Journal of Elementology ISSN 1644-2296

Grosicka-Maciąg E., Szumiło M., Kurpios-Piec D., Rahden-Staroń I. 2017.

Biomedical effects of selenium in a human organism. J. Elem., 22(4): 1269-1284.
DOI: 10.5601/jelem.2017.22.1.1357

REVIEW PAPER

BIOMEDICAL EFFECTS OF SELENIUM

IN A HUMAN ORGANISM*

Emilia Grosicka-Maciąg, Maria Szumiło,

Dagmara Kurpios-Piec, Iwonna Rahden-Staroń
Chair and Department of Biochemistry
Medical University of Warsaw, Poland

Abstract

Selenium, an essential nutrient in a human diet, can be administered in both organic and inor-
ganic forms. Organic forms are easier to ingested than inorganic ones. The biological functions
of selenium are mediated largely by selenoproteins. Selenium is present in mammalian seleno-
proteins as selenocysteine. Human selenoproteins encoded by 25 genes are involved in glu-
tathione-dependent hydroperoxide removal, reduction of thioredoxins, selenophosphate synthe-
sis, activation and inactivation of thyroid hormones, repair of oxidized methionine residues, and
ER-associated protein degradation. These functions are responsible for the role of selenium in
human health, including its pro- and anticancer activities, roles in the immune system, and
other functions. Selenium is regarded as a controversial trace element. Its deficiency is associat-
ed with cancer, cardiovascular diseases, infertility, thyroid diseases and poor immune functions.
On the other hand, selenium in high levels has been considered as a poison, causing symptoms
such as memory loss, fatigue, diarrhoea and vomiting, in addition to which it can increase the
risk of type 2 diabetes and cancer. There are many aspects of the metabolism of selenium and
selenoproteins that remain to be investigated. The purpose of this article is to bring up to date
the current status of the developing field of selenium research, centered around the health be-
nefits attributed to this element. The relationship between the selenium status in a human or-
ganism and selected health outcomes is discussed.

Keywords: selenium, metabolism, selenoproteins, health effects, supplements.

Emilia Grosicka-Maciąg, Department of Biochemistry, Medical University of Warsaw,

02-097 Warszawa, Banacha 1 st, Poland, phone: +48 22 5720 689, fax: +48 22 5720 679; e-mail:
[email protected]
* This work was supported by grant from WK/PM11D/15 from the Medical University of
Warsaw, Poland.
1270

INTRODUCTION

In 1957, selenium (Se) was recognized as an essential micronutrien

(Schawrz, Foltz 1957). Selenium is incorporated into proteins (selenopro-
teins) in a co-translational mechanism as the 21st amino acid, selenocysteine
(Sec). Selenoproteins have several functions, including selenium homeostasis
and transport, thyroid hormone metabolism, antioxidant defence, anti-
-inflammatory action and cardiac and skeletal muscle metabolism (reviewed
in ref. Frączek, Pasternak 2013, Mehdi et al. 2013, Hatfield et al. 2014).
Selenium is regarded as a controversial trace element. Selenium defi-
ciency is associated with cancer, cardiovascular disease, infertility, thyroid
disease and poor immune function. On the other hand, selenium in high
levels has been considered as a poison, causing symptoms such as memory
loss, fatigue, diarrhoea and vomiting (reviewed in ref. Navarro-Alarcon,
Cabrera-Vique 2008, Frączek, Pasternak 2013).
The purpose of this article is to bring up to date the status of the deve-
loping field of selenium research centered around the health benefits attribu-
ted to this element We discuss the relationship between the selenium status
in a human organism and selected health outcomes.

SOURCES, METABOLISM AND DISTRIBUTION

OF SELENIUM COMPOUNDS

Selenium exhibits valences of (II), (IV), and (VI). It is present in both

inorganic (Figure 1) and organic compounds (Figure 2).

