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Selenium biochemistry is reviewed in respect to its presumed relevance to age-related ocular diseases. Selenium is an essential trace element that exerts its physiological role as selenocysteine residue in at least 25 distinct selenoenzymes in mammals. Lack of GPx-1 due to alimentary selenium deprivation has been inferred to induce cataract in rats and was demonstrated to cause cataracts in mice by targeted gene disruption. The role of other selenoproteins in the eye remains to be worked out. Selenium in excess of the tiny amounts required for selenoprotein synthesis is toxic in general and causes cataracts in experimental animals. Clinical evidence for a protective role of selenium in the development of cataract, macula degeneration, retinitis pigmentosa or any other ocular disease is not available, likely because suboptimum selenium intake, as it may result from unbalanced diet, does not cause any pathologically relevant selenium deficiency in the eye. At present, there is neither theoretical nor an empirical basis to expect beneficial effects of selenium supplementation beyond the dietary reference intakes of 55 microg/day in the context of ocular diseases.
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Augustin A (ed): Nutrition and the Eye.
Dev Ophthalmol. Basel, Karger, 2005, vol 38, pp 89–102
Selenium, Selenoproteins and Vision
Leopold Flohé
MOLISA GmbH, Magdeburg, Germany
Selenium biochemistry is reviewed in respect to its presumed relevance to age-related
ocular diseases. Selenium is an essential trace element that exerts its physiological role as
selenocysteine residue in at least 25 distinct selenoenzymes in mammals. Lack of GPx-1 due
to alimentary selenium deprivation has been inferred to induce cataract in rats and was
demonstrated to cause cataracts in mice by targeted gene disruption. The role of other seleno-
proteins in the eye remains to be worked out. Selenium in excess of the tiny amounts required
for selenoprotein synthesis is toxic in general and causes cataracts in experimental animals.
Clinical evidence for a protective role of selenium in the development of cataract, macula
degeneration, retinitis pigmentosa or any other ocular disease is not available, likely because
suboptimum selenium intake, as it may result from unbalanced diet, does not cause any
pathologically relevant selenium deficiency in the eye. At present, there is neither theoreti-
cal nor an empirical basis to expect beneficial effects of selenium supplementation beyond
the dietary reference intakes of 55 g/day in the context of ocular diseases.
Copyright © 2005 S. Karger AG, Basel
In the context of ocular diseases, selenium is most frequently quoted as an
agent that causes cataracts in experimental rodents. However, deficient alimen-
tary supply of the essential trace element is also implicated in the development
of cataracts [1, 2]. The latter effect is commonly discussed to be related to an
antioxidant action of selenium. Since oxidative damage is also believed to
contribute to age-related macula degeneration and retinitis pigmentosa, the
presumed antioxidant selenium might equally be relevant to these diseases.
Supportive experimental or clinical data, however, are scarce, and the seem-
ingly conflicting findings demand a critical re-evaluation that is based on solid
knowledge of the biological roles of selenium.
This article will therefore briefly summarize relevant aspects of selenium
biochemistry in mammals, compile the knowledge on selenoproteins with special
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emphasis on those present in the eye, try to explain experimental or clinical
data by established molecular events and finally line out what should reason-
ably be considered to become clinically important.
Unspecific Selenium Effects versus Enzymatic
Selenium Catalysis
Selenium exerts its beneficial biological role as constituent of an estimated
total of 25 distinct proteins (table 1) [3]. They comprise five thiol-dependent
peroxidases, commonly called glutathione peroxidases (GPx), three deiodi-
nases (DI), which are involved in the synthesis and degradation of the thyroid
hormones, three thioredoxin reductases (TR), the selenium transport protein
(SelPP), the selenophosphate synthetase that is required for the synthesis of all
other selenoproteins, and a variety of further proteins known by deduced amino
acid sequence, the biological role of which is still poorly defined [4].
In these proteins, selenium is present as one or more selenocysteine
residues that are integrated into the amino acid chains at specific positions. The
specific incorporation of selenocysteine into the proteins is determined by a
complex coding mechanism, wherein the stop codon TGA is recoded by means
of a secondary mRNA structure called SECIS (for selenocysteine incorporation
sequence) and the pertinent translation factors, SBP-2 and mSelB. The former
recognizes the SECIS, the latter a specific selenocysteyl-loaded tRNA
Interestingly, charging of tRNA
differs from the common pathway; the
tRNA has first to be loaded with serine. The seryl residue is then transformed
into a selenocysteyl residue by selenocysteine synthase with selenophosphate
as substrate. If the charged selenocysteyl-tRNA
is not sufficiently available,
the stop codon nature of TGA becomes dominant again despite the presence of
the SECIS in the particular mRNA, that means the ‘selenoprotein’ is truncated
at the position where selenocysteine was to be inserted [reviewed in 4].
An important phenomenon to understand the biological consequences of
selenium shortage is the ‘hierarchy of selenoproteins’. The term describes the
observation that the individual selenoproteins respond differently to selenium
restriction. Out of the well-investigated selenoproteins, the classical glutathione
peroxidase, GPx-1, and GPx-3, the extracellular variant, decline most readily in
selenium deficiency and recover slowly upon re-supplementation. In contrast,
GPx-2, the gastrointestinal form, and phospholipid hydroperoxide GPx (GPx-4)
remain reasonably high even in moderate to severe selenium deficiency, the
remaining selenoproteins ranking in between. The underlying molecular mech-
anism is not completely understood. One of the reasons of the fast decline and
slow recovery of GPx-1 and GPx-3 is a degradation of the pertinent mRNAs in
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Selenium, Selenoproteins and Vision 91
response to selenium deprivation. A selenium-dependent affinity shift of
RNA-binding proteins likely contributes to the differential mRNA stabilities.
