical FAD- and
NADPH-binding domains, may reflect the higher specificity of
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Fig. 7
Scheme of the reduction of methionine-sulfoxide catalysed by SelR.
SelN for different substrates, that are not yet identified.138 SelN
localizes in the membrane of the ER, with the N-terminal
region facing the cytoplasm, while the bulk of the protein,
including the potential active site, resides within the lumen of
the ER.137,138 A recent study has shown that SelN co-localizes
and co-immunoprecipitates with the ryanodine receptor (RyR),
a component of the intracellular Ca2+ release channel.139 Also,
SelN modulates the activity of RyR and protects it against
oxidative stress. The association with Ca2+ release links SelN
to a potential function in the development of slow muscle fibers
in embryos.140
Despite its confirmed key role in muscle tissue, the specific
biological function of SelN remains unknown. Paradoxically, it
is the only Se-protein whose connection to a disease, SEPN1related myopathy, has been directly established as a consequence of mutations in the SelN gene. This connection is
discussed in Section 5.2.
4.14.
Metallomics
Selenoprotein I
The Se-protein I (SelI), also named ethanolaminephosphotransferase 1 (hEPT1), is a recently discovered protein which participates to the biosynthesis of phosphatidylethanolamine
(PE).141 PE resides in the inner leaflet of plasma membrane,
where it constitutes B25% of the whole pool of cellular
phospholipids in mammals. This phospholipid is an important
precursor of the glycosylphosphatidylinositol anchors and of
N-acylethanolamine, a neurotransmitter in the brain, and is
involved in membrane fusion events and proteins folding.142
One of the two possible routes for the biosynthesis of PE is the
CDP-ethanolamine (Kennedy) pathway (the other route is mitochondrial decarboxylation of phosphatidylserine, PS). The final
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step of the pathway, the transferring of phosphoethanolamine
from CDP-ethanolamine to diacylglycerol, is catalyzed by choline/
ethanolaminephosphotransferase 1 (CEPT1), an enzyme that
can also use CDP-choline as a substrate for the synthesis of
phosphatidylcholine (PC). It was originally thought that CEPT1
is only responsible for the biosynthesis of PE via the Kennedy
pathway. However, it has been shown that SelI may participate
in the process, exhibiting a specific affinity for CDP-ethanolamine.
SelI is ubiquitously expressed, with particularly high abundance
in the cerebellum.141
4.15.
Selenoprotein O
Selenoprotein O (SelO) has been identified as the largest
mammalian Se-protein, and is one of the most obscure human
proteins.1 A double function of kinase signalling and redox
detection/signalling has been recently predicted for the generic
family of SelO-like proteins,143 but no more specific structural
and functional characterizations are available.
5. Selenium and human diseases
It has been proven in the last two decades that Se may be
directly or indirectly linked to a large variety of human health
disorders. Most of these associations are due to the role of GPxs
and TrxRs enzymes in the reduction of oxidative stress, which
has been identified as a main cause in the development and
progression of several pathologies. Some other Se-proteins are
involved in specific processes such as Ca2+ signalling, brain
function and spermatogenesis. Alterations in their genes or
underexpression related to Se deficiency have been identified as
possible causes of the corresponding pathology. However, definitive
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Table 2 Hypothetical role of normally active Se-proteins with respect to human diseases. Evaluation a priori must always consider Se-proteins as concurrent factors.
An inhibitory effect implies a direct action within in the disease generating processes, whereas mitigation refers to posterior reduction of damage. Given each role
under normal activity, the contrary effect arises when the activity of the protein is sub/supra-normal
Disease
Se-protein
Role
Mechanism
Muscle disorders
Cardiovascular diseases
SelN, SelW
GPxs, TrxRx, SelR
DIO1
SelS
GPxs
GPxs
GPxs
SelP, GPxs, TrxRs,
SelW, SelH, SelM
TrxRs
GPxs
SelS
GPxs, others
GPxs
SelP
TrxRs
DIOs
GPx4
GPxs, SelP, TrxRs
Prevention
Prevention/mitigation
Prevention/mitigation
Prevention
Mitigation
Prevention/mitigation
Prevention
Mitigation
Homeostasis of Ca2+ signalling
Antioxidant defence
T3 hormone supply for lipid metabolism
Unknown
Antioxidant defence
Antioxidant defence
Antioxidant defence
Antioxidant defence
Promotion
Inhibition
Inhibition
Mitigation
Promotion/mitigation
Promotion
Prevention/mitigation
Prevention
Prevention
Prevention
Early regulation of immune cell signalling
Advanced regulation of immune cell signalling
Antioxidant defence, cytokine regulation
Antioxidant defence
Inhibition of the insulin signalling/antioxidant defence
Inhibition of insulin synthesis
Stimulation of the insulin signalling/antioxidant defence
Regulation of thyroid hormones metabolism
Antioxidant defence, structural support
Antioxidant defence
Hepatopathies
Renal failure
Epilepsy, mood disorders
Neurological disorders (other)
Inflammatory response
HIV
Type 2 diabetes
Endocrine disorders
Male infertility
Cancer
knowledge concerning the mechanisms underlying the action
of Se-proteins related to human diseases is still far from being
reached. Apparently conflicting data arise from the large number of epidemiological investigations where the total Se concentration in food/supplements, blood fractions and toenails was
assessed in relation to the onset or progression of pathological
status. Conversely, a wide range of biochemical information
has been collected on specific cellular processes involving Se
and Se-proteins. Finding causal connections between the cell
and population levels, passing through the individual is a
major challenge. Table 2 summarizes up to date information
on the role of Se-proteins in human health and the correlation
of their alteration with several human diseases. Each action
refers to the protein when present in normal activity, in such a
way that the opposite role can be inferred when the activity of
the protein is sub/supra-normal. Most of the Se-proteins exhibit
a beneficial action with respect to human diseases, meaning
that a deficient activity may be associated with the occurrence
or progression of the pathological state. However, it is important to emphasize that the role of individual proteins has to be
contextualised within a complex biochemical environment,
where antagonistic, additive and synergistic effects take place.
An example is given by the balancing action of TrxRs and GPxs
for the modulation of immune response and glucose cellular
uptake.
5.1.