Fig. 1 Structures of inorganic selenium-containing compounds: selenite (Se(IV)) – a,

selenide (Se(II)) – b and selenate (Se (VI)) – c

In living organisms, both organic and inorganic compounds containing

selenium are metabolized. Figure 3 presents metabolic pathways of sele-
nium-containing compounds in the human organism.
Bioavailability of selenated organic compounds is much higher than that
of inorganic compounds (Thomson 2004). The absorption of Se-species occurs
by different mechanisms mainly in the lower part of the small intestine.
The efficiency of absorption of inorganic and organic selenated compounds is
almost complete (70-90%) under physiological conditions. The exception
 1271

Fig. 2. Organoselenium compounds (Se(II)): Se-methylselenocysteine (SeMeSec) – a,

selenocysteine (Sec) – b, selenomethionine (SeMet) – c, 2-selenyl-Nα’Nα’Nα-trimethyl-L-histidine
(selenoneine) – d, γ-glutamyl-Se-methylselenocysteine (GGSeMeSec) – e

Fig. 3. Metabolic pathways of selenium in the human organism.

Adapted from Weekley et al. (2013)

is selenite absorption which does not exceed 60%. However, its absorption is
increased in the presence of reduced glutathione (GSH) in the gastrointestinal
fluid. The absorbed fraction of selenite is reduced to selenodiglutathione
(GSSeSG) by GSH, thioredoxin reductase (TrxR), thioredoxin (Trx), and glutare-
doxin (Grx) systems. GSSeSG is subsequently transformed to hydrogen sele-
nide (HSe-). In this form, selenium can be directed to the metabolic pathways
leading to the synthesis of selenosugars or selenoproteins. Hydrogen selenide
can also be metabolized into selenium in its 0 oxidative state (Weekley
2013).
1272

Selenate is actively absorbed by a Na+-dependent transport system like

sulphate. Then, it is reduced by ATP sulfurylase to selenite. After this pro-
cess, the metabolic pathway for selenate is the same as for selenite (Mataix
Verdu, Llopis 2002).
Selenium incorporated into amino acids undergoes different metabolic
processes. Selenomethionine is absorbed by the same Na+-dependent neutral
amino acid transport system used by methionine. On the other hand, seleno-
cysteine and selenite are not absorbed by active transport and their capture
is not inhibited by similar sulphur compounds as well as by selenium status
in the organism (Mataix Verdu, Llopis 2002). Selenomethionine can be meta-
bolized through three different pathways: (1) directly non-specifically incor-
porated into Se-containing proteins, (2) metabolised to selenocysteine or (3)
degraded to methyl selenol (MeSe-) by γ-lyase (Brozmanová et al. 2010).
Methyl selenol can also be formed via SeMeSeCys from g-glutamyl-Se-
-methylselenocysteine (g-glutamylSeMeSeCys) found in plants.
In humans, methylselenocysteine is changed by β-lyase to methyl sele-
nol, which can be metabolized to selenide (HSe-). It is next methylated to
di- and trimethylselenium ion. Selenide is the common point for regulation of
selenium metabolism in the human organism due to the fact that different
forms of selenated compounds are metabolized into it. Under a low-toxic
selenium status, selenide is converted on a major excretory pathway which is
the formation of selenosugars: Se-methyl-N-acetyl-galactosamine (MSeGalNAc),
Se-methyl-N-acetyl-glucosamine (MSeGluNAc), and Se-methyl-N-amino-
-galactosamine (MSeGalNH2) excreted in urine (Kobayashi et al. 2002).
When selenium intake is excessive, dimethylselenide may occur in the
breath and the trimethylselenonium ion may occur as a minor metabolite in
urine (Francesconi, Pannier 2004). Faecal excretion is also the path of sele-
nium elimination. A low amount of selenium is lost through the skin. Both,
biotransformation in the liver and excretion represent a major mechanism by
which selenium homeostasis is maintained during excessive exposure (Mataix
Verdu, Llopis 2002). The selenium requirement to compensate for minimal
losses in humans is 50-70 mg/day (Alexander, 2015).

SELENOPROTEINS

Selenium is incorporated as selenocysteine into at least 25 selenopro-

teins encoded by the human genome (Rayman 2012, Gladyshev et al. 2016).
Selenocysteine is found in the active centre of a number of selenoprotein
enzymes (Lu, Holmgren 2009). The majority of selenoproteins catalyze oxida-
tion-reduction reactions, particularly the families of glutathione peroxidases
(GPxs) and thioredoxin reductases (TrxRs). The family of glutathione peroxi-
dases consists of cytosolic and mitochondria GPx1, gastrointestinal GPx2,
plasma GPx3, phospholipid hydroperoxide GPx4, and the olfactory epithe-
 1273