Out of the proteins of the selenoprotein machinery only SBP-2 might function
as the required selenium sensor, as it only binds tRNA
if this is charged
with selenocysteine. However, since SBP-2 does not directly interact with the
mRNA, it would have to cooperate with an RNA-binding protein such as mSelB
Table 1. Selenoproteins 2003 [3]
Mammalian selenoproteins Common
Glutathione peroxidase GPx
Cytosolic or classical GPx cGPx, GPx-1
Phospholipid hydroperoxide GPx PHGPx, GPx-4
Plasma GPx pGPx, GPx-3
Gastrointestinal GPx GI-GPx, GPx-2
GPx3-homolog GPx-6
Iodothyronine deiodinases
5-deiodinase, type 1 5DI-1
5-deiodinase, type 2 5DI-2
5-deiodinase, type 3 5-DI-3
Thioredoxin reductases TR
Thioredoxin reductase TR-2
Mitochondrial thioredoxin reductase SelZf1
Thioredoxin reductase homologs SelZf2
Selenophosphate synthetase-2 SPS2
15-kDa selenoprotein (T cells)
Selenoprotein P SelP
Selenoprotein W SelW
Selenoprotein R (methionine sulfoxide MrsB
Selenoprotein T SelT
Selenoprotein M SelM
Selenoprotein N (knockout causes SelN
muscular dystrophy with
spinal rigidity and restrictive
respiratory syndrome)
Selenoprotein H
Selenoprotein I
Selenoprotein K
Selenoprotein O
Selenoprotein S
Selenoprotein V
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to signal the selenium status to the mRNA/protein complex, which is also called
the selenosome [reviewed in 4, 5].
Equally important is the differential delivery of selenium to particular
tissues. Privileged organs that retain their selenium status in pronounced sele-
nium deficiency are thyroid, brain and testis. The molecular basis of this up to
recently mysterious phenomenon is now emerging. Food-derived selenium is
incorporated in the liver into SelPP, a protein with up to 17 selenocysteine
residues (10 in humans). SelPP is secreted into the circulation apparently to
deliver its selenium to sites of particular demand. The present hypothesis is that
SelPP binds to a receptor in the privileged tissues, is internalized there and
degraded to provide selenium for de novo synthesis of selenoproteins. This
view is corroborated by a dramatic drop of selenium content in privileged
tissues associated with elevated selenium levels in livers of SelPP knockout
mice [6]. Unfortunately, it has so far not been investigated whether ocular
tissues are similarly supplied with selenium, as is the brain.
It remains to be discussed what happens to adsorbed selenium beyond the
amount required for the synthesis of selenoproteins. To some extent this depends
on the chemical nature of the particular seleno compound. Selenomethionine,
for instance, is stochastically incorporated into proteins instead of methionine,
the consequences thereof being unclear. As a rule, however, bioavailable sele-
nium, be it selenite from drinking water or selenoamino acids from meat or fish
protein, are transformed to the same intermediate, selenide. In case of selenite,
the reduction can be achieved directly by any of the thioredoxin reductases or
by reaction with GSH to selenaglutathione trisulfide and reduction thereof by
glutathione reductase or thioredoxin reductases. The selenoamino acids are
transformed by the transulfuration pathway and, ultimately, H
Se is released
from selenocysteine by (seleno)cysteine lyase [4]. H
Se serves as the precursor
of selenophosphate, which is used for selenoprotein synthesis, as outlined
above. Any excess beyond the tiny genetically determined demand needs to be
disposed immediately, because seleno compounds are highly reactive and
accordingly toxic and no storage mechanism, apart from the limited capacity of
SelPP synthesis, is known in mammals. The first line of defense against excess
selenium is SAM-dependent methylation of H
Se. It yields the volatile mono-
and dimethylselenium derivatives that are exhaled and account for the smell of
rotten horseradish or garlic that is typical of acute selenium poisoning. These
volatile metabolites easily penetrate the blood-brain barrier and are the main
culprits of selenium’s neurotoxicity. Further methylation yields the trimethyl-
selenonium ion that is excreted with the urine. Once the methylation capacity
is exhausted, which usually results from chronic overexposure to selenium, the
element starts to disclose it so-called antioxidant potential with disastrous
consequences [more details reviewed in 2, 4, 7].
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Selenium, Selenoproteins and Vision 93
For sake of clarity it has to be stressed that selenium is not an antioxidant,
either in the chemical meaning of this term or in a biological sense. As will be
discussed below, selenium plays an important role in the metabolism of H
and other hydroperoxides by being a functional heteroatom in peroxidases and
thereby contributes to the prevention of free radical formation and related
tissues damage. But this does not justify its mislabeling as an ‘antioxidant’. In
chemical terminology, an antioxidant is a compound that reacts with free radi-
cals, thereby becomes transformed into a less reactive radical itself, and thus
slows down or terminates free radical chain reactions. None of the selenium
compounds contained in food or metabolites thereof meets these characteris-
tics. More importantly, the mass law implies that the efficacy of an antioxidant
increases with its concentration. What instead happens in ‘supranutritional
dosing’ of selenium is easily predicted and has been amply verified experimen-
tally [8]: The excess selenium ends up in a pool of selenium compounds of the
oxidation state 2, i.e. selenides or selenols. Being strong reductants, such
compounds react with the most abundant oxidant, i.e. molecular dioxygen (O
with formation of superoxide anion radicals and hydrogen peroxide (H
The seleno compounds thereby oxidized are enzymatically reduced as outlined
above, and undergo autoxidation again. In short, any selenium surpassing the
biological needs and the very limited storage capacity starts redox cycling, which
is the most efficient way to cause oxidative damage in biological systems.
These basic principles of selenium biochemistry disclose why the thera-
peutic window of any selenium compound is inevitably small. They further
reveal why the symptoms of chronic selenium intoxication, which is associated
with the oxidative stress markers typical of redox cyclers, often resemble those
of selenium deficiency, which results in impaired detoxification of hydroper-
Selenoproteins of the Eye
The majority of the mammalian selenoproteins were discovered in the past
decade. Accordingly, understanding of their biology is mostly limited, and their
presence in ocular tissues has been verified in exceptional cases only.
It must be inferred that the eye contains cytosolic (TR1) and mitochondrial
(TR3) thioredoxin reductases that are indispensable for ribonucleotide reduction
via thioredoxin and also determine other functions of the pleiotropic redox
mediators of the thioredoxin family. Similarly, each cell has to be equipped
with selenophosphate synthetase to synthesize pivotal selenoproteins such as
the thioredoxin reductases. Selenoprotein W prevails in muscle and nervous
tissue but its presence in the eye remains to be established. Virtually nothing is
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known about iodothyronine deiodinases (DI) in the eye. They regulate local
thyroid hormone activity by generating the active 3,5,3-triiodothyronine from
thyroxin (DI-1 and DI-2) or degrading thyroxin and 3,5,3-triiodothyronine to
reverse T3 (3,3,5-triiodothyronine) or other inactive compounds, respectively
(DI-1 and DI-3), and their potential relevance to ocular affections in thyroid
disturbances such as Graves’ disease would certainly be of interest.
