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PubMed1998

[Effects of the combined deficiency of selenium and iodine on thyroid function].

Recent studies reported the role of several trace elements in health and disease. The role of iodine deficiency in thyroid dysfunction is well known. Also the selenium deficiency has been reported to be correlated to thyroid dysfunctions. In fact, although the major role of selenium is related to the glutathione peroxidase system, which protects cellular structures from oxidative damages, selenium plays also an important role in thyroid hormone metabolism as an essential component of the three deiodinase. These regulate inter-conversion of active and inactive forms of iodothyronines. Several studies have been carried out to establish the role of combined selenium and iodine deficiency. This review aims to provide information on the relationship between selenium and iodine intake and thyroid function. Furthermore, the state of art on the effects of the combined deficiency of selenium and iodine is also provided.

Cysteine↗
PubMed2006

The central role of metal coordination in selenium antioxidant activity.

Oxidative DNA damage occurs in vivo by hydroxyl radical generated in metal-mediated Fenton-type reactions. Cell death and mutation caused by this DNA damage are implicated in neurodegenerative and cardiovascular diseases, cancer, and aging. Treating these conditions with antioxidants, including highly potent selenium antioxidants, is of growing interest. Gel electrophoresis was used to directly quantify DNA damage inhibition by selenium compounds with copper and H(2)O(2). Selenocystine inhibited all DNA damage at low micromolar concentrations, whereas selenomethionine showed similar inhibition at 40 times these concentrations, and 2-aminophenyl diselenide showed no effect. DNA damage inhibition by these selenium compounds does not correspond to their glutathione peroxidase activities, and UV-vis and gel electrophoresis results indicate that selenium-copper coordination is essential for DNA damage inhibition. Understanding this novel metal-coordination mechanism for selenium antioxidant activity will aid in the design of more potent antioxidants to treat and prevent diseases caused by oxidative stress.

Antioxidants↗
PubMed1999

Selenium redox biochemistry of zinc-sulfur coordination sites in proteins and enzymes.

Selenium has been increasingly recognized as an essential element in biology and medicine. Its biochemistry resembles that of sulfur, yet differs from it by virtue of both redox potentials and stabilities of its oxidation states. Selenium can substitute for the more ubiquitous sulfur of cysteine and as such plays an important role in more than a dozen selenoproteins. We have chosen to examine zinc-sulfur centers as possible targets of selenium redox biochemistry. Selenium compounds release zinc from zinc/thiolate-coordination environments, thereby affecting the cellular thiol redox state and the distribution of zinc and likely of other metal ions. Aromatic selenium compounds are excellent spectroscopic probes of the otherwise relatively unstable functional selenium groups. Zinc-coordinated thiolates, e.g., metallothionein (MT), and uncoordinated thiolates, e.g., glutathione, react with benzeneseleninic acid (oxidation state +2), benzeneselenenyl chloride (oxidation state 0) and selenocystamine (oxidation state -1). Benzeneseleninic acid and benzeneselenenyl chloride react very rapidly with MT and titrate substoichiometrically and with a 1:1 stoichiometry, respectively. Selenium compounds also catalyze the release of zinc from MT in peroxidation and thiol/disulfide-interchange reactions. The selenoenzyme glutathione peroxidase catalytically oxidizes MT and releases zinc in the presence of t-butyl hydroperoxide, suggesting that this type of redox chemistry may be employed in biology for the control of metal metabolism. Moreover, selenium compounds are likely targets for zinc/thiolate coordination centers in vivo, because the reactions are only partially suppressed by excess glutathione. This specificity and the potential to undergo catalytic reactions at low concentrations suggests that zinc release is a significant aspect of the therapeutic antioxidant actions of selenium compounds in antiinflammatory and anticarcinogenic agents.

Animals↗
PubMed1999

Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis.