Deficiency and toxicity
Severe Se deficiency is directly associated with two endemic
diseases diffused in soil Se-poor regions of China and Russia:
Kashin-Beck and Keshan diseases. Kashin-Beck disease is an
osteoarthritis characterized by atrophy, degeneration, and
necrosis of cartilage tissue, which occurs primarily in children
between the ages of 5 and 13 years. The pathology results in
enlarged joints, shortened fingers and toes, and dwarfism in
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extreme cases.28,144 Keshan disease is a muscular disorder and
is discussed in Section 5.2.
Acute Se toxicity by inhalation exposure causes stomach
pain and headaches, and a number of respiratory symptoms
such as pulmonary edema, bronchial spasms, symptoms of
asphyxiation and persistent bronchitis, elevated pulse rates,
lowered blood pressure, vomiting, nausea, and irritability.145
Acute oral exposure to extremely high levels of Se provokes
nausea, vomiting, diarrhoea, and occasionally tachycardia.
Regarding chronic inhalation exposure, a number of occupational studies revealed respiratory effects such as irritation of
the nose, respiratory tract, and lungs, bronchial spasms, and
coughing.145 Chronic oral intake of very high levels of Se results
in selenosis, a specific pathology characterized by hair loss,
deformation and loss of nails, discoloration and excessive
decay of teeth, garlic breath, gastrointestinal disturbances, skin
rash, and abnormal functioning of the nervous system (numbness, paralysis and occasional hemiplegia).146,147 Related toxic
effects are the disruption of the endocrine function, synthesis
of thyroid hormones and growth hormones, and insulin-like
growth factor metabolism. Particularly high levels of dietary Se
are also significantly associated with impairment of natural
killer cells and hepatotoxicity.146
5.2.
Muscle disorders
Keshan disease is an endemic juvenile cardiomyopathy with
myocardial insufficiency, that primarily affects children
between 2 and 10 years old.28 This pathology is characterized
by cardiac enlargement, abnormal electrocardiogram (ECG)
patterns, cardiogenic shock, and congestive heart failure, with
multifocal necrosis of the myocardium.145 Selenium deficiency
was identified only in the 1970s as being the major cause of
Keshan Disease. Evidence was firstly based on extensive observational epidemiological studies carried out in northeast and
southwest areas of China, where the disease was endemic.148
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A strong association was revealed between the occurrence and
geographic distribution of the disease with low Se intake, and
blood Se status and GPxs activity in patients. Intervention trials
were conducted by administrating sodium selenite to large
population samples, resulting in a significantly reduced incidence of this disease.
The mechanism linking Se deficiency and Keshan disease is
not completely understood. Biochemical and clinical studies
suggest that a decreased activity of GPxs (particularly GPx1)
related to Se deficiency may impair the protection of mitochondria against membrane peroxides-induced damage.149 Further
studies have shown that Se deficiency is not sufficient to fully
explain the incidence of Keshan disease.150 Rather, its etiology
is triggered by a combination of Se deficiency and infection by
the enterovirus Coxsackie: insufficient Se intake impairs the
antioxidant action of Se-proteins, so viral DNA is exposed to
oxidative damage, which increases its virulence.
Muscular dystrophy is another group of pathologies involving the slow degeneration of muscle tissue.151 Some forms of
congenital muscular dystrophy, including multiminicore myopathy, rigid spine muscular dystrophy and desmin-related
myopathy with Mallory bodies, have been linked to mutations
of the SelN gene (SEPN1). All these pathologies share clinical
features and are referred to as SEPN1-related myopathies.
However, the role of SelN in muscular dystrophy has been
elusive because its biological function is still largely unknown.
The observed association of SelN with ryanodine receptors, that
are responsible for Ca2+ signalling, may provide an explanation.139 Mutations in SEPN1 prevent this association, and thus
may be responsible for multiminicore disease by the inhibition
of Ca-stimulated release of Ca2+ from intracellular stores.152
However, as long as the biological function of SelN remains
obscure, no more conjecture can be proposed.
SelW has also been linked to muscular functions since a
lower concentration of this protein has been observed in
animals affected by white muscle disease (WDM).153 As for
SelN, such an association may be due to a role of the Seproteins in the regulation of Ca2+ homeostasis, because the
sarcoplasmic reticulum of WDM animals exhibits a defective
Ca2+ sequestration, resulting in the calcification of skeletal and
cardiac muscles.153 A possible action of SelW in the regulation
of Ca2+ metabolism was originally proposed, but the hypothesis
has not been demonstrated at a later stage, and no link to
humans has been documented.
5.3.
Cardiovascular diseases
Oxidative stress damages the vascular endothelial cells and
exacerbates cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and congestive heart failure.154 Since most
Se-proteins are involved in the cellular antioxidant defence
system, a potential prevention effect of adequate Se intake
has been hypothesized for non-infectious CVD. This topic has
been investigated by a large number of epidemiological studies
based on both observational data and clinical trials, without
reaching a conclusive response. The general CVD incidence in
supplementation trials has been recently reviewed considering
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Metallomics
twelve research publications, revealing no significant association with Se intake.155 Two meta-analyses observational studies
were also conducted on blood, serum/plasma or toenail Se
levels and compared with the incidence of coronary heart
disease (CHD); a moderate inverse correlation between total
Se concentration and CHD risk was found.156,157 However, a
clear causal connection cannot be inferred under the observed
differences, mainly because of the potential confounding effect
of the other co-supplemented antioxidants. Similar shortcomings also affect randomized trials carried out to assess the
effects of Se supplementation on CHD,156 as well as most of the
studies in the literature.158
Apart from possible preventive actions, Se-proteins may play
a more evident role in cellular defence against ROS production
during or after the development of CVD. A positive correlation
was observed between GPx3, TrxR1 and SelR, with ROS production in heart hypertrophy.159 The function of TrxRs in CVD may
pass through the modulation of Trxs, that in turn regulates the
response to ventricular remodelling after myocardial infarction.160 Conversely, Se supplementation, resulting in higher
GPxs and TrxRs activity, has been shown to reduce the oxidative
damage after cardiac ischemia–reperfusion.161
Another Se-protein associated to CVD through a more specific action is DIO1.162 This protein controls the conversion of
T4 into T3, which is the active form of thyroid hormone and
plays a key role in normal lipid metabolism. Hypothyroidism
causes qualitative changes in circulating lipoproteins, increasing their artherogenicity. Thus, an adequate activity of DIO1
during hypercholesterolemia is particularly important to preserve the homeostasis of lipid metabolism through the efficient
supply of T3.