The only two selenoproteins that have unambiguously been shown to be
present in the eye are GPx-1 and GPx-3. As early as 1965, i.e. long before the
selenoprotein nature of any mammalian enzyme was recognized [9], the ‘classic’
cytosolic glutathione peroxidase (GPx-1) was isolated from lens by the pioneer
of eye biochemistry, Antoinette Pirie [10]. The extracellular form GPx-3, which
is primarily derived from the kidney, was found to be also synthesized in the cil-
iary body [11] and to be released into the aqueous humor [12]. Like all other
members of the GPx family, these two enzymes reduce H
, organic hydroper-
oxides and peroxynitrite at the expense of thiols with high efficiency. Depending
on the nature of the hydroperoxide, the bimolecular rate constants for the reac-
tion of reduced enzyme with ROOH ranges between some 10
and 10
These extreme rate constants depend on the selenium moiety, which forms a cat-
alytic triad consisting of a selenocysteine, a glutamine and a tryptophan residue
wherein the selenol function of the selenocysteine is dissociated and polarized
for nucleophilic attack on peroxo groups [4] (fig. 1). In case of GPx-1, the
reducing substrate is glutathione (GSH), whereas GPx-3 also accepts thiore-
doxin and glutaredoxin as reductants. The metabolic context of GPx-1 is
Trp 165
Gln 87
Sec 52
Fig. 1. The glutathione peroxidase reaction. a The catalytic triad that is strictly con-
served by the whole GPx superfamily with the only exception that selenocysteine may be
replaced by cysteine, which is associated with low peroxidases activity. Residue numbers of
bovine GPx-1 are given as example. b The catalytic cycle of GPx that is essentially charac-
terized by redox shuttling of its selenium moiety. In case of GPx-1, GSH serves as reducing
substrate, other isoenzymes accept different thiols (RSH).
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Selenium, Selenoproteins and Vision 95
straightforward. The reducing substrate GSH is regenerated by glutathione
reductase, which predominantly receives its reduction equivalents as NADPH
from the pentose-phosphate shunt (fig. 2). Instead, GPx-3 depends on the tiny
amounts of thiols that are released into the extracellular space and has therefore
been addressed as ‘orphan enzyme’ [7]. The lack of any known thiol-regenerating
system in the extracellular space limits the capacity of GPx-3 to cope with an
extensive hydroperoxide challenge. The different localization of these otherwise
similar enzymes thus points to distinct biological roles: While GPx-1 has been
established as the most important device of hydroperoxide detoxification in gen-
eral, GPx-3 may regulate the extracellular peroxide tone that is implicated in the
biosynthesis of inflammatory lipid mediators by lipoxygenases and may affect
other signaling cascades [reviewed in 5, 7].
Glutathione Peroxidases and Experimental Cataracts
The interest of ophthalmologists in the relationship of the glutathione sys-
tem and cataract development dates back to the 1950s of the last century and
was extensively reviewed by Kinoshita [13] already in 1964. The observations
were: (i) the lens has been reported to have a GSH content that, with about
10 mM, surpasses that of any other tissue [14]; (ii) GSH of the lens drops with
age [15]; (iii) it is even more decreased in cataractous lenses [15], where
(iv) glutathionylated proteins increase [15].
The first to recognize the link of these findings to H
detoxification was
evidently Antoinette Pirie, who not only identified GPx-1 in the lens but simulta-
neously presented a source of H
that attacks the lens from the aqueous humor,
where it is formed by autoxidation of another ‘antioxidant’, ascorbate [10].
Fig. 2. Main metabolic context of GPx-1. The selenoprotein is typically supplied with
reduction equivalents (NADPH) from the pentose phosphate shunt. Deficiencies in this
pathway may impair regeneration of GSH and, in consequence, hydroperoxide (ROOH)
detoxification via GPx-1. Accumulating hydroperoxide, by decomposing into alkoxyl (RO
and hydroxyl radical (
OH), may then initiate free radical chain reactions.
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The role of H
in inducing cataract was then corroborated by Srivastava and
Beutler [16] by incubating rabbit lenses with tyrosine and tyrosinase, which pro-
duces superoxide and/or H
as by-product. Preceding cataract development
GSH became oxidized and released to the medium as GSSG. Interestingly, a sim-
ilar loss of GSH in the lens and export of GSSG to the aqueous humor was
observed upon naphthalene feeding to rabbits [17], which likely is mediated by a
metabolite of naphthalene, 1,2-naphthoquinone. The latter is a known redox
cycler which oxidizes GSH by continuously generating H
but aggravates the
loss of GSH by reacting to covalent adducts [18]. Analogous reactions of
1,2-naphthoquinone with SH groups of - and -crystallin, that are favored at
low GSH concentrations, lead to insoluble colored proteins that contribute to
cataract manifestations.
The latter findings reveal that H
itself is not necessarily the agent that
induces the cataractogenic protein modification. H
-derived free radicals
may be the main culprits, and oxygen-centered radicals may be directly formed
in the eye, e.g. by UV irradiation. To mimic such radical damage, rats were poi-
soned with the herbicide diquate. This compound is reduced univalently by
NADPH and induces cataract via a radical that does not cause any significant
loss of GSH [19]. Further evidence for GSH-independent cataracts is provided
by genetics. A dominant cataract mutant (Nop/) did not display any abnor-
malities in the enzymes related to the glutathione redox balance. In particular
the activities of GPx, glutathione reductase and glucose-6-phosphate dehydro-
genase were not affected [20]. Similarly, mutations in the Huntingtin interact-
ing protein were found to be associated with cataracts [21].
On the other hand, inverse genetics finally corroborate the early hypotheses
on hydroperoxides being key players in cataract development and the GSH sys-
tem being protective: GPx-1
mice spontaneously develop complete lens
opacification at an age of 15 months. This is preceded by progressive nuclear
light scattering, distortion of fiber membranes and distension of interfiber space
starting at 3 weeks of age and lamellar cataracts between 6 and 10 months [22].