The cancer chemopreventive effect of selenium cannot be fully accounted for by the role of selenium as a component of the antioxidant enzyme glutathione peroxidase, which suggests that chemoprevention occurs by another mechanism. Several studies have shown that thiol oxidation and free radical generation occur as a consequence of selenium catalysis and toxicity. In the present study, we evaluated three different selenium compounds; selenite, selenocystamine, and selenomethionine to determine the relative importance of the prooxidative effects of these compounds with regard to their ability to induce apoptosis. The experimental results suggest that, in addition to supporting an increased activity of glutathione peroxidase, an antioxidant function that the three selenium compounds did with equal efficacy, catalytic selenite, and selenocystamine generated 8-hydroxydeoxyguanosine DNA adducts, induced apoptosis and were found to be cytotoxic in mouse keratinocytes. The noncatalytic selenomethionine was not cytotoxic, did not generate 8-hydroxydeoxyguanosine adducts and did not induce cellular apoptosis at any of the selenium concentrations studied. In keratinocytes, apoptosis may be initiated by superoxide (O2*-) and oxidative free radicals that are generated by selenite and selenocystamine, but not by selenomethionine.

Animals↗
PubMed2006

Enzymatic and non-enzymatic antioxidant status in stage (III) human oral squamous cell carcinoma and treated with radical radio therapy: influence of selenium supplementation.

BACKGROUND: Oxidative stress is implicated in oral carcinogenesis and has been found to be aggravated during radiotherapy. A great deal of attention has been focused on the possible therapeutic implications of selenium as a potent antioxidant. We determined whether selenium supplementation to radiation treated oral cancer patients render improvement in the antioxidant status against oxidative stress. METHOD: Blood samples were collected from stage (III) oral cancer patients before initiating radiotherapy (Group B) (n=63) and this group is bifurcated into Group C-patients given radiotherapy alone (n=27) and Group D-patients given radiotherapy and supplemented with selenium (400 mug/day for 6 months) (n=36). Both Group C and D were followed up for 6 months. We evaluated the plasma selenium concentration, non-enzymatic system including GSH, vitamins E, C, A and ceruloplasmin and enzymatic antioxidant system including superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase. RESULTS: The concentrations of selenium, all non-enzymatic antioxidants and the activities of enzymatic antioxidants were found to be lowered in oral cancer patients (Group B), compared to normal (Group A) (p<0.05). Similar decrease in the concentration of selenium and antioxidants status was observed in radiotherapy group (Group C) (p<0.05). On the contrary, selenium group (Group D) showed marked increase in the concentrations of selenium and antioxidant status at 6 months compared to radiation group (Group C) (p<0.05). CONCLUSION: The observed result represents the antioxidant property of selenium through the improvement of antioxidant defense system. Selenium supplementation could be of great interest in protecting cells against oxidative stress.

Adult↗
PubMed2002

Restorative effects of zinc and selenium on cadmium-induced kidney oxidative damage in rats.

OBJECTIVE: To investigate whether cadmium-induced oxidative stress in the kidney is influenced by zinc and selenium. METHODS: Five groups of rats were maintained: (A) Cd (CdCl2, 400 micrograms.kg-1.day-1 intraperitoneal injection); (B) Cd + Zn (ZnCl2, 20 mg.kg-1.day-1 hypodermic injection); (C) Cd + Se (Na2SeO3, 350 micrograms.kg-1.day-1 via a stomach tube); (D) Cd + Zn + Se; (E) treated with physiological saline as a sham-handled control. The rats were given treatment for a period of 4 weeks. The activities of superoxide dismutase (SOD), glutathione peroxidase (GH-Px), catalase (CAT), and the level of malondialdehyde (MDA) in the kidney tissue were measured to assess the oxidative stress. Urinary lactate dehydrogenase (LDH) activity was used as an indicator of tubular cell damage caused by lipid peroxidation. RESULTS: In group C and D, activities of SOD (110.5 +/- 5.2, 126.8 +/- 7.0; P < 0.05) and GSH-Px (85.7 +/- 4.9, 94.6 +/- 7.3; P < 0.05) were higher than those in group A (84.7 +/- 3.3; 56.9 +/- 3.8); and in group B, only the activity of GSH-Px (80.0 +/- 4.3, P < 0.01) increased in comparison with that in group A (56.9 +/- 3.8). Significant increase of MDA (P < 0.05) was seen in group B (31.1 +/- 4.7) and C (35.0 +/- 4.1) when compared with control values (17.2 +/- 1.8). No difference was found in the level of MDA between group D (18.9 +/- 2.6) and control. The activity of LDH in urine of control group (0.06 +/- 0.02) was lower than that of group A (0.46 +/- 0.19, P < 0.05), B (0.10 +/- 0.05, P < 0.05) and C (0.14 +/- 0.07, P < 0.05), and there was no significant change between control (0.06 +/- 0.02) and group D (0.08 +/- 0.02). CONCLUSION: Zinc or selenium could partially alleviate the oxidative stress induced by cadmium in kidney, but administration cadmium in combination with zinc and selenium efficiently protects kidney from cadmium-induced oxidative damage.