lium GPx6. GPx1 is a major antioxidant enzyme in vivo and it is irreplaceable

by any other selenoproteins (Brigelius-Flohé, Flohé 2016). GPx2 may serve
as a first line of defense in exposure to ROS induced by ingested prooixdant
or gut microbiota. (Roman et al. 2014). GPx3 is the only extracellular enzyme
of GPxs family. It is primarily synthesized in the kidney and from there it is
released as glycosylated protein into the extracellular spaces, but the major
fraction remains bound to the base membrane of a kidney (Avissar et al.
1994). GPx3 is also expressed by the gastrointestinal tract, lung, liver, heart,
brain, breast and adipose tissue (Roman et al. 2014). Moreover, this enzyme
is highly expressed in the thyroid gland, where it catalyzes the polymeriza-
tion of thyroglobulin to the highly cross-linked storage form (Schmutzler et
al. 2007). GPx4 specifically prevents lipid peroxidation in cell membranes.
The expression of GPx2 and GPx4 is more resistant to dietary Se deficiency
in comparison to the expression of GPx1 and GPx3. Another form of glu-
tathione peroxidase is found in high concentrations in spermatozoa, where it
is involved in sperm maturation and the prevention of cellular apoptosis
(Patrick 2004).
Three isoforms of human thioredoxin reductases (cytosolic TrxR1, mito-
chondrial TrxR2, and thioredoxin glutathione reductase TrxR3) catalyze the
NADPH dependent reduction of thioredoxin and therefore play a regulatory
role in its metabolic activity. They provide reducing equivalents to the disul-
phide bonds in enzymes such as thioredoxin peroxidase, ribonucleotide reduc-
tase, in and transcription factors (Rundolf, Arner 2004). Therefore they play
important role in the reduction of nucleotides (Mustacich, Powis 2000), regu-
lation of transcription, and sperm maturation, the cell growth and inhibition
of apoptosis (Roman et al. 2014). TrxR1 and TrxR2, both appear to be invol-
ved in embryogenesis, TrxR2 is involved in control of mitochondrial redox
processes by reduction of cytochrome c, and takes part in apoptosis signaling
(Nalvarte et al. 2004). Activity of thioredoxin reductase depends on the cel-
lular selenium level.
The second major active class of selenoproteins are the iodothyronine
deiodinases (DIOs), the family of three integral membrane enzymes. They
take part in the thyroid hormone metabolism by catalyzing the activation
(DIO1, DIO2) or inactivation (DIO3) of tetraiodothyroxine (T4), triiodothy-
ronine (T3), and reverse-triiodothyronine (rT3). DIO1 and DIO3 are found in
plasma membrane, whereas DIO2 is localized in the endoplasmic reticulum
membranes. DIO1 is responsible mainly for the control of circulating triiodo-
thyronine level, whereas DIO2 and DIO3 are involved in the regulation of
deiodination processes in the thyroid gland (Baqui et al. 2003). If the thyroid
gland functions properly, it has the ability to maintain a high level of selenium
in serum even if the dietary intake of this element is insufficient (Szybiński
et al. 2010)
Expression of selenoproteins is strictly controlled by the selenocysteine
translational process, which is highly dependent on the presence of selenium
(Turanov et al. 2011). Selenium deficiency reduces the intracellular amount
1274