This finding is of particular interest, since it represents the so far only phenotype
observed in unstressed GPx-1
mice. These animals grow normally if not
exposed to hydroperoxides, bacterial toxins that trigger an oxidative burst in
phagocytes, redox-cycling herbicides or viral infections [reviewed in 7]. It has
therefore to be concluded that the lens, in contrast to other tissues, is physiologi-
cally exposed to a certain oxidative stress that needs continuous protection by the
selenoprotein GPx-1. In short, the GSH-dependent hydroperoxide detoxification
may thus be rated as one of the genetically validated systems that protect against
age-related cataract formation. The knockout experiments also provide a rational
to explain the early observations of cataract development in selenium-deprived
rodents [23, 24], which thus is likely the consequence of GPx-1 deficiency.
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Selenium, Selenoproteins and Vision 97
How then does the proven protection by selenium against cataract forma-
tion comply with the cataractogenic potential of the very same element?
Cataracts can consistently be induced in young rats, rabbits and guinea pigs by
selenite at dosages below the threshold causing acute systemic toxicity. The
narrow time window of susceptibility and the comparatively low dosages sug-
gested specific effects of selenite on the lens, and indeed a variety of phenom-
ena have been observed in this cataract model that are not easily explained by
unspecific selenium toxicity, e.g., a dramatic increase in calcium and phosphate
in the lens, binding of radioactive selenium to lens proteins [compiled in 2],
impairment of protein tyrosine phosphorylation and phosphatidylinositol-
3-kinase activity [25], and calcium-induced proteolysis of -crystallin [26].
However, whatever the seemingly specific mechanism of lens toxicity may be,
all these effects are observed at dosages that surpass the ones required for opti-
mum production of selenoproteins by more than three orders of magnitude:
several milligrams/kilogram instead of 1 g/kg. Under these conditions, sele-
nium has clearly changed its face from an essential micronutrient to a pro-
oxidative redox cycler. Accordingly, the total reducing capacity of the lens is
decreased, as is evident from a decrease in GSH, NADPH and total protein
sulfhydryls, and markers of oxidative damage such as malondialdehyde are
substantially increased [2]. It therefore may be doubted if the seemingly spe-
cific effects of selenium reflect more than sites of the young lenses that are par-
ticularly prone to oxidative damage. In line with this view, selenite-induced
cataract could be inhibited in vitro and in vivo with antioxidant extracts of
green tea (Camellia sinensis) [27] or other antioxidants [28]. In conclusion, as
an essential trace element up to daily dosages of 1 g/kg body weight, sele-
nium prevents cataract formation by guaranteeing optimum H
tion via GPx-1. If given in marked excess, it induces cataracts by causing
oxidative damage to the lens.
Animal Experiments versus Clinical Experience
The unequivocal demonstration of the indispensability of GPx-1 in the eye
of mice justifies discussing the potential impact of the selenoenzyme in respect
to ophthalmic diseases believed to be caused or aggravated by oxidative stress.
Since GPx-1 belongs to the group of selenoproteins that declines rapidly in
selenium deficiency, the problem addressed is intimately related to the question
if selenium supplementation can ameliorate such diseases. To state it right
away, supportive clinical evidence is surprisingly scarce.
To our knowledge there is not a single report that relates a genetic defi-
ciency of GPx-1 or of any other selenoprotein to ocular diseases. Congenital
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cataract was reported in 1 out of 14 cases of heredited deficiency of GSH
biosynthesis [27]. The evidence for a role of GPx-1 in the human eye becomes
slightly more persuasive if the GSH-regenerating system GPx-1 depends on is
considered. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency has for
long been implicated as a risk factor for cataract formation [29], but the
attempts to statistically verify an association of G-6-PD deficiency and cataract
incidence remained largely disappointing [30, 31]. The results varied between
geographical regions and, likely, between different types of G-6-PD mutations.
Nevertheless, a trend towards higher cataract incidence was observed at least in
younger or presenile patients [30, 32–34]. Likely the genetic deficiencies in
GSH regeneration remain silent as long as the subjects are not challenged by
pro-oxidant agents, as they do in respect to associated hematological disorders.
A statistically verified association of cataract incidence and selenium defi-
ciency is equally missing and has not even been reported for countries where
selenium deficiency syndromes such as Keshan disease or Kashin-Beck dis-
ease were endemic. At first glance, this surprises in view of the experimental
background. It may be revealing, however, that cataract induction in rats
required second-generation selenium deprivation. This implies that either the
selenium deficiency must be extreme and has to be sustained for years to mimic
the GPx-1 status of GPx-1
mice or that the lenses of rats and man, respec-
tively, are less prone to oxidative damage. Evidently a critically low selenium
status of the eye is hardly achieved even at low, and not at all at suboptimum
supply, because the eye is likely as privileged in selenium supply as the nervous
tissue in general.
The second ophthalmic disease believed to result from, or to be aggravated
by, oxidative damage, is retinitis pigmentosa (RP). The pigmented deposits
reminding of lipofuscin are considered to result from co-oxidation of unsatu-
rated lipid and proteins. The most convincing clinical support of the oxidative
damage hypothesis of RP is the almost consistent association of the disease
with untreated genetic deficiency of the -tocopherol transfer protein that leads
to a dramatic decrease of vitamin E in nervous tissue, ataxia and mental retar-
dation [35]. The preventive efficacy of megadoses of vitamin E (up to 2 g/day)
is commonly attributed to its antioxidant capacity that essentially consists in
scavenging peroxyl radicals of lipids. The products of this reaction, hydroper-
oxides of fatty acids or complex lipids are substrates of GPx’s, in particular of
GPx-4. This biochemical link is often quoted to explain the synergism of sele-
nium and vitamin E in preventing experimental deficiency syndromes [2, 7].
However, GPx-4, which is the isoenzyme specialized for the prevention of lipid
peroxidation, ranks high in the hierarchy of selenoproteins, will not markedly
decrease, unless selenium deficiency is extreme. The few clinical studies
addressing this problem did not suggest any link between RP and selenium
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Selenium, Selenoproteins and Vision 99
deficiency. Unexpectedly, GPx-1, which readily declines in selenium defi-
ciency, was found to be elevated in RP [36, 37], a finding that, in principle, cor-
roborates the oxidative stress hypothesis for RP, but rules out the contribution
of selenium deficiency as a common etiological factor.
