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PubMed1983

Mode of in vitro interaction of mercuric mercury with selenite to form high-molecular weight substance in rabbit blood.

Mode of interaction of mercuric mercury and selenite in rabbit blood was investigated in vitro. After the incubation of rabbit blood with 10(-5) M each of 203HgCl2 and Na2(75)SeO3, the amounts of both 203Hg and 75Se incorporated into erythrocytes were markedly larger than the case where the blood was treated separately with one of these compounds. Most of 203Hg and 75Se distributed into plasma and erythrocytes were found in high-molecular weight substance(s) (HMWS) fractionated by gel filtration at a molar ratio of 1:1. The 203Hg and 75Se in HMWS found in plasma and erythrocytes were hardly diffusable through the erythrocytes membrane. The formation of the HMWS containing mercury and selenium was observed in stroma-free hemolysate incubated with mercuric chloride and selenite, but not in plasma. Addition of reduced glutathione (GSH) to the plasma, however, gave the HMWS as reaction products containing equimolar amounts of mercury and selenium. Further the binding properties of selenium to proteins were studied in the plasma incubated with selenodiglutathione (GSSeSG) or with selenite in the presence of GSH. The results indicated that GSH, a cellular component, is essential for the formation of an active selenium compound from selenite and that the interaction of mercuric mercury and selenite in plasma in the presence of GSH may occur through the other mechanism than the formation of GSSeSG.

Animals↗
PubMed1991

Selenium: inhibition of microtubule formation and interaction with tubulin.

We have studied the interaction of Na2SeO3 with microtubule proteins and tubulin. This selenium compound inhibits the polymerization of MTP (half-inhibition occurred for Na2SeO3 10 microM), and to a lesser that of tubulin. This effect of selenite is related to the formation of disulfide bridges between tubulin sulfhydryl groups, inducing a conformational change of the protein. This is corroborated by the modified binding of colchicine and vinblastine in presence of selenium. The selenite inhibitory concentrations are similar to the toxic blood levels of selenium (40 microM).

Animals↗
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↗
PubMed2002

Modern trends in the speciation of selenium by hyphenated techniques.

The complexity of selenium speciation in the environment and in living organisms results in broad analytical challenges. The importance of the selective determination of the particular species of this element, to understand its metabolism and biological significance in clinical chemistry, biology, toxicology, and nutrition, calls for state-of-the-art analytical techniques. In this paper hyphenated techniques are evaluated with particular emphasis on interfaced separation with element-selective detection and identification of the selenium compounds detected.

Chromatography, Gas↗
PubMed2002

Selenomethionine regulation of p53 by a ref1-dependent redox mechanism.

The cancer chemopreventive properties of selenium compounds are well documented, yet little is known of the mechanism(s) by which these agents inhibit carcinogenesis. We show that selenium in the form of selenomethionine (SeMet) can activate the p53 tumor suppressor protein by a redox mechanism that requires the redox factor Ref1. Assays to measure direct reduction/oxidation of p53 showed a SeMet-dependent response that was blocked by a dominant-negative Ref1. By using a peptide containing only p53 cysteine residues 275 and 277, we demonstrate the importance of these residues in the SeMet-induced response. SeMet induced sequence-specific DNA binding and transactivation by p53. Finally, cellular responses to SeMet were determined in mouse embryo fibroblasts wild-type or null for p53 genes. The evidence suggests that the DNA repair branch of the p53 pathway was activated. The central relevance of DNA repair to cancer prevention is discussed.

Animals↗
PubMedDate not supplied

Report on the 1986 A.S.P.E.N. Research Workshop on selenium in clinical nutrition.

Selenium in human nutrition was the theme of the 1986 Research Workshop of the American Society for Parenteral and Enteral Nutrition. At the workshop, evidence for the nutritional essentiality of selenium to humans was reviewed, and it was concluded that Keshan disease, the cardiomyopathy of children and young women described in China, is now firmly linked to selenium deficiency, although other factors may be involved. Selenium metabolism and techniques for assessing selenium status also received attention at the workshop. A measurement of blood selenium levels was accepted, in general, as a valid technique for assessing selenium status in individuals with relatively constant selenium intakes. Clinical practitioners at the workshop reported that some of their total parenteral nutrition patients not receiving selenium presented biochemical evidence of selenium deficiency, but no characteristic clinical syndrome due to selenium deficiency has yet been observed in such patients. The workshop attendees acknowledged the need for an official guideline for selenium use in total parenteral nutrition, but were unable to develop a consensus regarding such a guideline. However, the workshop agreed that any guideline established in the future should specify the type of patients to be supplemented, the dose of selenium to be administered, and the selenium compound to be used. Until that time, the physician supervising the therapy must assume responsibility both for determining the need for selenium supplementation, and for the administration of the supplemental selenium.

Adult↗
PubMed1984

Comparison of cytotoxicity of mercury-selenium and mercury compounds on cultured cells.