of mature tRNA-Sec, which in turn results in decreased selenoproteins syn-

thesis. However, there is a hierarchy of selenoproteins expression. Selenopro-
tein synthesis is also considered to be modulated by different expression of
two selenocysteine tRNA isoforms, which are distinguished by the presence
of 2-O-methylribose at position 34 (Um34). The Um34 modification is also
dependent on selenium availability. The mutation of the selenocysteine tRNA
gene (TRSP) which interferes with the Um34 modification has recently been
described in a human organism, where authors noted decreased expression
of stress-related selenoproteins (GPx1 and GPx3), while the expression of
housekeeping selenoproteins, essential for survival, was largely preserved
(Schoenmakers et al. 2016).
Selenoprotein biosynthesis is hierarchically organized, which means that
an individual selenoprotein level does not respond identically to the alimen-
tary selenium supply. Additionally, the fact that there is hierarchical de-
mand of tissues for selenium complicates this hierarchy (Sunde 2012, Barret
et al. 2016). GPx1 and GPx3 rank low in the hierarchy, GPx4, depending on
the tissue, ranks medium to high, and GPx2 ranks the highest. This implies
that the hydroperoxide metabolism responds to selenium restriction in a
tissue-specific manner depending on the expression pattern of the enzymes
involved. TrxR3 ranks higher than TrxR1 and TrxR2. The three deiodinases
rank high. Selenium is delivered to particular tissues as selenoprotein-P,
whose uptake by lipoprotein receptors differs among tissues. In consequen-
ces, a protein like GPx4 ranks so high in the testis that it can hardly be de-
pleted, but will readily decline due to selenium restriction in a non-privileged
tissue such as the liver (Sunde 2012).
Approximately 60% of selenium in the plasma is incorporated in seleno-
protein-P (SEPP1), which contains 10 Se atoms per molecule as selenocysteine.
Selenoprotein-P is expressed in many tissues, suggesting that it plays a cen-
tral role in selenium supply to tissues and participates in the regulation of
selenium metabolism in an organism. However, it is important to note that
SEPP1 acts also as an antioxidant enzyme and may serve as a heavy-metal
(eg. mercury) chelator (Reeves, Hoffman 2009, Barret et al. 2016). Aside
from the normal antioxidant activity contributed by selenocysteine, seleno-
protein S (SepHS2 – selenophosphate synthetase 2) and selenoprotein 15
(selenoprotein F, the 15 kDa selenoprotein Sep15) can process and remove
misfolded proteins (Labunskyy et al. 2009), while MsrB1 (methionine-R-sul-
foxide reductase 1) is capable of regulating antioxidant protein repair thro-
ugh protein disulfide shuffling (Kaya et al. 2015). The role of many human
selenoproteins is still unknown or not fully elucidated.
 1275

SELENIUM AND HEALTH OUTCOMES

Health effects of deficiency or excess of selenium

Selenium deficiency can result in significant deterioration of health and
development of serious illnesses. Recently the German, Austrian and Swiss
nutrition societies have revised and published (February 2015) the reference
values for the intake of selenium. The saturation of selenoprotein P in the
plasma is used as a criterion for the derivation of reference values for sele-
nium intake in adults (Kipp et al. 2015).
It is very hard to establish what dose becomes toxic because toxicity of
selenium is dependent on its form present in food, exposure time, physiologi-
cal status, interaction with other metals as well as specific interactions
between metabolites and gene expression mechanisms in the human organism
(Fairweather-Tait et al. 2010). The total amount of selenium in a human
organism varies from 10 to 20 mg and depends on personal features, diet
and geographical location of particular population. The kidneys, testes and
liver have the highest concentration of Se. Normal blood concentration of
selenium varies from 50 to 340 mg L-1. Toxic effects in humans have been
seen at blood levels ranging from 300 to 7500 mg L-1. In most parts of the
world, normal urine level is <30 mg L-1. In Poland, the average daily dose of
selenium does not exceed 30-40 μg, which is an insufficient dose (Zagrodzki,
Łaszczyk 2006).
Selenium toxicity can be attributed to redox cycling, whereby the super-
oxide anion and ultimately H2O2, and other reactive oxygen species (ROS)
are generated. This process can trigger programmed cell death, the mecha-
nism which appears to depend on a cell type (Park et al. 2012). Comparison
of a large variety of selenium compounds revealed that this kind of selenium
toxicity is restricted to compounds with selenium in the oxidation state -2
(i.e. the selenol state) or to those that can be physiologically metabolized to
selenol (see Figure 1). Partial or complete regeneration of the selenol state is
achieved by thiols. In apoptosis driven by redox cycling of selenium com-
pounds, the oxidant culprits are ROS. Therefore, all kinds of peroxidases, in
particular of the GPx family, inhibit oxidant-triggered apoptosis. This implies
that enzyme-bound selenium has an opposite effect to redox-cycling of free
selenium compounds, which agrees with the observation that selenium defi-
ciency can resemble selenium toxicity in many respects.
Insufficient dietary supplementation of selenium is associated with seve-
ral health problems. The first documented pathological state is ROS-depend-
ent damage. It is proven that the extent of damage caused by ROS can be
alleviated or even eliminated by the administration of organoselenocom-
pounds in diet. Decrease of glutathione peroxidase gene expression due to
deficiency of selenium has been associated with a decrease in concentrations
of thyroid hormones, known to increase after selenium supplementation
(Zagrodzki, Łaszczyk 2006, Köhrle 2015). Glutathione peroxidase was also
1276