For age-related macular degeneration (ARMD) finally, the assumption of a
radiation-triggered oxidative damage is theoretically most appealing. The
invoked oxidative processes, however, are initiated by singlet oxygen, which is
more readily quenched by the carotenoids of the macula lutea than by any other
non-enzymatic or enzymatic process. Accordingly, the macula lutea protects
itself against potential damage by the focused light by accumulation of
carotenoids, specifically lutein and zeaxanthin, which are responsible for its typ-
ical color [38]. The protective role of other antioxidants or enzymatic mechanism
is less clear. A study on 18 ARMD patients showed a lower blood glutathione
reductase activity but comparable GPx activity when compared to age-matched
controls [39]. More recently, a genome scan for ARMD-related markers identi-
fied a region on chromosome 5, where GPx-3 is located [40]. Altogether, how-
ever, the evidence for an impact of the selenium status to ARMD is weak.
Unfortunately, clinical trials with patient numbers that promise statistical
power have preferentially been performed with complex mixtures of minerals
and vitamins that are believed to act primarily as antioxidants. Despite the high
number of patients involved, e.g., in the Linxian cataract study or the ARED
study, beneficial effects, if evident at all, can hardly be attributed to any of the
individual components of the supplement mixtures. The kind of study design
may be relevant to evaluate the sense of current trends to expect miracles from
supranutritional dosages of micronutrients, be they antioxidants or not. The
dose-dependent switch in mechanism of action, which here has been exempli-
fied for selenium and could easily be extended to other micronutrients, makes
the outcome of such studies hard to interpret. The problem whether ocular dis-
eases are aggravated by oxidative stress and which presumed antioxidant might
retard disease manifestation could not be solved this way.
Selenium has an established role in ocular physiology. As an integral part
of glutathione peroxidase type 1, it prevents oxidative damage and, in conse-
quence, cataract formation in the eye lens of rodents, as is demonstrated by ali-
mentary selenium deprivation and genetic disruption of the GPx-1 gene. The
roles of other selenoproteins in the eye remain to be established.
Excess selenium that is not incorporated specifically into selenoproteins
causes cataracts in postnatal animals presumably via redox cycling.
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There is no theoretical basis, nor any experimental evidence for the hope
that any selenium supplementation that exceeds the dietary reference intakes of
55 g/day has a beneficial effect on the eye. Moreover, animal experimentation
reveals that only severe and sustained selenium deficiency affects eye physiol-
ogy. Accordingly, any reliable clinical data revealing a beneficial effect of sele-
nium on ocular diseases are missing.
Taking into account the documented difficulties to induce any pathologi-
cally relevant selenium deficiency in the eyes of experimental animals and the
known hazards of excess selenium, supranutritional selenium supplementation
to prevent age-related ocular diseases can at present not be recommend.
In view of the established function of selenium in the eye, it nevertheless
appears advisable to screen oxidative stress-related ocular diseases for distur-
bances of selenium biochemistry that, in exceptional cases, might be a cause or
complicating factor of the disease.
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Prof. Dr. Leopold Flohé
MOLISA GmbH, Universitätsplatz 2
DE–39106 Magdeburg (Germany)
Tel. 49 䊏䊏䊏 䊏䊏䊏, Fax 49 䊏䊏䊏 䊏䊏䊏, E-Mail
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... Selenium-induced cataract in animal models causes an alteration in the lens protein profile that is similar to ageing-induced cataract; thus, selenite cataract is a good representative model of human age-related cataract [50]. The mechanism of seleniuminduced cataratogenesis is attributed to: (1) decreased calcium-ATPase activity and increased calcium-induced proteolysis [15,51], and (2) stimulated ROS production and decreased GSH levels [51,52]. In vitro studies revealed that PRX attenuated selenite cataract via chelating Se ions and subsequently by decreasing the degradation of crystallin proteins [15,16]. ...
... Selenium-induced cataract in animal models causes an alteration in the lens protein profile that is similar to ageing-induced cataract; thus, selenite cataract is a good representative model of human age-related cataract [50]. The mechanism of seleniuminduced cataratogenesis is attributed to: (1) decreased calcium-ATPase activity and increased calcium-induced proteolysis [15,51], and (2) stimulated ROS production and decreased GSH levels [51,52]. In vitro studies revealed that PRX attenuated selenite cataract via chelating Se ions and subsequently by decreasing the degradation of crystallin proteins [15,16]. ...
... Although this theory is not now accepted [59], exogenous quinones such as naphthalene have been used in a simulation of age-related cataract [60]. Exogenous substances exert a cataractogenic effect via two mechanisms: (1) interaction with thiol groups of β-and γcrystallins, leading to formation of insoluble colored proteins as observed in aged lens [51], and (2) ROS generation, leading to a decrease in GSH level. An in vitro study revealed that PRX competed with quinonic substances, in which PRX could bind to the thiol groups of the lens proteins, preventing further oxidation [22]. ...
Full-text available
Cataract is the leading cause of blindness worldwide. A diverse range of medication has been invented to prevent or treat cataract. Pirenoxine (PRX), a drug with strong antioxidant properties, has been used topically to treat cataract, and there is much evidence to demonstrate the beneficial effects of PRX on lens opacity from in vitro and in vivo models. In clinical use, PRX has been prescribed worldwide by ophthalmologists for over six decades; however, there is still controversy with regard to its efficacy, and thus PRX remains an off-label use for cataract treatment. This comprehensive review summarizes and discusses evidence pertinent to the mechanisms of PRX and its efficacy mainly on cataract models. The issues that have been deemed uncertain over the six-decade use of PRX are examined. The information summarized in this review should provide insights into contriving novel approaches for the treatment of cataract.
... There are reports suggesting that insufficient Se levels may negatively affect lens metabolism, increasing the opacity [81,[86][87][88]. Research by Post [89] confirmed the association between low serum selenium levels and age-related cataracts and suggested that it may constitute a potential risk factor for both nuclear and cortical age-related cataracts. ...