Animals↗
PubMed2003

Reduced inotropic heart response in selenium-deficient mice relates with inducible nitric oxide synthase.

Atria from mice fed a selenium-deficient (Se(-)) diet have a diminished beta-adrenoceptor-inotropic cardiac response to isoproterenol or norepinephrine compared with atria from mice fed the same diet supplemented with 0.2 mg/kg Se as sodium selenite (Se(+)). This diminished response could be reversed by feeding Se(-) mice the Se(+) diet for 1 wk or by pretreatment with nitric oxide synthase (NOS) inhibitors such as N(G)-monomethyl-l-arginine or aminopyridine. Elevated serum concentrations of nitrite/nitrate as well as a threefold increase in the atrial NOS activity were seen in the Se(-) versus Se(+) mice. Western blotting and indirect immunofluorescence indicated an enhanced expression of inducible NOS in hearts from Se(-) mice. Increased expression and activity of NOS and increased nitrite/nitrate levels from Se(-) mice correlated with an impaired response to beta-adrenoceptor inotropic cardiac stimulation. Elevated nitric oxide levels may account for some of the pathophysiological effects of Se deficiency on the heart.

Adrenergic alpha-Agonists↗
PubMed2003

Role of copper, zinc, selenium and tellurium in the cellular defense against oxidative and nitrosative stress.

The trace elements copper, zinc and selenium are linked together in cytosolic defense against reactive oxygen and nitrogen species. Copper, zinc-superoxide dismutase catalyzes the dismutation of superoxide to oxygen and hydrogen peroxide. The latter and other hydroperoxides are subsequently reduced by the selenoenzyme glutathione peroxidase (GPx). Cytosolic GPx can also act as a peroxynitrite reductase. The antioxidative functions of these trace elements are not confined to being constituents of enzymes: 1) copper and zinc ions may stimulate protective cellular stress-signaling pathways such as the antiapoptotic phosphoinositide-3-kinase/Akt cascade and may stabilize proteins, thereby rendering them less prone to oxidation; and 2) selenium does not only exist in the cell as selenocysteine (as in GPx) but also as selenomethionine, which is regularly present in low amounts in proteins in place of methionine. Selenomethionine catalyzes the reduction of peroxynitrite at the expense of glutathione. Also, low-molecular-weight organoselenium and organotellurium compounds of pharmacologic interest catalyze the reduction of hydroperoxides or peroxynitrite with various cellular reducing equivalents.

Copper↗
PubMedDate not supplied

Selenium. Preclinical studies of anticancer therapeutic potential.