proven to affect cholesterol hydroxides or oxysterols levels. Oxysterols mani-

fest apoptotic activity on smooth muscle vessel cells, which is inhibited by
selenoproteins (Poirier et al. 2010). Selenium deficiency contributes to various
forms of heart disease such as endemic cardiomyopathy, termed the Keshan
disease, or the degeneration of organs and tissues manifested as Kashin-
-Beck disease (Navarro-Alarcon, Cabrera-Vique 2008).
High intake of selenium causes selenosis, which can affect people expo-
sed to selenium intake that reaches 1000 µg per day or more. However, sele-
nium poisoning or selenosis is very rare. Selenium toxicity (endemic chronic
selenosis) was reported among Chinese people who ate crops with high Se
content. Nail deformation, hair loss and skin rash, lesions of the nervous
system, fatigue and irritability were observed (reviewed in ref. Navarro-
-Alarcon, Cabrera-Vique 2008, Zvolak, Zaporowska 2012). In addition, acute
Se poisoning was observed a few years ago in the United States among
people who took liquid dietary supplement containing 200-times higher Se
content than was labelled (Macfarquhar et al. 2010). Acute selenium toxicity
causes severe neuronal lesions, gastrointestinal and respiratory symptoms,
kidney failure and cardiac disorders (Navarro-Alarcon, Cabrera-Vique 2008).
Exposure to the toxic level of selenium can have a negative impact on genetic
integrity, although the International Agency for Research on Cancer (IARC)
concluded that there are no sufficient data to consider selenium to be a car-
cinogen for humans (IARC 1987).

Immunomodulatory effect of selenium

Organoselenium compounds show an immunomodulatory effect, which
has been examined recently in studies regarding the effect of selenium on
two autoimmune diseases: Grave’s hyperthyroidism and Hashimoto’s thyroid-
itis (Watt et al. 2013, Van Zuuren et al. 2014). The concentration of selenium
is high in the thyroid gland and three important groups of enzymes within
the thyroid are selenoproteins. Most authors claim that selenium affects the
immune system through the regulation of the production of reactive oxygen
species and their metabolites. Selenium supplementation appears to reinfor-
ce intrathyroidal GPx and TrxR activity, probably by increasing the concen-
tration of selenium within the thyroid. The beneficial effects of selenium on
thyroid autoimmune parameters appear to be interesting but very few data
are available on clinical applications (Drutel et al. 2013).
Selenium may have beneficial effects on autoimmune hypothyroidism
and on Graves’ orbitopathy. Watt et al. (2013) hypothesize that adjuvant
selenium may be beneficial in the treatment of Graves’ hyperthyroidism.
The authors explored whether selenium supplementation combined with
standard treatment with anti-thyroid drugs versus standard treatment
with anti-thyroid drugs led to a decline in anti-thyroid drug treatment failure,
more rapid and longer lasting remission and improved quality of life in patients
with Graves’ hyperthyroidism (Watt et al. 2013). Graves’ disease, which can
 1277

be occasionally associated with thyroid eye disease (TED), needs further stu-
dies to determine whether selenium supplementation is beneficial for pa-
tients diagnosed with Graves’ disease to prevent development of TED (Khong
et al. 2014). Research suggests that there is a small but significant difference
in selenium levels between Graves’ disease patients with TED compared
with patients who do not have TED. Recently, Dehina et al. (2016) has
published results of studies showing lack of association between a selenium
status and the severity of an illness due to Graves‘ ophtalmopathy.
Selenium supplementation of people with Hashimoto’s thyroiditis may
reduces anti-TPO antibody levels and result in a decreased dosage of
levothyroxine. Van Zuuren et al. (2014) published results of systematic
review assessing the effects of selenium supplementation on this thyroiditis.
The conclusion was that the evidence to support or refute the efficacy of
selenium supplementation of people with Hashimoto’s thyroiditis is incom-
plete and not reliable to help informed clinical decision making (Van Zuuren
et al. 2014).