Full-text available
Cataracts are one of the most common causes of effective vision loss. Although most cases of cataracts are related to the ageing process, identifying modifiable risk factors can prevent their onset or progression. Many studies have suggested that micro and macroelement levels, not only in blood serum but also in the lens and aqueous humour, may affect the risk of the occurrence and severity of cataracts. This systematic review aims to summarise existing scientific reports concerning the importance of trace elements in cataractogenesis. Many authors have pointed out elevated or decreased levels of particular elements in distinct ocular compartments. However, it is not known if these alterations directly affect the increased risk of cataract occurrence. Further studies are needed to show whether changes in the levels of these elements are correlated with cataract severity and type. Such information would be useful for determining specific recommendations for micronutrient supplementation in preventing cataractogenesis.
... The body must maintain a balanced Se concentration (4). Longterm Se deficiency can lead to many diseases, such as cancer, liver disease, cardiovascular disease, pancreatic disease, cataracts, diabetes, and other diseases (5)(6)(7)(8)(9)(10)(11)(12)(13). Some studies have found that many animals with selenium deficiency develop diarrhea symptoms (14)(15)(16). ...
Full-text available
Selenium (Se) is a micronutrient that plays a predominant role in various physiological processes in humans and animals. Long-term lack of Se will lead to many metabolic diseases. Studies have found that chronic Se deficiency can cause chronic diarrhea. The gut flora is closely related to the health of the body. Changes in environmental factors can cause changes in the intestinal flora. Our study found that Se deficiency can disrupt intestinal flora. Through 16s high-throughput sequencing analysis of small intestinal contents of mice, we found that compared with CSe group, the abundance of Lactobacillus, Bifidobacterium, and Ileibacterium in the low selenium group was significantly increased, while Romboutsia abundance was significantly decreased. Histological analysis showed that compared with CSe group, the small intestine tissues of the LSe group had obvious pathological changes. We examined mRNA expression levels in the small intestine associated with inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junctions, and smooth muscle contraction. The mRNA levels of NF-κB, IκB, p38, IL-1β, TNF-α, Beclin, ATG7, ATG5, LC3α, BaK, Pum, Caspase-3, RIP1, RIPK3, PERK, IRE1, elF2α, GRP78, CHOP2, ZO-1, ZO-2, Occludin, E-cadherin, CaM, MLC, MLCK, Rho, and RhoA in the LSe group were significantly increased. The mRNA levels of IL-10, p62 BcL-2 and BcL-w were significantly decreased in the LSe group compared with the CSe group. These results suggest that changes in the abundance of Lactobacillus, bifidobacterium, ileum, and Romboutsia may be associated with cellular inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junction, and abnormal smooth muscle contraction. Intestinal flora may play an important role in chronic diarrhea caused by selenium deficiency.
... At present, there is no selenium, in any form, present in Age-related Eye Disease Study (AREDS I and AREDS II) formulations [43], and to our present knowledge, there is no plan to incorporate selenium as such [44]. This is not because of any concrete evidence of a lack of gain in terms of antioxidant benefit or the presence of unwanted detrimental effects but rather is likely due in part to the large number of inconsistencies across the various studies conducted to date [40,45,46]. There are a large number of reports, clinical and experimental, touting the beneficial effects of selenium therapy in other diseases in which oxidative stress and resultant cellular damage are majorly involved (e.g., various types of cancer, HIV, and Alzheimer's, etc.) [47][48][49]. ...
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Oxidative damage has been identified as a major causative factor in degenerative diseases of the retina; retinal pigment epithelial (RPE) cells are at high risk. Hence, identifying novel strategies for increasing the antioxidant capacity of RPE cells, the purpose of this study, is important. Specifically, we evaluated the influence of selenium in the form of selenomethionine (Se-Met) in cultured RPE cells on system xc- expression and functional activity and on cellular levels of glutathione, a major cellular antioxidant. ARPE-19 and mouse RPE cells were cultured with and without selenomethionine (Se-Met), the principal form of selenium in the diet. Promoter activity assay, uptake assay, RT-PCR, northern and western blots, and immunofluorescence were used to analyze the expression of xc-, Nrf2, and its target genes. Se-Met activated Nrf2 and induced the expression and function of xc- in RPE. Other target genes of Nrf2 were also induced. System xc- consists of two subunits, and Se-Met induced the subunit responsible for transport activity (SLC7A11). Selenocysteine also induced xc- but with less potency. The effect of Se-met on xc- was associated with an increase in maximal velocity and an increase in substrate affinity. Se-Met increased the cellular levels of glutathione in the control, an oxidatively stressed RPE. The Se-Met effect was selective; under identical conditions, taurine transport was not affected and Na+-coupled glutamate transport was inhibited. This study demonstrates that Se-Met enhances the antioxidant capacity of RPE by inducing the transporter xc- with a consequent increase in glutathione.
... Selenocysteine amino acid has protective potential to the brain, acting against oxidative damages [18] [19]. Furthermore, some authors suggest that, in the human diet, Se boosts visual function and protects against cataracts and maculopathy [20][21] [22]. So far, only two studies evaluated Hg and Se concentrations in fishes consumed by riparian communities in the Tapajós River basin [23] [24]. ...
This work aimed to evaluate associated risks of fish consumption to human health, concerning mercury (Hg) and selenium (Se) concentrations in fish species largely consumed in the Tapajós River basin in the Brazilian Amazon. Total mercury (THg), methylmercury (MeHg) and Se concentrations were measured in 129 fish specimens from four sites of the Tapajós River basin. Estimated daily intake (EDI) of Hg and Se were reported regarding fish consumption. EDI were compared with the reference value of provisional tolerable daily intake proposed by the World Health Organization (WHO). Se:Hg ratios and selenium health benefit values (Se HBVs) seem to offer a more comprehensive fish safety model. THg concentrations in fishes ranged from 0.03 to 1.51 μg g⁻¹ of wet weight (w.w.) and MeHg concentrations ranged from 0.02 to 1.44 μg g⁻¹ (w.w.). 80% of the samples were below the value of Hg recommended by the WHO for human consumption (0.5 μg g⁻¹ w.w.). However, Hg EDI exceeded the dose suggested by the United States Environmental Protection Agency (0.1 μg kg⁻¹ day⁻¹), due to the large level of fish consumption in that area. Se concentrations in fishes ranged from 0.02 to 0.44 μg g⁻¹ w.w. An inverse pattern was observed between Hg and Se concentrations in the trophic chain (highest levels of Se in the lowest trophic levels). The molar ratio Se:Hg and Se HBVs were higher in iliophagous and herbivorous fishes, which is noteworthy to reduce toxic effects of Hg contamination. For planktivores, the content of Se and Hg was almost equimolar. Carnivorous fishes – with the exception of Hemisorubim platyrhynchos and Pseudoplatystoma fasciatum –, showed Se:Hg ratios <1. Thus, they do not act as a favorable source of Se in the diet. Therefore, reduced intake of carnivorous fishes with preferential consumption of iliophages, herbivores and, to some extent, even planktivores should be promoted as part of a healthier diet.