SelS was found to be associated with CVD, carrying out a
protective effect on astrocytes during ischemia, but its mechanism of action is unknown.163 Finally, variations in the SEPS1
locus are associated with CHD risk in females.164
5.4.
Hepatopathies
Hepatopathies are another family of disorders that have been
linked to high levels of oxidative stress, in which antioxidant
enzymes may play beneficial actions.165 The liver pathology
provoked by alcoholism is characterized by an infiltration of
leukocytes and formation of collagen in hepatocytes. This
process is driven by increased production of free radicals,
resulting in lipidic peroxidation of the cell membranes. The
actions of ethanol-cytochrome P450 3E1 and aldehyde oxidase
on ethanol and acetaldehyde, respectively, generate superoxides. These ROS produce hydroxyl radicals which can directly
react with ethanol, generating 1-hydroxyl-ethyl radicals. In this
context, it has been proposed that antioxidant enzymes such as
GPxs could play an important role to oppose the augmented
ROS entailing high alcohol intake.165 Several studies investigated the total Se level in the liver, whole blood, erythrocytes,
plasma or serum of patients with hepatopathies, most of them
finding lower values with respect to control subjects.9 Recent
works have confirmed this observation for cyrrotic
patients,166,167 and have also found an association between
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depleted Se status and increased mortality.168 No additional
correlation is documented between serum Se and severity of the
disease.167 Considering these data, many authors suggested
that Se supplementation may improve the hepatic functionality
in the treatment of cyrrosis, an effect confirmed by recent
randomized trials.166,169
Despite the fact that serum Se may be partially related to
structural liver dysfunction, evidence supports that low Se in
alcoholic individuals is mainly due to a low nutritional supply
of the element because the excessive intake of alcohol is
accompanied by a decrease in the consumption of other
food.168,170 This provides additional support to the potential
benefit of Se supplementation and general antioxidant therapy
in the care of hepatic diseases caused by alcoholism.
5.5.
Renal failure
Plasma GPx3 activity and Se level in RBCs, whole blood or
plasma were found to be significantly lower in patients with
chronic renal failure (CRF) and in hemodialyzed (HD) uremic
patients compared to healthy controls, in some cases it has also
been associated with progression of the disease.171–173
Decreased dietary intake of Se, increased urinary (or dialytic)
loss, impaired intestinal absorption, abnormal binding to Se
transport proteins and other mechanisms have been proposed
to explain this association, but conclusive results are still
missing. Since the circulating levels of Se are low in CRF and
HD patients, Se supplementation could lead to positive effects,
as recently demonstrated for immune function improvement
and oxidative stress reduction,174 at least in some cases, but
may be insufficient in others. For example, Se supplementation
was found to not increase the activity of GPx3 in CRF patients,
showing that a basic impairment exists in the ability of the
kidney to synthesize this Se-protein.175 Other factors such as
dialysis and treatment procedures for renal failure have a
controversial relationship to Se levels. Starting from low Se
status in all cases, some authors have found that dialysis
contributes to a drop of blood Se at a grade which depends
on the type of membrane used,176 whereas other authors have
observed an increase of plasma Se level and GPxs activity after
dialysis.177 Collateral treatments are also relevant, i.e. the low
Se level in blood could be reversed by treating HD patients with
statins (that have anti-inflammatory and antioxidant properties).173 More studies are needed to elucidate the role of specific
factors in interaction with the altered Se metabolism that
characterizes uremic patients. Similarly to other diseases, a
decreased Se level may be a direct or indirect consequence of
renal failure, but could also exacerbate the oxidative damage,
enhancing the susceptibility to complications occurring in
CVD.178
5.6.
Neurological disorders
Selenium distribution within the different regions of the brain
appears to follow a specific scheme, characterized by higher
levels in the regions with abundant grey matter and in the
glandular parts.179 Brain Se showed an exceptional tendency
to be preserved into the organ under conditions of dietary
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deficiency,180 whereas knockout of the supply routes is accompanied by the onset of severe neurological dysfunction.179
These observations suggest important roles for Se and
Se-proteins in the brain, which is also highly exposed to
oxidative stress due to elevated oxygen consumption. Damage
from ROS takes place in several neurodegenerative disorders
such as Alzheimer’s disease, Parkinson’s disease, ischaemic
damage, exposure to environmental toxins, abuse of drugs,
brain tumors, multiple sclerosis, Batten’s disease and epilepsy.181,182
Considering the antioxidant action carried out by many Se-proteins,
these species are of potential interest as disease biomarkers in
neurological disorders.
Oxidative damage to macromolecules is an early indication
of Alzheimer’s disease (AD) that can appear before clinical
symptoms.183 The brain of AD patients is characterized by
intracellular neurofibrillary tangles and extracellular plaques
consisting of the protein amyloid b. Both features have been
observed in mice with genetic deletion of SelP, together with
impairment of synaptic function in the hippocampus, a region
involved in memory, and the reduction of spatial learning and
long-term potentiation, a cellular model for learning and
memory.184 SelP presents a characteristic expression pattern
within the centre of neuritic (dense-core) plaques.185 Although
a specific action of SelP in AD is still uncertain, its distribution
in the brain suggests a role in mitigating the oxidation accompanying plaques. The age-related alteration of other Se-proteins
activity in brain of AD patients results in increased oxidative
stress and reduced protection against neurodegeneration
through redox regulation. Other Se-proteins including GPx1,
GPx4, TrxR1, SelW, SelH and SelM may be involved in these
functions.182 Most of them are up-regulated in response to
brain injury and ROS exposure and can be considered necessary
for the maintenance of redox homeostasis in the brain, but
their specific mechanism of action is unknown.