Selenium and inflammation

Selenium is involved in a decrease of prostaglandins, prostacyclins,
thromboxanes, and the leukotrienes synthesis from arachidonic acid released
from membrane phospholipids by phospholipase A2 (Kaushal et al. 2012).
Glutathione peroxidases keep all kinds of lipoxygenases and cyclooxygenases
in a dormant status. GPx1 has been shown to inhibit leukotrienes biosynthe-
sis in human monocytes (Straif et al. 2000). In the intestine, it is primarily
GPx2, which inhibits inflammation by downregulation of cyclooxygenase 2
(COX2) (reviewed in ref. Brigelius-Flohé, Kipp 2012). However, silencing
lipoxygenases by Gpx may also prolong their life time and, thus, the dura-
tion of an inflammatory response, since all lipoxygenases tend to be irrever-
sibly inactivated by excess of their own products. GPx1 and GPx4 also decre-
ase inflammatory response by inhibiting TLR4- or TNFa-mediated activation
of NF-kB (Maehira et al. 2003). Because patients with inflammatory bowel
disease demonstrate nutritional deficiencies and are at increased risk for
colon cancer due to heightened inflammation and oxidative stress, dysfunc-
tion of selenoproteins may contribute to disease progression. Over the years,
numerous studies have analyzed the effects of selenoprotein loss and shown
that they are important mediators of intestinal inflammation and carcinoge-
nesis. Recently, Barrett et al. (2016) has focused on the role of selenoprotein
P, a major selenium transport protein, which also has an endogenous anti-
oxidant function. These authors showed that SEPP1 loss altered immune
and epithelial cellular function in a murine model of colitis-associated carcinoma.

Selenium and cancer

Certain selenoproteins provide a tool to regulate hydroperoxide-mediated
signalling. Three selenoproteins have been particularly instructive for under-
1278

standing the role of selenoproteins in cancer. These proteins, TrxR1, Sep15,

and GPx2, were found to exhibit a split “Dr Jekyll and Mr. Hyde” faces, both
preventing and promoting cancer (Brigelius-Flohé, Kipp 2012, Yoo et al.
2012). TrxR1 is over-expressed in breast cancer (Turunen et al. 2004), col-
orectal cancer (Raffel et al. 2003), hepatocellular carcinoma (Kawahara et al.
1996) and gastric carcinoma (Grogan et al. 2000). Mammalian gastrointesti-
nal GPx2, which ranks high in the hierarchy of selenoproteins, plays the role
in tumorigenesis. Colocalization of GPx2 with the Wnt pathway in crypt
bases of the intestine and its induction by Wnt signals point to a role in mu-
cosal homeostasis, but GPx2 might also support tumor growth when
increased by a dysregulated Wnt pathway. In contrast, the induction of GPx2
by Nrf2 activators and the upregulation of COX2 in cells with a GPx2 knock-
down reveal inhibition of inflammation and suggest prevention of inflamma-
tion-mediated carcinogenesis. The Janus-faced role of GPx2 has been con-
firmed in a mouse model of inflammation-associated colon carcinogenesis,
where GPx2 deletion increased inflammation and consequently tumor develop-
ment, but decreased tumor size. The model further revealed GPx2-indepen-
dent decrease in tumor development by selenium and detrimental effects of
the Nrf2-activator sulforaphane in moderate Se deficiency (Brigelius-Flohé,
Kipp 2012). Selenium deficiency is known to increase cancer risk by so far
unclear mechanisms. Selenium deficiency does not only reduce synthesis of
selenoproteins but also affects the expression of other proteins and, thus,
affects pathways. A moderate Se deficiency activates the Nrf2 and the Wnt
pathways. The link between both pathways appears to be GSK3β (glycogen
synthase kinase 3 B), which in the active state prepares Nrf2 as well as
β-catenin, the key player in Wnt signalling, for ubiquitination and proteaso-
mal degradation, thus silencing their transcriptional activity. Upon stimula-
tion by Wnt signals, GSK3β becomes inactivated and transcription factors
are stabilized. Many intermediate steps in both pathways can be modulated
by hydroperoxides, making them predestined to be regulated by selenopro-
teins. The Keap1/Nrf2 system is generally believed to protect against oxida-
tive stress, xenobiotics, inflammation and carcinogenesis, while the Wnt
response is considered rather a risky one in these respects. However, not
only healthy cells but also malignant cells benefit from intact Keap1/Nrf2
signalling, making a dysregulated hydroperoxide signalling a plausible expla-
nation for the increased cancer risk in selenium deficiency (Brigelius-Flohé,
Kipp 2013).
There is growing evidence regarding the anticancer activity of organose-
lenium compounds. Anticancerogenic activities have been demonstrated for
selenodiglutathione, hydrogen selenide, methylated metabolites of selenide,
selenomethionine and methylselenol. These metabolites execute several func-
tions of Se-anticarcinogenesis at (i) underlying levels (redox cycling, modifi-
cation of protein-thiols, methionine mimicry) and (ii) intermediate levels
(DNA damage and repair) (Jackson, Combs 2012). Irons et al. (2006) descri-
bed that Se in the form of both low molecular weight compounds and seleno-
 1279