Selenium is a trace element that is essential to the human diet. Deficiency states have been described in both animals and humans. In addition, selenium compounds have demonstrated toxicity in humans, as well as in human tissues in culture. As early as 1956, one form of selenium was used as an antineoplastic agent in humans with some demonstrated activity. Recently, evidence in both tumor-bearing animals and human tumor cells in culture have confirmed an antitumor effect of potential clinical benefit. The mechanism of this cytoxic effect appears, at least in part, to relate to the property of some forms of selenium to oxidize critical sulfhydral groups in the cell. Evidence for this, and the resulting implications for the use of selenium in anticancer treatment, is presented in this manuscript.

Antineoplastic Agents↗
PubMed1991

Serum selenium concentrations in rheumatoid arthritis.

Selenium is a trace element and an essential part of the enzyme glutathione peroxidase, which protects cells from oxidative damage. Selenium has been shown to have antiproliferative, anti-inflammatory, antiviral, and immune altering effects. Serum selenium concentrations in 101 patients with seropositive rheumatoid arthritis were found to be significantly lower than those in 29 normal, healthy controls (mean (SD) 148 (42) v 160 (25) micrograms/l) and also lower than those in eight patients with fibrositis (148 (42) v 166 (25) micrograms/l). It is speculated that serum selenium concentrations may modulate the effect of viral or other infections in subjects with the appropriate genetic background and in this way enhance the development or progression of rheumatoid arthritis.

Adult↗
PubMedDate not supplied

The role of selenium peroxidases in the protection against oxidative damage of membranes.

The present review deals with the chemical properties of selenium in relation to its antioxidant properties and its reactivity in biological systems. The interaction of selenite with thiols and glutathione and the reactivity of selenocompounds with hydroperoxides are described. After a short survey on distribution, metabolism and organification of selenium, the role of this element as a component of the two seleno-dependent glutathione peroxidases is described. The main features of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are also reviewed. Both enzymes reduce different hydroperoxides to the corresponding alcohols and the major difference is the reduction of lipid hydroperoxides in membrane matrix catalyzed only by the phospholipid hydroperoxide glutathione peroxidase. However, in spite of the different specificity for the peroxidic substrates, the kinetic mechanism of both glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase seems identical and proceeds through a tert-uni ping pong mechanism. In the reaction cycle, indeed, as supported by the kinetic data, the oxidation of the ionized selenol by the hydroperoxide yields a selenenic acid that in turn is reduced back by two reactions with reduced glutathione. Special emphasis has been given to the role of selenium-dependent glutathione peroxidases in the prevention of membrane lipid peroxidation. While glutathione peroxidase is able to reduce hydrogen peroxide and other hydroperoxides possibly present in the soluble compartment of the cell, this enzyme fails to inhibit microsomal lipid peroxidation induced by NADPH or ascorbate and iron complexes. On the other hand, phospholipid hydroperoxide glutathione peroxidase, by reducing the phospholipid hydroperoxides in the membranes, actively prevents lipid peroxidation, provided a normal content of vitamin E is present in the membranes. In fact, by preventing the free radical generation from lipid hydroperoxides, phospholipid hydroperoxide glutathione peroxidase decreases the vitamin E requirement necessary to inhibit lipid peroxidation. Finally, the possible regulatory role of the selenoperoxidases on the arachidonic acid cascade enzymes (cyclooxygenase and lipoxygenase) is discussed.

Antioxidants↗
PubMed2002

Influence of selenium-enriched yeast supplementation on biomarkers of oxidative damage and hormone status in healthy adult males: a clinical pilot study.