Parkinson’s disease (PD) is another well studied neurodegenerative disorder. It is characterized by severe loss of
dopamine-releasing neurons in the substantia nigra, where
particularly high levels of Se were observed under normal
conditions. Se deficiency was proven to exacerbate the chemical
lesions of dopaminergic terminals and neurons in PD mouse
models,186 whereas Se supplementation and over-expression of
GPx1 have a protective action.187 However, the role of GPxs and
other Se-proteins in protecting dopaminergic transmission and
preventing PD is still unsupported by the evidence of a direct
correlation between proteins expression or function and PD.188
Epilepsy, ischaemia and brain trauma cause a signal cascade
of free radicals and activation of pro-apoptotic transcription
factors, resulting in neuronal loss.189 So, these pathologies
could also be associated with altered Se-proteins activity in
ROS reduction. As a support, GPx1 activity appears to be
correlated with induced seizures in mice.190,191 SelP-knockout
mice develop neurological seizures and movement disorders on
a Se-deficient diet, providing further evidence for the possible
role of Se-proteins in the prevention of epilepsy.125
Potential alterations in Se status and Se-proteins activity
are expected to be investigated in the near future in relation to
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many other neuropsychiatric disorders. For example, lower
levels of total Se and GPx activity were found in obsessive–
compulsive disorder,192 while a reduced Se intake was identified as risk factor for the development of major depressive
disorder (MDD).193 Mood was also shown to be potentially
conditioned by Se intake, so the influence of Se on brain
functions may take place at a very essential level.194
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5.7.
Immune defence and inflammatory disorders
The immune system relies on many processes including the
generation of ROS as a defence against microbial pathogens,
coordinated regulation of adhesion molecules and the expression of soluble mediators such as eicosanoids and cytokines
and their receptors. Se influences immunity through many
mechanisms, which have recently been reviewed in detail.195
As a part of the antioxidant system, GPxs and TrxRs contribute
to control ROS when they are produced in excessive concentrations during an immune reaction. The same Se-proteins also
coparticipate to a complex redox equilibrium that modulates
immune cell signalling.
GPxs may function as a secondary messenger in leukocyte activation by mediating the action of H2O2.196 According
to conventional theory, H2O2 acts directly as signalling molecule for the oxidation of adjacent Cys residues and formation
of disulphide bonds in proteins with redox-regulated Cys
residues, resulting in a change of their activation state. In
this context, the depletion of H2O2 by GPxs may interrupt the
signalling process. Conversely, a recent model proposed that
under specific conditions the oxidized GPxs may promote the
formation of disulfide bonds in regulated proteins.196 As a whole,
this complex mechanism modulates the activation/deactivation of
important signalling proteins involved in the immune response,
for example protein thyrosine phosphatases (PTPs).
In addition, in T cells TrxRs mediate the reduction of
disulphide bonds through Trx.197 Free thiols stimulate the
efficacy of T cell receptor (TCR) -induced signals including
Ca2+ flux and nuclear factors of activated T cells (NFAT), which
are the processes involved in the generation of oxidative burst
and in the regulation of cytokines.
Thus, GPxs and TrxRs play complementary roles where
equilibrium is a key factor in the modulation of immune
response. Studies carried out on Se or GPx1-deficient T cells
marked this equilibrium: compared to normal T cells, the
lack of GPx1 resulted in increased interleukin-2 receptor
(IL-2) expression and interferon-g (IFN-g) production (this
enhances the oxidative burst), according to the action of
TrxR1, whereas Se deficiency resulted in the opposite effect,
according to globally reduced Se-proteins.197,198 This picture of
the redox regulation suggests that in T cells TrxRs stimulate the
early TCR signalling events, whereas GPxs are devoted to limiting the extension of the inflammatory response after TCR
signalling.
Another specific Se-protein involved in the immune response
is SelS. Its expression in liver cells is regulated by inflammatory
cytokines and extracellular glucose concentration.199 SelS has
an antiapoptotic role, and reduces ER stress in peripheral
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macrophages.200 A particular polymorphism of SelS was
proven to be responsible for increased plasma level of the
inflammatory cytokines.201 A possible increased risk of several
inflammatory diseases could be the consequence, but a direct
correlation with stroke, autoimmune disorders or inflammatory bowel disease is still not proven.188
As a whole, Se participates in the immune response through
several actions: it regulates the balance of activity in the
eicosanoid synthesis pathways, leading to preferential synthesis of leukotrienes and prostacyclins over thromboxanes and
prostaglandins, and down-regulates cytokine and adhesion
molecule expression.202 By up-regulation of the interleukin-2
receptor expression, it leads to enhanced activity of both T and
B lymphocytes, natural killer and lymphokine activated killer
cells. Mice with a T cell-specific deletion in tRNA[Ser]Sec resulted
in knockout of all Se-proteins in the T cell.203 This produced
many effects, including decrease in their functionality, reduced
antigen-specific production of immunoglobulins in vivo, moderate to severe atrophy of the thymus, spleen and lymph nodes.
Se-deficient mice exhibit increased pathology from viral infection, owing to an exaggerated pro-inflammatory immune
response.204,205 Se deficiency or deletion of GPx1 in mice also
increases viral mutations and virulence.206
Accordingly from these functions, it is expected that Se
carries out beneficial effects on inflammatory conditions.
Negative correlations were observed between serum Se level
and rheumatoid arthritis, asthma, and immune activation
(through soluble interleukin-2 receptor and erythrocyte sedimentation rate) in Crohn’s disease.207–209 Plasma Se and SelP
concentration is lower in patients with sepsis at different levels
of seriousness or sepsis-like illness.210 Blood, plasma or erythrocytes Se level is generally lower in patients with psoriasis, a
chronic immune-mediated skin lesion.211 However, neither the
reason for such a decrease and its mechanisms are known with
certainty. Intervention studies have been carried out in patients
with severe sepsis, suggesting potential benefits for the clinical
outcome, but confirmatory data based on large populations
are needed.195
5.8.
HIV
The implications of Se for the immune system have stimulated
the investigation of its role in HIV contrasting. Chronic oxidative stress has been reported during the early and advanced
stages of HIV-1 infection, and has been linked to HIV-induced
apoptosis of T cells, development and progression of AIDS,
Kaposi sarcoma, and related neural damage.212,213 Several
studies on Se status and HIV-1 progression observed a direct
association between low plasma/serum Se concentration or
erythrocytes GPx1 activity, and reduced CD4+ counts, progression from AIDS to HIV and mortality.214 Nevertheless, other
studies have not found relatively low serum Se in HIV-1infected subjects, suggesting that its deficiency in HIV-1 infection may be most likely to occur in subjects with poor diets,
such as intravenous drug abusers and those living in poverty.215,216
Thus, maintaining an optimal Se status in HIV-1 patients may help
to increase the enzymatic defence, improve general health and
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reduce their risk of hospitalization for opportunistic infections
and complications.217
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5.9.