... In addition, adult zebrafish vision has been investigated using behavioural assays, and adults fed with Se-Met spiked diets exhibited reduced escape responses and their F1 progeny had smaller eyes and fewer positive responses in phototaxis, oculomotor and optokinetic response assays (Raine et al., 2016). Glutathione peroxidases (GPx1 and GPx3; both selenoproteins) found in the eye (Pirie, 1965) normally protect the lens from oxidative damage (Flohe, 2005), but a previous study reported excess Se caused decreased anti-oxidants and increased oxidative damage in the eye (Combs and Combs, 1986). Based on the results of the current study, future studies should also include examination of the relative roles of methylglyoxylated lens proteins versus oxidative stress or protein dysfunction due to Se-Met inclusion after excess Se exposure in adult versus developing fish. ...
Full-text available
Selenium (Se) is considered an essential trace element, involved in important physiological and metabolic functions for all vertebrate species. Fish require dietary concentrations of 0.1-0.5 μg Se/g dry mass (d.m.) to maintain normal physiological and selenoprotein function, however concentrations exceeding 3 μg/g d.m. have been shown to cause toxicity. As Se is reported to have a narrow margin between essentiality and toxicity, there is growing concern surrounding the adverse effects of elevated Se exposure caused by anthropogenic activities. Previous studies have reported that elevated dietary exposure of fish to selenomethionine (Se-Met) can cause significant cardiotoxicity and alter aerobic metabolic capacity, energy homeostasis and swimming performance. The goal of this study aims to further investigate mechanisms of sublethal Se-Met toxicity, particularly potential underlying cardiovascular and metabolic implications of chronic exposure to environmentally relevant concentrations of dietary Se-Met in juvenile rainbow trout (Oncorhynchus mykiss). Juvenile rainbow trout were fed either control food (1.3 μg Se/g d.m.) or Se-Met spiked food (6.4, 15.8 or 47.8 μg Se/g d.m.) for 60 d at 3% body weight per day. Following exposure, ultrahigh resolution B-mode and Doppler ultrasound was used to characterize cardiac function in vivo. Chronic dietary exposure to Se-Met significantly increased stroke volume, cardiac output, and ejection fraction. Fish fed with Se-Met spiked food had elevated liver glycogen and triglyceride stores, suggesting impaired energy homeostasis. Exposure to Se-Met significantly decreased mRNA abundance of citrate synthase (CS) in liver and serpin peptidase inhibitor, clad H1 (SERPINH) in heart, and increased mRNA abundance of sarcoplasmic reticulum calcium ATPase (SERCA) and key cardiac remodelling enzyme matrix metalloproteinase 9 (MMP9) in heart. Taken together, these responses are consistent with a compensatory cardiac response to increased susceptibility to oxidative stress, namely a decrease in ventricular stiffness and improved cardiac function. These cardiac alterations in trout hearts were linked to metabolic disruption in other major metabolic tissues (liver and skeletal muscle), impaired glucose tolerance with increased levels of the toxic glucose metabolite, methylglyoxal, increased lipid peroxidation in skeletal muscle, development of cataracts and prolonged feeding behaviour, indicative of visual impairment. Therefore, although juvenile rainbow trout hearts were apparently able to functionally compensate for adverse metabolic and anti-oxidant changes after chronic dietary exposure Se-Met, complications associated with hyperglycemia in mammalian species were evident and would threaten survival of juvenile and adult fish.
Synchrotron-based X-ray fluorescence microscopy (XFM) coupled with X-ray absorption near-edge structure (XANES) imaging was used to study selenium (Se) biodistribution and speciation in Limnodynastes peronii tadpoles. Tadpoles were exposed to dissolved Se (30 μg/L) as selenite (SeIV) or selenate (SeVI) for 7 days followed by 3 days of depuration. High-resolution elemental maps revealed that Se partitioned primarily in the eyes (specifically the eye lens, iris, and retinal pigmented epithelium), digestive and excretory organs of SeIV-exposed tadpoles. Speciation analysis confirmed that the majority of accumulated Se was converted to organo-Se. Multielement analyses provided new information on Se colocalization and its impact on trace element homeostasis. New insights into the fate of Se on a whole organism scale contribute to our understanding of the mechanisms and risks associated with Se pollution.
This systematic review aimed to evaluate existing evidence on the associations between trace elements exposure and age-related eye diseases. PubMed and Google scholar databases were searched for epidemiological and postmortem studies on the relationship between exposure to trace elements and Age-related eye diseases such as age-related macular degeneration (AMD), cataract, glaucoma and diabetic retinopathy (DR), in population groups aged 40 years and above. Available evidence suggests that cadmium (Cd) exposure may be positively associated with the risks of AMD and cataract. There is also evidence that exposure to lead (Pb) may be positively associated with higher risk of cataract and glaucoma. There is limited number of relevant studies and lack of prospective studies for most of the investigated associations. Evidence for other trace elements is weak and inconsistent, and the number of available studies is small. Likewise, there are very few relevant studies on the role of trace elements in DR. Chemical elements that affect the distribution and absorption of other trace elements have never been investigated. The suggestive but limited evidence motivates large and quality prospective studies to fully characterize the impact of exposure to trace (toxic and essential) elements on age-related eye diseases.
