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Arthur
Selenium and endocrine systems.Beckett GJ, Arthur JR. J Endocrinol. 2005 Mar;184(3):455-65. Review.
"The trace element selenium (Se) is capable of exerting multiple actions on endocrine systems by modifying the expression of at least 30 selenoproteins, many of which have clearly defined functions. Well-characterized selenoenzymes are the families of glutathione peroxidases (GPXs), thioredoxin reductases (TRs) and iodothyronine deiodinases (Ds). These selenoenzymes are capable of modifying cell function by acting as antioxidants and modifying redox status and thyroid hormone metabolism. Se is also involved in cell growth, apoptosis and modifying the action of cell signalling systems and transcription factors. During thyroid hormone synthesis GPX1, GPX3 and TR1 are up-regulated, providing the thyrocytes with considerable protection from peroxidative damage. Thyroidal D1 in rats and both D1 and D2 in humans are also up-regulated to increase the production of bioactive 3,5,3'-tri-iodothyronine (T3). In the basal state, GPX3 is secreted into the follicular lumen where it may down-regulate thyroid hormone synthesis by decreasing hydrogen peroxide concentrations. The deiodinases are present in most tissues and provide a mechanism whereby individual tissues may control their exposure to T3. Se is also able to modify the immune response in patients with autoimmune thyroiditis. Low sperm production and poor sperm quality are consistent features of Se-deficient animals. The pivotal link between Se, sperm quality and male fertility is GPX4 since the enzyme is essential to allow the production of the correct architecture of the midpiece of spermatozoa. Se also has insulin-mimetic properties, an effect that is probably brought about by stimulating the tyrosine kinases involved in the insulin signaling cascade. Furthermore, in the diabetic rat, Se not only restores glycaemic control but it also prevents or alleviates the adverse effects that diabetes has on cardiac, renal and platelet function."
Selenium, selenoproteins and human health: a review.Brown KM, Arthur JR. Public Health Nutr. 2001 Apr;4(2B):593-9. Review. [abstract only]
"Selenium is of
fundamental importance to human health. It is an essential
component of several major metabolic pathways, including thyroid
hormone metabolism, antioxidant defence systems, and immune
function. The decline in blood selenium concentration in the UK
and other European Union countries has therefore several
potential public health implications, particularly in relation to
the chronic disease prevalence of the Western world such as
cancer and cardiovascular disease. Ten years have elapsed since
recommended dietary intakes of selenium were introduced on the
basis of blood glutathione peroxidase activity. Since then 30 new
selenoproteins have been identified, of which 15 have been
purified to allow characterisation of their biological function.
The long term health implications in relation to declining
selenium intakes have not yet been thoroughly examined, yet the
implicit importance of selenium to human health is recognised
universally. Selenium is incorporated as selenocysteine at the
active site of a wide range of selenoproteins. The four
glutathione peroxidase enzymes (classical GPx1, gastrointestinal
GPx2, plasma GPx3, phospholipid hydroperoxide GPx4)) which
represent a major class of functionally important selenoproteins,
were the first to be characterised. Thioredoxin reductase (TR) is
a recently identified seleno-cysteine containing enzyme which
catalyzes the NADPH dependent reduction of thioredoxin and
therefore plays a regulatory role in its metabolic activity.
Approximately 60% of Se in plasma is incorporated in
selenoprotein P which contains 10 Se atoms per molecule as
selenocysteine, and may serve as a transport protein for Se.
However, selenoprotein-P is also expressed in many tissues which
suggests that although it may facilitate whole body Se
distribution, this may not be its sole function. A second major
class of selenoproteins are the iodothyronine deiodinase enzymes
which catalyse the 5'5-mono-deiodination of the prohormone
thyroxine (T4) to the active thyroid hormone
3,3'5-triiodothyronine (T3). Sperm capsule selenoprotein is
localised in the mid-peice portion of spermatozoa where it
stabilises the integrity of the sperm flagella. Se intake effects
tissue concentrations of selenoprotein W which is reported to be
necessary for muscle metabolism. It is of great concern that the
health implications of the decline in Se status in the UK over
the past two decades have not been systematically investigated.