Diabetes
The association between Se and type 2 diabetes involves several
mechanisms, schematized in Fig. 8. Type 2 diabetes is characterized by defects in insulin secretion and action caused by
inability of the body cells to respond to the presence of insulin
(insulin resistance). Binding of insulin to its receptor initiates a
signalling cascade which induces a mild oxidative burst where
H2O2 acts as a secondary messenger.7 Hydrogen peroxide
oxidizes redox regulated Cys residues, leading to the deactivation of tyrosine phosphatase 1B (PTP-1B) and phosphatase and
tensin homolog protein (PTEN). PTP-1B deactivates the insulin
receptor substrate (IRS), whereas PTEN inhibits the phosphatidylinositol 3-kinase (PI3K), resulting in the overall stimulation of
signalling pathway for glucose uptake. GPx1 and GPxs reduce
H2O2, so they are supposed to carry out an inhibitory action on
the signalling cascade. Experimental evidence supports this
hypothesis because transgenic mice over-expressing GPx1 exhibit
insulin resistance,218 whereas knockout of GPx1 improves insulin
sensitivity.219 Confirmation in humans raised from the observation that increased erythrocyte GPx1 activity associates with
mild insulin resistance in pregnant women,220 and systemic
Se-proteins deficiency (by mutations into the SBP2 gene)
enhances insulin sensitivity.221
However, other Se-proteins participate in glucose metabolism, making the global effects of Se more complex. SelP is
supposed to inhibit the insulin signalling pathway by inactivating the adenosine monophosphate-activated protein kinase
(AMPK), a positive regulator of insulin synthesis in pancreatic
insulin-producing b cells.222 In vitro studies demonstrated
also that SelP expression in human subcutaneous adipocytes
is up-regulated by insulin.223
TrxRs may positively influence insulin signalling by providing reducing equivalents in the form of Trx. In skeletal muscle,
proteins S-nitrosylation operated by NO has been proposed to
contribute to the induction of muscle insulin resistance.224
Fig. 8
S-Nitrosylation of the subunit b of IR and Akt attenuates their
kinase activities, and S-nitrosylation of IRS-1 reduces its expression, resulting in the inhibition of glucose uptake.225 Trx and
its recycling, mediated by TrxR1, play an important role in the
regulation of this cellular process by reducing NO.226 Additionally, both Trx1 and GSH (that is regulated by GPx) in the
disulfide form can be nitrosylated and subsequently transnitrosylate proteins, thus functioning either to denitrosylate
or nitrosylate proteins depending on their redox state.227 So,
the overall effect of Se level in the context of insulin signalling
under normal conditions is arduous to extricate.
In addition, hyperglycaemia induces oxidative stress
through activation of the polyols pathway, which increases
the utilization of NADPH and the production of superoxide
anions. The toxicity of high glucose levels is also related to free
radicals generated by auto-oxidation of sugars, prostanoids
metabolism, and proteins glycation. A consistently high oxidative stress level or low antioxidant defence were revealed in
patients with diabetes, which are responsible for many pathogenic processes of diabetic complications.228 As for some other
pathologies, a general protective function of Se may rely on the
action of Se-proteins for ROS reduction. Several studies demonstrated that Se prevents or alleviates the adverse effects that
diabetes has on cardiac and renal functions, vascular complications, and atherosclerosis progression.229,230
Observational studies on Se supplementation have shown
that the element can have insulin-mimetic properties, being
effective in the stimulation of glucose uptake both in vitro
and in vivo, the regulation of glycolysis, gluconeogenesis, fatty
acid synthesis and the pentose phosphate pathway.231 Selenate
in particular has been proposed to influence two important
mechanisms involved in insulin resistance: firstly it reduces
the activity of liver cytosolic protein tyrosine phosphatases
(PTPs) as negative regulators of insulin signalling; and secondly
it increases the expression of the peroxisome proliferatoractivated receptor gamma (PPARg).232 These two mechanisms
are responsible for the changes in the intermediary metabolism, in particular gluconeogenesis and lipid metabolism.
Scheme of the potential role of Se-proteins in the regulation of the insulin signaling cascade.
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Several case-control and randomized trials have been conducted to investigate the possible direct association between
the Se status and the incidence of type 2 diabetes, resulting in
apparently contradictory results. Some studies have shown that
mean plasma, serum or blood total Se concentrations, GPx3
and SeAlb level, or GPx3 activity are lower in patients with
diabetes than in controls.233–236 Lower plasma/serum Se levels
have also been found in gestational diabetic pregnancies with
respect to normal pregnancies.237,238 Conversely, other works
have found high Se status in patients with diabetes, or did not
observe any significant differences.239,240 Finally, in some cases
the difference in Se status was limited to specific sub-groups
such as males241 or patients with a disease duration r2 years.234
The latest results from randomized trials confirmed such conflicting data, showing that Se supplementation could either
increase the risk of type 2 diabetes or be ineffective.242,243 As a
whole, the association between Se and type 2 diabetes appears to
follow a U-shape, so that it may show variable effects depending
on the position of the population baseline level of Se intake.
5.10.
Endocrine disorders
Pathologic conditions directly caused by DIOs deficiency in
humans have so far not been documented; however several
disorders involving the metabolism of thyroid hormones are
characterized by abnormal regulation of these Se-proteins.