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Incomplete illustrated autobiographic article
Selenium is an important macronutrient with a very narrow margin between essentiality and toxicity. Amphibians are hypothesized to be particularly sensitive due to the potential for metamorphosis-driven mobilization, which could transfer or concentrate contaminant burdens within specific organs. We explored the potential role of tissue degeneration and remodeling during anuran metamorphosis as a mechanism for altering tissue-specific Se burdens. Limnodynastes peronii tadpoles were exposed to dissolved ⁷⁵Se (as selenite) for 7 days and depurated until completion of metamorphosis. Bioaccumulation and retention kinetics were assessed in whole tadpoles and excised tissues using gamma spectroscopy, and temporal changes in biodistribution were assessed using autoradiography. Tadpoles retained Se throughout metamorphosis, and partitioned the element predominantly within digestive and excretory tissues, including livers > mesonephros > guts > gallbladder. Importantly, our results demonstrate that Se biodistribution varies significantly throughout development. This is indicative of tissue transference, and particularly in tissues developing de novo after depuration. To the best of our knowledge, this is the first study demonstrating Se transference during metamorphic tissue remodelling. Further research is warranted to explore the fate and metabolism of Se (and other metal and metalloids) during anuran development and the implications of transference for influencing toxicity.
Dietary selenium (10 to 100 ppb) was found to significantly increase the growth rate of selenium depleted rats fed diets containing adequate levels of vitamin E. This stimulatory effect of selenium on growth could not be duplicated by chromium, excessive levels of vitamin E (1000 to 1,360 I.U./kg diet), sulfate or several synthetic antioxidants (ethoxyquin, ascorbate, N,N' diphenyl p phenylenediamine, methylene blue or butylated hydroxy toluene). Neither did any of these prevent cataracts in eyes of deficient rats. A proportional increase of selenium concentration in livers of rats fed increasing levels of this element in the diet was found, and the presence or absence of dietary vitamin E did not affect this accumulation. In general, as the dietary selenium levels increased in the diet, a reduction in plasma tocopherol levels in rats occurred. Fasted plasma cholesterol levels were significantly higher in selenium deficient rats than supplemented ones, but no differences in fasted blood glucose or plasma galactose levels were found. Dietary chromium significantly reduced both plasma cholesterol and blood glucose, but ethoxyquin and 1000 ppm (1360 I.U.) dietary D α tocopherol acetate significantly reduced only blood glucose in deficient rats. Dietary ascorbate significantly reduced plasma cholesterol but had no effect on blood glucose levels.
Age-related macular degeneration or age-related maculopathy (ARM) is a major public health issue, as it is the leading cause of irreversible vision loss in the elderly in the Western world. Using three diagnostic models, we have genotyped markers in 16 plausible candidate regions and have carried out a genome-wide screen for ARM susceptibility loci. A panel of 225 ARM families comprising up to 212 affected sib pairs was genotyped for 386 markers. Under our most stringent diagnostic model, the regions with the strongest evidence of linkage were on chromosome 9 near D9S301 and on 10 near D10S1230, with peak multipoint heterogeneity LOD scores (HLOD) of 1.87 and 1.42 and peak GeneHunter-Plus non-parametric LOD scores (GHP LOD) of 1.69 and 1.83. After expanding our initial set of families to 364 ARM families with up to 329 affected sib pairs, the linkage signal on chromosome 9 vanished, while the chromosome 10 signal decreased to a GHP LOD of about 1.0, with a SimIBD P -value of 0.008 under the broadest diagnostic model with marker D10S1236. After error filtration, the GHP LOD increased to 1.27 under our most stringent model and 1.42 under our broadest model, peaking near D10S1236. This peak was seen consistently across all three diagnostic models. Our analyses also excluded up to nine different candidate regions and identified a few other regions of potential linkage, suitable for further studies. Of particular interest was the region on chromosome 5 near D5S1480, where a reasonable candidate gene, glutathione peroxidase 3, resides.
The G6PD activity of erythrocytes in 113 male patients with senile and presenile cataract and 86 controls, and G6PD activity of lens in 30 patients with senile cataract and 42 controls were reported. The cataractous group had higher frequency of G6PD deficiency and lower average G6PD level in erythrocytes and lenses, but without statistical significance. The frequency of G6PD deficiency of erythrocytes in presenile cataractous group was higher than that of senile cataractous group but with no statistical significance too. However, the average G6PD level of erythrocytes in presenile cataractous group was lower than that of senile cataractous group and with statistical significance (P < 0.05). The G6PD activity of lenses only presenile in the cortex and have a positive correlation with that of erythrocytes. There was a case with deficiency of G6PD both of erythrocytes and cataractous lenses in both eyes. The results indicate that the deficiency of G6PD might be one of the cataractous pathogenetic factor for presenile cataract. Measurement of G6PD activity of erythrocytes among population might be of significance in finding the risk factor for cataract.
Recent advances in understanding the mechanism of selenite cataract have resulted from locating the cleavage sites on proteolyzed beta-crystallins from the cataract, mimicking the insolubilization of crystallins found in the cataract in an in vitro system, studying cataract produced in lenses cultured in selenite, and permanently or temporarily reducing the rate formation of selenite cataract by use of various inhibitors. The present review discusses the selenite cataract as a useful model for understanding the role calcium-induced proteolysis in cataract formation.
The fatty acid composition and the glutathione-peroxidase activity (GSH-Px) of erythrocytes and platelets, the production of malondialdehyde (MDA) by platelets and the activity of the main systems of transmembrane cation transport in erythrocyte have been studied in 12 patients (5 males and 7 females) affected by retinitis pigmentosa (RP). A remarkable increase of saturated fatty acids (SFA), particularly of stearic acid (C18:0), has been noted in these patients. The reduced unsaturated/saturated fatty acids ratio (PUFA/SFA) observed in both erythrocytes and platelets and the decrease of arachidonic acid in platelets may depend by an active peroxidation process as documented by the increase of MDA. Platelet glutathione-peroxidase (PTL-GSH-PX) and plasma retinol were in the normal range, whereas erythrocyte glutathione-peroxidase (E-GSH-PX), MDA and plasma alfa-toco-pherol were increased in patients with RP. The activities of Na(+)-K+ pump, cotransport and Na(+)-Li+ countertransport were normal in RP erythrocytes.
Erythrocytic glucose-6-phosphate dehydrogenase (G-6-PD) was tested in 163 cases of senile cataract and 79 age- and sex-matched controls. There was no statistically significant difference between the overall incidence of G-6-PD deficiency in cataract in comparison to controls. However, amongst the cataract patients the frequency of G-6-PD deficiency was significantly higher in the age group 40 to 50 years (12.1%) as compared to those aged 51 years or more.