In vitro effects of mercury-selenium (Hg-Se) compounds, as compared with their original mercury compounds, against growth and viability of HeLa cells were studied. A water-soluble, ethanol-insoluble black complex (GX) formed from HgCl2, Na2SeO3 and GSH was less toxic than HgCl2, but the cytotoxicity of bis(methylmercuric) selenide (BMS) seemed to be similar to that of methylmercury. This may be due to the instability of BMS; i.e., there is a possibility that BMS decomposed to methylmercury and selenium under our culture conditions.

Cell Survival↗
PubMed1982

Selenocysteine lyase, a novel enzyme that specifically acts on selenocysteine. Mammalian distribution and purification and properties of pig liver enzyme.

We have found a novel enzyme that exclusively decomposes L-selenocysteine into L-alanine and H2Se in various mammalian tissues, and have named it selenocysteine lyase. The enzyme from pig liver has been purified to homogeneity. It has a molecular weight of approximately 85,000, and contains pyridoxal 5'-phosphate as a coenzyme. Its maximum reactivity is at about pH 9.0. Balance studies showed that 1 mol of selenocysteine is converted to equimolar amounts of alanine and H2Se. The following amino acids are insert: L-cysteine, L-serine, L-cysteine sulfinate, selenocysteamine, Se-ethyl-DL-selenocysteine, and L-selenohomocysteine. L-Cysteine (Ki, 1.0 mM) competes with L-selenocysteine (Km, 0.83 mM) to inhibit the enzyme reaction. The enzyme is the first proven enzyme that specifically acts on selenium compounds.

Animals↗
PubMed2000

A method for measuring disulfide reduction by cultured mammalian cells: relative contributions of glutathione-dependent and glutathione-independent mechanisms.

A method is described for measuring bioreduction of hydroxyethyl disulfide (HEDS) or alpha-lipoate by human A549 lung, MCF7 mammary, and DU145 prostate carcinomas as well as rodent tumor cells in vitro. Reduction of HEDS or alpha-lipoate was measured by removing aliquots of the glucose-containing media and measuring the reduced thiol with DTNB (Ellman's reagent). Addition of DTNB to cells followed by disulfide addition directly measures the formation of newly reduced thiol. A549 cells exhibit the highest capacity to reduce alpha-lipoate, while Q7 rat hepatoma cells show the highest rate of HEDS reduction. Millimolar quantities of reduced thiol are produced for both substrates. Oxidized dithiothreitol and cystamine were reduced to a lesser degree. DTNB, glutathione disulfide, and cystine were only marginally reduced by the cell cultures. Glucose-6-phosphate deficient CHO cells (E89) do not reduce alpha-lipoate and reduce HEDS at a much slower rate compared to wild-type CHO-K1 cells. Depletion of glutathione prevents the reduction of HEDS. The depletion of glutathione inhibited reduction of alpha-lipoate by 25% and HEDS by 50% in A549 cells, while GSH depletion did not inhibit alpha-lipoate reduction in Q7 cells but completely blocked HEDS reduction. These data suggest that the relative participation of the thioltransferase (glutaredoxin) and thioredoxin systems in overall cellular disulfide reduction is cell line specific. The effects of various inhibitors of the thiol-disulfide oxidoreductase enzymes (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), arsenite, and phenylarsine oxide) support this conclusion.

Animals↗
PubMed1985

Effect of ascorbic acid supplementation on selenium bioavailability in humans.

The study was designed to investigate the effect of supplemental ascorbic acid on the bioavailability of selenium (Se) in humans by using plasma Se levels and plasma glutathione peroxidase (GSH-Px) activity as indicators of the body Se status. Three groups of female university students were supplemented for 4 weeks with either 50 micrograms sodium selenate, 50 micrograms sodium selenate together with 200 mg ascorbic acid, or with 200 mg ascorbic acid three times daily during meals. Plasma Se levels increased significantly (P less than 0.01) in all three groups regardless of the type of supplementation. The increase was highest in the group having both Se and ascorbic acid and smallest in the group receiving only ascorbic acid. The changes in plasma GSH-Px activities reflected those in plasma Se, but the increases were smaller (P less than 0.05). These results suggest that supplemental ascorbic acid may have a beneficial effect on the bioavailability of the natural Se in foods. However, ascorbic acid did not seem to affect the availability of the supplemental sodium selenate. Therefore, the effect of ascorbic acid on the bioavailability of selenium may vary depending on the ingested selenium compound.

Adult↗
PubMed2002

Intracellular glutathione is a cofactor in methylseleninic acid-induced apoptotic cell death of human hepatoma HEPG(2) cells.