Some of these disorders have a genetic origin. A recent study
identified a homozygous missense mutation of SBP2 gene as
responsible for abnormal thyroid functions in humans due to
decreased activity of DIO2 and unexpressed DIO1 and DIO3,244
a defect which cannot be corrected by SeMet supplementation.245
Another SBP2 gene mutation was then identified, which
produces an early stop codon and results in a relatively mild
clinical profile.246
In other endocrine disorders, altered levels of DIOs can be
significantly correlated to the Se intake. A combined deficient
intake of Se and iodine has been identified to be the cause of
the endemic mixedematous cretinism.247 Several studies have
linked a moderate deficiency of Se to autoimmune thyroiditis
(AIT), demonstrating that long-term supplementation with
SeMet or selenite entails a reduction of anti-thyroid peroxidase
antibodies (anti-TPO) in most cases, with positive effects on the
course of AIT.247 Graves’ hyperthyroidism is an example of
thyroid autoimmune disorder, caused by the production of
autoantibodies to the thyrotropin (TSH), a receptor that stimulates the activity of DIOs, particularly DIO1, for the production
of T3 and T4. Under moderate Se deficiency, Se supplementation
was shown to favour the normalization of thyroid hormones
metabolism, an effect that was ascribed to the increased efficacy
of deiodination mediated by DIOs, coupled to enhanced contrast
to the elevated level of ROS mediated by GPxs.248 A similar
inadequate contrast to ROS by GPxs, but conversely combined
with insufficient thyroid hormone synthesis due to reduced
level of DIOs, may be hypothesized also in autoimmune
hypothyroidism, such as Hashimoto’s disorder.249 Therefore, a
poor Se diet may be a risk factor for autoimmune thyroiditis,
particularly in genetically predisposed subjects.
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5.11.
Male infertility
Moderate Se deficiency leads to impaired sperm motility and
morphological alterations of the midpiece architecture, often
resulting in disconnections of heads and tails, while in extreme
Se deficiency spermatogenesis is completely abrogated.250 The
important structural and antioxidant actions played by GPx4 in
human spermatozoa make it a major candidate as a mediator
of such effects. This Se-protein was recognized as one of the
possible causes of oligoasthenozoospermia, a form of infertility
characterized by a reduction of both the number and the
motility of spermatozoa.251 In addition, a decrease in the
expression level of GPx4 in the spermatozoa results in defected
incorporation of rhodamine 123, with a loss of mitochondria
membrane potential that affects their morphology.251 As an
antioxidant enzyme, GPx4 reduces phospholipid hydroperoxide
and H2O2, which are important secondary messengers in
spermatogenesis. While these species are responsible for protamine
sulfoxidation, an important process favouring sperm DNA
condensation, they also contribute to oxidative stress, which
may have dramatic effects on the integrity and motility of
spermatozoa.252 An extremely fine modulation of the messengers
is necessary, in which GPx4 plays an important role. However,
despite elevated level of H2O2-mediated oxidative stress in
spermatozoa being commonly associated with male infertility,
GPx4 polymorphism or reduced activity/concentration remain
unverified as causal factors in human patients.
5.12.
Cancer
5.12.1. Cancer and total selenium intake/status. Selenium
has become mostly known in recent years due to its assumed
preventive properties against some types of cancer, mainly due
to its antioxidant action. The ability of Se to reduce carcinogen
induced and spontaneous cancer incidence has been widely
investigated over the last 20 years in both animal and human
models, in most organs, and against a broad range of cancer
forms. Table 3 reports the most recent meta-analyses conducted to extrapolate a general interpretation of the relationship between Se-status and cancer risk.
Although many studies have revealed a potential association
between Se status and cancers incidence, inferring a conclusive
interpretation appears still to be arduous. Several studies
observed an inverse correlation between Se levels and risk of
prostate,254 bladder261 and lung257 cancers. On the contrary, no
significant effects were found in Se supplementation randomized trials for prostate262 and colorectal263 cancers, as well as
in case-control studies regarding primary liver cancer.264 Some
indications can be gathered on the possible factors underlying
the complexity of the relation between Se and cancers. Genderdependent effects were found for colorectal cancer256 and a
pooled set of different cancer forms,260 suggesting that men
may respond to Se supplementation more significantly than
women. Another important indication arises from the observation that Se status might show an effect on cancer risk in
a limited range of levels only, whose boundaries are defined by
the insufficient and saturated activity of Se-enzymes. For example,
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Table 3
Selected meta-analyses on Se and of various types of cancer. RR: relative risk, OR: odds ratio; CL: confidence limits
Tissue
Prostate
Number
of studies Type of study
12
20
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Colorectal
7
15
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16
Randomized trial, case-control,
cohort
Case-control, nested case-control,
cohort
Comparison
RR/OR (95% CL)
Ref.
a
Highest vs. lowest in plasma/ 0.29 (0.14 to 0.61)
serum, toenail, diet
0.23 ( 0.40 to 0.5)a
Pooled standardized mean
difference in plasma/serum,
toenail
Hurst et al. (2012)253
Brinkman et al. (2006)254
Case-control, nested case-control, Highest vs. lowest in plasma/ 0.67 (0.55 to 0.81)a
Ou et al. (2012)255
cross-sectional
serum
Randomized trial, observational
Highest vs. lowest in blood,
Women 0.97 (0.79 to 1.18) Takata et al. (2011)256
toenail
men 0.68 (0.57 to 0.82)a
Case-control, cohort
Highest vs. lowest in serum,
toenail, diet
0.74 (0.57 to 0.97)a
Zhuo et al. (2004)257
Amaral et al. (2010)258
Bladder
7
Case-control, nested case-control, Highest vs. lowest in serum,
cohort
toenail
0.61 (0.42 to 0.87)a
Various
9
7
4
Randomized trial
Randomized trial
Randomized trial
0.76 (0.58 to 0.99)a
Lee et al. (2011)259
0.64 (0.53 to 0.78)a
Lee et al. (2011)259
Women 1.00 (0.89 to 1.13) Bardia et al. (2008)260
men 0.77 (0.64 to 0.92)a
a
Supplement vs. placebo
Low vs. high in serum
Highest vs. lowest in diet
Significant.
a study noticed that Se supplementation associates with a reduced
risk of lung cancers in populations with baseline serum Se level
o106 ng mL 1, whereas increases the risk in those with Se level
>121.6 ng mL 1.265 A similar relation was observed in a metaanalysis on prostate cancer, where plasma/serum Se negatively
correlated with prostate cancer risk only below 170 ng mL 1.253
These findings suggest that Se exhibits a U-shape relation with
cancer risk, in analogy with many other antioxidants.3 Still, all
observational studies and randomized trials appear to be highly
conditioned by the composition of the population with respect to
covariates and confounding factors including baseline levels of Se
intake, co-supplemented antioxidants, age, gender, diet, lifestyle,
time scale and others.
5.12.2. Cancer and selenoproteins. Another important
factor usually unconsidered in both individual studies and
meta-analyses is the actual representative parameter chosen
to assess the Se status. Almost all epidemiological research has
determined Se status using the total concentration of the
element in plasma/serum, toenail, hair or food/supplements.