The mechanisms responsible for the protective role of selenium against the development of prostate cancer remain to be determined (L. C. Clark et al., J. Am. Med. Assoc., 276: 1957-1963, 1996). In the present study, we tested the hypothesis that selenium supplementation reduces oxidative stress. A secondary aim was to determine whether selenium-induced changes in testosterone (T) metabolism may also be involved. To this end, we conducted a double-blind, randomized, placebo-controlled trial of 247 micro g selenium/day administered p.o. in the form of Se-enriched yeast. Study subjects were 36 healthy adult males, 11 blacks and 25 whites, 19-43 years of age. Supplementation occurred over the first 9 months, after which all subjects were placed on placebo for an additional 3 months. Blood and urine were collected at baseline and after 3, 9, and 12 months. In the selenium group, plasma selenium levels were 2-fold higher than baseline values after 3 and 9 months and returned to 136% of baseline after 12 months (P < 0.0001), whereas in the placebo group, levels were unchanged. A 32% increase in blood glutathione (GSH) levels was observed after 9 months in the selenium group only (P < 0.05). This change coincided with a 26% decrease in protein-bound GSH (bGSH) and a 44% decrease in bGSH:GSH ratios (P < 0.05). The changes in GSH and bGSH were highly correlated with changes in plasma selenium concentrations and may reflect a decrease in oxidative stress. No changes were observed in either group for plasma T, dihydrotestosterone (DHT) or DHT:T ratios, suggesting that selenium had no effect on the alpha-reductase involved in the conversion of T to DHT. A small but significant decrease in prostate-specific antigen levels was observed after 3 and 9 months (P < 0.001), and this difference disappeared after 12 months. Future trials will test the above hypothesis in prostate cancer patients and in subjects at high risk for prostate cancer.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Selenoxidation by flavin-containing monooxygenases as a novel pathway for beta-elimination of selenocysteine Se-conjugates.

Previously, it was shown that beta-elimination of selenocysteine Se-conjugates by rat renal cytosol leading to pyruvate formation was not solely catalyzed by pyridoxal phosphate-dependent enzymes. It was hypothesized that selenoxidation of the selenocysteine Se-conjugates, followed by syn-elimination, may be an alternative mechanism for pyruvate formation. In this study, selenoxidation of selenocysteine Se-conjugates was studied using rat liver microsomes and recombinant human oxidative enzymes. For all six selenocysteine Se-conjugates that were tested, it was found that rat liver microsomal incubations led to the formation of pyruvate, whereas the corresponding selenoxides were not observed. Microsomal pyruvate formation from Se-benzyl-L-selenocysteine (SeBC) was NADPH-dependent, but only marginally inhibited by several P450 inhibitors. Inhibition by methimazole and by heat pretreatment and stimulation by n-octylamine indicated that flavin-containing monooxygenases are mainly responsible for pyruvate formation from the selenocysteine Se-conjugates in rat liver microsomes. In the case of S-benzyl-L-cysteine, the sulfur analogue of SeBC, pyruvate formation was not observed. For this substrate, a chemically stable sulfoxide could be observed, as previously described. By using recombinantly expressed human flavin-containing monooxygenases and P450 enzymes, it was delineated that SeBC is selenoxidized by human FMOs, but not by human P450s. The k(cat)/K(m) of selenoxidation was 3.8-fold higher for FMO-1 than for FMO-3. In conclusion, selenoxidation of selenocysteine Se-conjugates catalyzed by FMOs and subsequently syn-elimination has taken place as an alternative route for the formation of pyruvate from selenocysteine Se-conjugates. Although selenoxides are known to be easily reduced by thiol compounds, microsomal pyruvate formation from SeBC was only 75% inhibited in the presence of an excess of glutathione. This indicates that even in the presence of physiological concentrations of reducing thiol compounds, selenoxides of selenocysteine Se-conjugates may undergo syn-elimination to some extent. Whether selenoxides and/or selenenic acids that are formed are involved in the activity of chemopreventive selenocysteine Se-conjugates remains to be established.

Animals↗
PubMed1998

Ebselen, a selenium-containing redox drug, releases zinc from metallothionein.