proteins reduced colon cancer risk in transgenic mice. Methylselenol, a meta-

bolite of selenobetaine or Se-methylselenocysteine, is also thought to have
anticancer effect. It kills transformed cells through mechanisms that include
increased formation of ROS, induction of DNA damage, triggering of apopto-
sis and inhibition of angiogenesis (Hagemann-Jensen et al. 2014). The most
promising results of studies on selenium supplementation were obtained in
prostate cancer research. This particular cancer type represents high suscep-
tibility to selenium. Studies regarding the use of organoselenium compounds
in prostate cancer treatment showed a decrease of cancer development (Zhao
et al. 2006). The chemo-preventive role of selenium appears to be related to
its anti-inflammatory action outlined above.

SUPPLEMENTS AS AN ALTERNATIVE SOURCE

OF SELENIUM

Apart from dietary sources of selenium, people can consume this element
in the form of supplements, which allows them to control doses and avoid
selenium poisoning. At present, there is a wide range of dietary supplements
containing inorganic and organic Se-compounds. There are two types of nutri-
tional supplements based on selenium: (i) multi-vitamin and multi-mineral
preparations containing inorganic selenium, other trace elements and vita-
mins, and (ii) supplements based on Se-enriched Saccharomyces cerevisiae
yeasts (Se-yeasts) (Navarro-Alarcon, Cabrera-Vique 2008). The first batches
of Se-yeasts became available in the early 1970s. It has the ability to assimi-
late up 3000 mg g-1 of Se starting from sodium selenite added to the growth
medium (Roman et al. 2014). High-quality Se-yeasts do not differ in respect
to taste, appearance and smell from traditional yeasts. The use of such
yeasts as an additive to food has a number of advantages compared with
undiluted selenium compounds. Se-yeasts are stable on storage and safeguarded
against dosage errors that can occur when undiluted selenium compounds
are directly added to food. The SeMet from yeast proteins represents a slow
-release form of selenium, eliminating the possibility of a sudden increase in
the levels of selenium after consumption (Schrauzer, Surai 2009). Because
Se in Se-yeasts is stable even at higher temperature, it can be used instead
of conventional yeast for baking bread (Dumont et al. 2006). Additionally,
S. cerevisiae have a high protein content, which improves Se absorption.
SeMet is also the main selenium compound detected in the fruit bodies
of Agaricus bisporus and Lentinula edodes (Shiitake), one of the most popu-
lar edible mushrooms in the world, when is cultivated on a medium supple-
mented with selenium (Turło et al. 2010).
1280

CONCLUSIONS

Selenium, which was discovered in the 19th century, is an essential

nutritional element in a human diet. It can be administrated in both organic
and inorganic forms, although organic forms are easier to be ingested than
inorganic ones. The biological functions of selenium are largely mediated by
selenoproteins. Human selenoproteins encoded by 25 genes are involved in
glutathione-dependent hydroperoxide removal, reduction of thioredoxins,
selenophosphate synthesis, activation and inactivation of thyroid hormones,
repair of oxidized methionine residues and ER-associated protein degrada-
tion. These functions are responsible for the role of selenium in human
health, including its pro- and anticancer activities, roles in the immune sys-
tem and other functions. There are many aspects of the metabolism of sele-
nium and selenoproteins that remain to be investigated, and there are still
many unresolved questions, e.g. What are the biological roles of the approxi-
mately one-half of the human selenoproteins which functions are unknown?
Can dietary selenium have protective effect not only as a component of seleno-
proteins? What is the contribution of dietary selenium to healthy ageing and
how does selenoprotein expression affect diseases like diabetes, different
cancers, cardiovascular or neurological disorders? Furthermore, despite
intensive evaluation of the beneficial and detrimental effects of selenium in
human clinical trials, we still do not exactly know how selenium and seleno-
proteins act to prevent and, in some cases, promote cancer. Explanation of
these basic processes will lead to new strategies for therapeutic intervention.

DECLARATION OF INTEREST
The authors declare no conflict of interests.

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