Only a few studies investigated the relationship between cancer
and individual serum, plasma or tissue Se-proteins concentration. A recent work reported a significantly higher level of
SeAlb in early-stage colorectal cancer patients compared to the
advanced stage and controls. No significant differences
emerged in this case if considering GPx3, SelP or total serum
Se, demonstrating that these parameters may be inadequate to
figure out a complex association with cancer under non-deficient conditions. Other works did not reveal any association
between colorectal cancer and total Se, GPx3 and SelP levels in
plasma or serum.266,267 Conversely, some studies found an
inverse correlation between plasma GPx3 and colorectal cancer
or uterine cervix cancer,268 plasma SelP and various types of
cancer,269 tissue SelP and colorectal adenoma,270 tissue GPx4
and pancreas271 as well as breast272 cancers. The level of TrxR1
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in tumour cells was suggested to be higher than in normal
tissues.273 The limited amount of epidemiological information,
still contradictory in some cases, on the relationship between
individual Se-species and cancer marks the importance of
improving these investigations, which are often limited in
sample size due to their higher analytical complexity.
More numerous are the studies in genetics and biochemical
behaviour of Se-proteins in cancer tissues or cell lines. The
biochemical association between Se-species and cancer is
mainly mediated by their action in oxidative stress control.
Oxidative stress plays an important role in carcinogenesis by
means of DNA damage induction and its effects on intracellular
signal transduction pathways.274 Reactive oxygen species can
induce almost all forms of DNA damage that have been
reported in genes dysfunctions which are involved in the
genesis of cancer, and play a key role in cancer development
by inducing and maintaining the oncogenic phenotypes.275 As a
consequence, genetic polymorphisms, gain or loss of functions
of antioxidant enzymes, such as GPxs, has attracted great
interest in the study of cancer and its therapy.276 The loss of
the heterozygosity of GPx1 gene has been implicated in lung
cancer development, while GPx1 polymorphism is associated
with an increased risk of breast,277 bladder,278 hepatocellular,279
prostate280 carcinomas, and non-Hodgkin’s lymphoma.281 SelP
polymorphism is associated with colorectal adenoma.282 GPx3
hypermethylation has been shown to occur frequently in prostate
cancer and Barrett’s esophagus.4 Sep15 polymorphism is associated with lung cancer.283 GPx2 is upregulated in some types of
cancer, particularly of gastrointestinal origin.284 A recent study
has shown that lower expression of GPx2 increases migration and
invasion of cancer cell clones, but decreases their growth, thus
depending on the stage of tumour development.285 Finally, TrxR1
is probably the most investigated Se-protein in its relationship to
cancer. This Se-protein presents both prevention and promoting
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properties for tumours: it regulates the redox state in the cell
and activates the p53 tumor suppressor286 and its deficiency
alters cell morphology,287 but it is also targeted by a number of
anticancer drugs.288
5.12.3. Selenium in cancer therapy. A number of nonproteic Se-species have also been tested in cancer therapy for
many clinical aspects. Sodium selenite systemic or topical administration elicits radioprotective effects in normal tissues.289 Such
an effect was not observed in the corresponding malignant tissues,
where dose-dependent radiosensitizing capacities, including apoptosis induction and cytotoxicity, were on the contrary noticed.290 In
general, the substitution of sulfur by Se in cancer chemopreventive
agents is supposed to result in more effective analogues. This idea
was confirmed for the action of a Se-analogue of the chemopreventive agent S,S0 -(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), also known to inhibit inducible nitric oxide synthase
(iNOS), as an inducer of apoptosis and inhibitor of cell growth in
the case of lung cancer.291 Following the same principle, a number
of organic Se-compounds have been synthesized and tested as
chemopreventive agents.292 The production of monomethylated Se
from methylselenocysteine or methylseleninic acid has been postulated as a key step in the mechanism of Se-species anticancer
activity.293 In particular, methylseleninic acid synergizes with
tamoxifen to induce caspase-mediated apoptosis in breast cancer
cells.294
An additional aspect to be considered is that Se deficiency is
nearly the norm in cancer patients treated with radio- and
chemotherapy, or even just hospitalized.295 Supplementation of
cancer patients with Se at doses of up to 2000 mg per day, alone
or in combination with vitamins, has been suggested as a way
to improve their general quality of life.295
5.13.
Ageing-related diseases
The relationship between Se levels and ageing is still controversial. Plasma/serum Se concentration seems to remain stable
with age, but the tissue distribution may be altered.213 The
association of Se with ageing is generally indirect, due to the
fact that most of the biological processes in which Se is
involved change with age. Several studies have shown that
ageing cells accumulate oxidative damage.296 Ageing-related
oxidative stress influences many of the processes mentioned
Fig. 9
Metallomics
in the sections above, including damage to both mitochondrial
and nuclear DNA, lymphocyte population fall, telomere length
decrease in peripheral leukocytes and thyroid hormones alterations. In this context, an inadequate Se intake (even if moderately deficient) should be considered as a risk factor for many
ageing-related diseases such as cancers, cardiovascular and
immune disorders.297
5.14.
Interaction with toxic metals
A particular relationship of Se with human diseases concerns
its interaction with toxic metals and metalloids. Selenium has a
generic antagonistic effect against metals’ toxicity through a
dual action, represented in Fig. 9: direct sequestration of the
toxicant and mitigation of the metal-induced oxidative
stress.298 Low molecular weight Se-species including selenide,
free SeCys and SeMet, compete with GSH, Cys and thiols in
general for conjugation of the metal. Theoretically, many metal
cations may form insoluble colloids or complexes with selenide, as has been observed in yeast cultures,299 but only silver
(Ag) has been documented to accumulate in mammalian cells
in this way.300 Conversely, Se is generally associated to a
decreased bioaccumulation of arsenic (As) and cadmium
(Cd), so that excretion mediated by conjugation of these
elements with organic Se-species may be gathered as the
favoured route.298 The antioxidant action of Se-proteins mitigates the cellular damage induced by metal-generated ROS. On
the other hand, Se-proteins are also a target for metals’ toxicity
due to two effects: (i) their selenolic group make them susceptible to metal binding and consequent inactivation; (ii) each
intermediate Se-metabolite engaged by the metal is also taken
away from the synthesis pathway, thus from essential biological
functions, resulting in a possible indirect damage.298 A limited
number of studies investigated until now the molecular
mechanisms driving these interactions, most of them focusing
on As and mercury (Hg) metabolism, whereas most works were
limited to observing associations between physiological/intake
Se and metal levels or biological markers.298
The interaction of Se with As leads to a mutual inhibition
of the methylation pathways and suppression of As-induced
signalling, but also synergistic toxicity may be generated in
some cases by the inactivation of the zinc-finger proteins.301,302
Scheme of the potential role of Se-species in the toxicity and detoxification of exogenous metals (Mx).