It is well recognised that dietary selenium is important for a
healthy immune response. There is also evidence that Se has a
protective effect against some forms of cancer; that it may
enhance male fertility; decrease cardiovascular disease
mortality, and regulate the inflammatory mediators in asthma. The
potential influence of Se on these chronic diseases within the
European population are important considerations when assessing
Se requirement."
Selenoproteins in human thyroid tissues.Zagrodzki P, Nicol F, Arthur JR, Slowiaczek M. Biofactors. 2001;14(1-4):223-7. [abstract only]
"The aim of the present work was to clarify whether the activities of selenoenzymes can serve as markers for different tumors or goiters, as classified by histological criteria. The following parameters were determined: 1) selenium content of plasma (Se), 2) activities of the selenoenzymes: plasma glutathione peroxidase (plGSHPx), cytosolic glutathione peroxidase (cGSHPx), type I and type II iodothyronine deiodinases (ID-I, ID-II), thioredoxin reductase (THRR) in human thyroid tissues. The material came from follicular neoplasm, papillary carcinoma, struma nodosa, struma lymphomatosis Hashimoto, other thyroid surgery specimens, and normal tissues. There was no difference in Se nor in plGSHPx between patients and healthy volunteers. No significant differences were found for any parameter in thyroid carcinoma versus normal or goitrous thyroid tissue. In the whole group of thyroid surgery specimens the statistically significant correlations were found between ID-I and ID-II and between THRR and selenoperoxidases. Principal components analysis confirmed the above correlation and moreover revealed correlation between Se and plGSHPx, but did not detect any clear distinction between patients with the different diagnoses."
Selenium deficiency, thyroid hormone metabolism, and thyroid hormone deiodinases.Arthur JR, Nicol F, Beckett GJ. Am J Clin Nutr. 1993 Feb;57(2 Suppl):236S-239S. Review. [abstract only]
"Much research into the functions of selenium in the cell has concentrated on its role in selenium-containing glutathione peroxidases. However, selenium was recently shown to be an essential component of type I iodothyronine 5'-deiodinase in rats, which converts thyroxin to the more biologically active hormone 3,5,3'-triiodothyronine. Thus, selenium-deficient rats have low tissue deiodinase activities and abnormal thyroid hormone metabolism. The discovery of this function for selenium in thyroid hormone metabolism has important implications for the interpretation of the effects of selenium deficiency, especially in individuals with an adequate vitamin E status."
The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism.Arthur JR, Nicol F, Beckett GJ. Biol Trace Elem Res. 1992 Sep;34(3):321-5. Review. [abstract only]
"Selenium deficiency
impairs thyroid hormone metabolism by inhibiting the synthesis
and activity of the iodothyronine deiodinases, which convert
thyroxine (T4) to the more metabolically active 3,3'-5
triiodothyronine (T3). Hepatic type I iodothyronine deiodinase,
identified in partially purified cell fractions using affinity
labeling with [125I]N-bromoacetyl reverse triiodothyronine, is
also labeled with 75Se by in vivo treatment of rats with
75Se-Na2SeO3. Thus, the type I iodothyronine 5'-deiodinase is a
selenoenzyme. In rats, concurrent selenium and iodine deficiency
produces greater increases in thyroid weight and plasma
thyrotrophin than iodine deficiency alone. These results indicate
that a concurrent selenium deficiency could be a major
determinant of the severity of iodine deficiency."
Selenium deficiency and type II 5'-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine.Chanoine JP, Safran M, Farwell AP, Tranter P, Ekenbarger DM, Dubord S, Alex S, Arthur JR, Beckett GJ, Braverman LE, et al. Endocrinology. 1992 Jul;131(1):479-84.