Selenium compounds oxidize the thiolate ligands in the zinc clusters of metallothionein and release zinc. This chemistry defines new cellular targets for biological forms of selenium and suggests important interactions between zinc and selenium, two biologically essential elements. In the course of delineating the redox chemistry of biological zinc complexes with thiolate ligands, we have found that the non-toxic experimental drug ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) releases zinc from metallothionein. The reaction follows a 1:1 stoichiometry for thiols, is very rapid (t1/2 < 1 min), and proceeds through the opening of the isoselenazol ring and formation of a selenodisulfide with metallothionein. Despite the fast reaction of ebselen with glutathione (t1/2 < 1 s), which proceeds past the stage of the selenodisulfide adduct to the selenol and diselenide derivatives, ebselen reacts with MT even in the presence of glutathione, suggesting that it can also react with MT in vivo. These findings reveal a new mode of action for ebselen and therefore suggest therapeutic applications in zinc-related medical disorders as well as a possible role of biological selenium compounds in zinc metabolism.

Animals↗
PubMed2003

Selenium-deficient diet enhances protein oxidation and affects methionine sulfoxide reductase (MsrB) protein level in certain mouse tissues.

Mammals contain two methionine sulfoxide (MetO) reductases, MsrA and MsrB, that catalyze the thioredoxin-dependent reduction of the S-MetO and R-MetO derivatives, respectively, to methionine. The major mammalian MsrB is a selenoprotein (except in the heart). Here, we show that there is a loss of MsrB activity in the MsrA-/- mouse that correlates with parallel losses in the levels of MsrB mRNA and MsrB protein, suggesting that MsrA might have a role in MsrB transcription. Moreover, mice that were grown on a selenium-deficient (SD) diet showed a substantial decrease in the levels of MsrB-catalytic activity, MsrB protein, and MsrB mRNA in liver and kidney tissues of both WT and MsrA-/- mouse strains. Whereas no significant protein-MetO could be detected in tissue proteins of young mature mice grown on a selenium-adequate diet, growth on the SD diet led to substantial accumulations of MetO in proteins and also of protein carbonyl derivatives in the liver, kidney, cerebrum, and cerebellum, respectively. In addition, accumulation of protein-MetO derivatives increased with age in tissues of mice fed with a selenium-adequate diet. It should be pointed out that even though the total Msr level is at least 2-fold higher in WT than in MsrA-/- mice, SD diet causes an equal elevation of protein-MetO (except in brain cerebellum) and carbonyl levels in both strains, suggesting involvement of other selenoproteins in regulation of the level of cellular protein-MetO accumulation. Furthermore, the development of the "tip-toe" walking behavior previously observed in the MsrA-/- mice occurred earlier when they were fed with the SD diet.

Animals↗
PubMed1997

Oxidation reactions of acetylenic fatty esters with selenium dioxide/tert-butyl hydroperoxide.

Reaction of methyl undec-10-ynoate (1) with selenium dioxide/tert-butyl hydroperoxide (TBHP) in aqueous dioxane gave methyl 9-oxo-undec-10-ynoate (2, 9%) and 9-hydroxy-undec-10-ynoate (3, 60%), while methyl octadec-9-ynoate (4) yielded mixtures of positional isomers of mono-keto (viz. methyl 8-oxo- and 11-oxo-octadec-9-ynoate, 5, 5%), hydroxy-keto (viz. methyl 8-hydroxy-11-oxo- and 11-hydroxy-8-oxo-octadec-9-ynoate, 6, 10%), and dihydroxy (viz. methyl 8,11-dihydroxy-octadec-9-ynoate, 7, 24%) derivatives. Similar treatment of a conjugated diacetylenic fatty ester (methyl octadeca-6,8-diynoate, 8) furnished a mixture of methyl 5-oxo- and 10-oxo-octadeca-6,8-diynoate (9, 12%) and a complex mixture of very polar products. Reaction of methyl octadec-11E-en-9-ynoate (methyl santalbate) (10) with selenium dioxide/TBHP in aqueous dioxane gave exclusively a mixture of regiospecific products, viz. methyl 8-oxo-octadec-11(E)Z-en-9-ynoate (11, 6%) and methyl 8-hydroxy-octadec-11E-en-9-ynoate (12, 70%). The structures of the various products were determined by a combination of spectroscopic and mass spectral analyses.

Fatty Acids↗