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In animal models, arsenite and selenite were shown to react
with GSH in erythrocytes and the liver, forming the complex
(GS)2AsSe .302 This complex is biliary excreted into the gastrointestinal tract, leading to both a counteraction of As accumulation in the organism and an alteration of Se metabolism in
case of contamination. Biliary excretion of As would conversely
reduce its level in the urine. A number of epidemiologic studies
support the existence of an inverse association between blood
Se and urinary As in humans, but the formation of Se–As
conjugates has not yet been demonstrated.303,304
The association between Se and inorganic Hg in exposed
subjects is well established.305 In the bloodstream, selenite
reacts also with Hg2+ to form a species with a core of HgSe
and GS-moieties ligated on the surface in the form
(HgSe)100(GS)5.302 This species binds to SelP up to a proportion
of 35 units per protein, so that this Se-protein is actively
involved in a detoxification mechanism for Hg. Methyl-Hg
(MeHg) is another highly toxic species which exhibits high
affinity for selenide and selenols.306 The potential interaction
of MeHg with free SeCys, SeMet and selenide in serum (where
they constitute B10% of the Se pool) may sequestrate the
species from thiols binding and crossing the blood–brain
barrier, so limiting its neurotoxic effect. Conversely, MeHg
binding to selenoproteins inhibits their activity of contrasting
the oxidative stress. A number of epidemiological studies have
revealed some association between supplemented selenospecies, Hg poisoning and excretion, Se-proteins activity and
oxidative damage.307–309 However, the mechanisms appear to
be difficult to extricate as low molecular weight selenospecies
and selenoproteins have different roles, and Se–Hg interaction
may result in antagonistic, additive, or synergistic effects depending on the context.
Among the other metals, Ag is considered an emerging
pollutant of which the biochemistry and toxicity is important
as much as it is obscure. The biological transformation of Ag
nanoparticles has been proposed to occur by means of gastric
dissolution and ions absorption, circulatory thiol transport,
photoreduction to secondary Ag0 particles and superficial
sulfidation.300 Reduced Se-species have also been shown to
react with the surface of Ag nanoparticles. Kinetic and thermodynamic evidence support the hypothesis that Se cannot compete with the initial sulfidation, but Se/S exchange reactions
occur afterwards, leading to the formation of Ag/S/Se particulate deposits in tissues.300 Further studies are strongly needed
to shed light on the exact metabolic pathways through which
individual selenospecies influence the biological transformation and toxicity of heavy metals in vivo.
6. Conclusions and perspectives
Remarkable progress has been achieved in recent years about
the knowledge of the processes driving the biological action of
Se and its species. A complex picture has emerged, where
multiple Se-proteins cooperate in the regulation of transcription mechanisms, oxidative stress and redox signalling. Experiments carried out using animal models, such as knockout or
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overexpressing mice for specific Se-proteins, allow explicit
investigation of the specific action of individual species; nevertheless uncertainty rises over the reliability of results when
extended to humans under normal conditions. The lack of a
clear definition of what is a ‘‘normal’’ Se status, and a corresponding adequate set of parameters to assess it, prevents the
identification of those factors related to health disorders.
The complexity of this issue lies in a number of interacting
key aspects, as follows: (i) bioactive Se-species intervene on the
equilibrium of biological functions in a quantitative way. As
well being represented by the example of immune response,
Se-proteins may play opposite actions with other substances or
themselves, depending on the biochemical context, the regulatory mechanisms and the relative concentration/activity. A wide
variety of new methods have been developed in recent years for
the quantification of Se-species, among which Se-proteins are
the most challenging.310 A full integration of these methods
with qualitative biological and clinical approaches will provide
new tools to elucidate the unknowns in the Se-regulated
processes. (ii) Genetic polymorphism of Se-proteins has arisen
as a potential forcing variable in the regulation of both Se
status and disease risk, progression and prognosis. Exhaustive
studies are strongly needed to elucidate how genetic factors
influence the response of the organism to the Se intake and
metabolism under disease conditions. (iii) The advancement in
the understanding of genetic and biochemical processes must
be used to drive epidemiological studies in detail. Despite the
large number of both observational studies and randomized
trials that have been conducted over the years, many of them
have been criticized because of the inadequate selection criteria
or scarce collection of complementary data. Particular attention
should be paid to the genetic characterization of subjects, the
distribution of Se status within the population, and the quality
of the marker(s) adopted for assessment of Se status.311 Finally,
a number of unresolved questions need to be dealt with, such
as the dynamics and regulation of the biosynthesis of Se-proteins,
and the comprehension of the biochemical function for most of
the Se-proteins.
The emergent discipline of Systems Biology offers promising
tools to integrate all these key aspects, by combining large
amounts of experimental data coming from genomics, transcriptomics, proteomics and metabolomics, to generate comprehensive networks models.312 A number of Bioinformatic applications
like Gene Ontology (GO) or List2Networks can be used to integrate
experimental data with existing databases, to generate protein–
protein interaction and gene regulatory networks. Network analysis
could allow the detection of potential key features of the complex
Se-proteins system, such as: the existence of gateway proteins
(hubs) in biochemical pathways; new regulatory mechanisms of
the global and local Se status; reactions and robustness of the
system to be perturbed due to the altered intake, disease onset/
progression and pharmacological treatment. Overall this new
information may constitute an important base to figure out the
dynamics of Se-proteins-regulated processes under normal status
situations, to predict the changes under altered diet and health
conditions, and to drive reliable epidemiological studies.
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Acknowledgements
This work has been financially supported (PJ) by a Marie-Curie
Intra-European Project (MEIF-CT-2006-024156/ELSA-BIM) funded
by the European Commission.
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