"Selenium deficiency in rats is characterized by elevated serum T4 and decreased serum T3 concentrations, and low liver type I (5'D-I) and brain type II (5'D-II) iodothyronine 5'-deiodinase activities. These findings are partially explained by the demonstration that type I 5'D is a selenoprotein; however, 5'D-II does not contain selenium. Since 5'D-II varies inversely with serum T4 concentrations, and serum T4 is elevated in selenium deficiency, the decreased cerebrocortical 5'D-II activity may be secondary to the increased serum T4 levels. To determine the mechanism(s) by which selenium influences 5'D-II activity, we examined the effects of altered selenium intake on brain 5'D-II levels and enzyme turnover in euthyroid and thyroidectomized rats. Rats were fed a selenium-supplemented or selenium-deficient diet for 5 weeks from weaning; half of the animals were also thyroidectomized 3 weeks before death. Selenium deficiency was confirmed by decreased liver and brain glutathione peroxidase activities. In euthyroid rats, selenium deficiency caused a 38% increase in serum T4, and 91% and 39% decreases in 5'D-I and 5'D-II, respectively, compared to those in selenium-supplemented rats. In the thyroidectomized hypothyroid rats, selenium deficiency caused a 60% decrease in 5'D-I, but had no effect on 5'D-II activity, fractional turnover of the enzyme, or the calculated enzyme synthesis rate. The lack of effect of selenium deficiency on 5'D-II levels in hypothyroid rats is consistent with the finding that 5'D-II is not a seleno-enzyme. Thus, the decrease in brain and pituitary 5'D-II activity in selenium-deficient euthyroid rats is due to the T4-dependent increase in the turnover of the enzyme polypeptide."
Effects of selenium deficiency on thyroid hormone economy in rats.Chanoine JP, Safran M, Farwell AP, Dubord S, Alex S, Stone S, Arthur JR, Braverman LE, Leonard JL. Endocrinology. 1992 Oct;131(4):1787-92.
"In selenium-deficient
rats, peripheral T4 to T3 conversion is markedly decreased due to the
loss of the selenoprotein, type I iodothyronine 5'-deiodinase (5'D-I).
Despite the marked increase in circulating T4 that results from this
loss of 5'D-I, serum T3 concentrations in selenium-deficient rats
remain in the normal range. To determine the physiological mechanism(s)
that maintains circulating T3 when peripheral T4 to T3 conversion is
impaired, we examined the interrelationships between selenium intake
and the metabolism of T3 and T4 in the rat. In euthyroid rats,
selenium deficiency caused the expected loss of 5'D-I, with a 52%
increase in serum T4, which paralleled an increase in the T4
biological half-life. Consistent with the prolonged t1/2 of T4, short
term thyroidectomy (48 h) in selenium-deficient rats failed to
decrease serum T4 concentrations to the levels observed in short term
thyroidectomized, selenium-supplemented rats. Short term thyroidectomy
also caused an expected 33% decrease in liver 5'D-I and a 44% increase
in brain type II iodothyronine 5'-deiodinase (5'D-II) activities in
selenium-supplemented rats. However, in selenium-deficient rats, short
term thyroidectomy did not affect 5'D-I or 5'D-II activities. In
contrast to the selenium-dependent changes in circulating T4 levels,
little or no change in circulating T3 concentrations occurred. There
was a 20% increase in the T3 half-life in selenium-deficient rats. The
serum T3 sulfate concentration was increased, and T3 deiodination was
reciprocally decreased in the selenium-deficient rats. These data
suggest that increased T3 sulfate generation in selenium-deficient
rats may lead to greater T3 availability through enterohepatic
recycling of the iodothyronine and may explain why there are only
minor changes in serum T3 concentrations in selenium-deficient rats."
The role of selenium in thyroid hormone metabolism.Arthur JR. Can J Physiol Pharmacol. 1991 Nov;69(11):1648-52. Review. [abstract only]
"In animals, decreases
in selenium-containing glutathione peroxidase activity and the
resultant impairment of peroxide metabolism can account for many,
but not all of the biochemical and clinical changes caused by
selenium deficiency. Recently, however, type I iodothyronine
5'-deiodinase has also been shown to be a selenium-containing
enzyme. This explains the impairment of thyroid hormone
metabolism caused by selenium deficiency in animals with a normal
vitamin E status. Since iodothyronine 5'-deiodinases are
essential for the production of the active thyroid hormone
3,5,3'-triiodothyronine, some of the consequences of selenium
deficiency may result from thyroid changes rather than inability
to metabolise peroxides. In particular, the impaired thyroid
hormone metabolism may be responsible for decreased growth and
resistance to cold stress in selenium-deficient animals. A
further consequence of the role of selenium in thyroid hormone
metabolism is the exacerbation of some of the thyroid changes in
iodine deficiency by a concurrent selenium deficiency. Selenium
status may therefore have a major influence on the outcome of
iodine deficiency in both human and animal populations."
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