Selenium is a widely studied dietary anticancer agent. Among various selenium compounds, the methylated forms appear to be particularly effective in cancer prevention. Intracellular glutathione (GSH) is known to be involved in the metabolism of many methylated forms of selenium. In this study, we investigated the role of intracellular GSH in methylseleninic acid (MSeA)-induced apoptosis in human hepatoma (HepG(2)) cells. MSeA was shown to deplete intracellular GSH rapidly, preceding the typical apoptotic changes such as DNA fragmentation as measured by the TUNEL assay. When the intracellular GSH concentration was enhanced using N-acetylcysteiene (NAC) (a GSH synthesis precursor) and decreased using buthionine sufoxamine (BSO) (a GSH synthesis inhibitor), NAC markedly augmented MSeA-induced apoptosis, while BSO significantly inhibited MSeA-induced apoptosis. Different from the effect of sodium selenite, there was no measurable superoxide radical level in MSeA-treated cells. These observations suggest that intracellular GSH mainly acts as a cofactor to facilitate MSeA-induced apoptosis, while its antioxidant function becomes largely irrelevant. It is thus postulated that some cancer cells, such as liver cancer cells with higher level of intracellular GSH, would be more susceptible to MSeA cytotoxicity.

Anticarcinogenic Agents↗
PubMed2002

Reactive oxygen species from mitochondria mediate SW480 cells apoptosis induced by Na2SeO3.

A number of selenium compounds have been found to inhibit tumorigenesis in a variety of animal and cell models. In order to explore the molecular mechanism involved in the anticarcinogenesis activity of selenium, we examined the effects of sodium selenite on cell viabilty, generation of reactive oxygen species (ROS), and mitochondrial transmembrane potential (delta(psi)m) in human colonic carcinoma cells SW480. The result from MTT test showed that sodium selenite reduced cell viability. Morophologic and flow cytometric results indicated that Na2SeO3 induced the apoptosis of SW480 cells. Na2SeO3 increased the generation of intracellular ROS, whereas BAPTA-AM, rotenone, and NaCN completely inhibited the increase of ROS induced by Na2SeO3. Na2SeO3 also caused the disruption of delta(psi)m. The intracellular ROS increase and apoptosis induced by Na2SeO3 were significantly decreased by superoxide dismutase (SOD), catalase. These data suggest that the ROS mediate apoptosis induced by Na2SeO3 and mitochondria may be a major source of Na2SeO3-induced ROS.

Apoptosis↗
PubMed1984

[Dynamics of changes in the electroretinogram of isolated frog and turtle retinas during rhythmic photic stimulation in conditions of induced lipid peroxidation].

Comparative study of isolated retinas of frogs and turtles exposed to rhythmical photostimulation was conducted. It was shown that there are marked differences between the responses of isolated retinas of frogs and turtles to the rhythmical photostimulation. A considerable depression of the total amplitude of the rhythmical electroretinogram was observed under the conditions of induced lipid peroxidation. Introduction of a selenium compound to the superfusing medium increased to a certain extent both the single and rhythmical responses of isolated retinas of the animals.

Animals↗
PubMed2003

Cellular zinc and redox states converge in the metallothionein/thionein pair.

The paramount importance of zinc for a wide range of biological functions is based on its occurrence in thousands of known zinc proteins. To regulate the availability of zinc dynamically, eukaryotes have compartmentalized zinc and the metallothionein/thionein pair, which controls the pico- to nanomolar concentrations of metabolically active cellular zinc. Interactions of zinc with sulfur ligands of cysteines turn out to be critical both for tight binding and creation of a redox-active coordination environment from which the redox-inert zinc can be distributed. Biological oxidants such as disulfides and S-nitrosothiols oxidize the zinc/thiolate clusters in metallothionein with concomitant zinc release. In addition, selenium compounds that have the capacity to form selenol(ate)s catalytically couple with the glutathione/glutathione disulfide and metallothionein/thionein redox pairs to either release or bind zinc. In this pathway, selenium expresses its antioxidant effects through redox catalysis in zinc metabolism. Selenium affects the redox state of thionein, an endogenous chelating agent. With its 20 cysteines, thionein contributes significantly to the zinc- and thiol-redox-buffering capacity of the cell. Thus, hitherto unknown interactions between the essential micronutrients zinc and selenium on the one hand and zinc and redox metabolism on the other are key features of the cellular homeostatic zinc system.

Animals↗
PubMed2002

Rhesus monkey simian immunodeficiency virus infection as a model for assessing the role of selenium in AIDS.

The objective of this study was to determine whether simian immunodeficiency virus (SIV) infection of macaques could be used as a model system to assess the role of selenium in AIDS. Plasma and serum selenium levels were determined by standard assays in monkeys before and after inoculation of SIV. SIV-infected cells or cells expressing the HIV Tat protein were labeled with 75Se, and protein extracts were prepared and electrophoresed to analyze selenoprotein expression. Total tRNA was isolated from CEMx174 cells infected with SIV or from KK1 cells infected with HIV, and selenocysteine tRNA isoforms were characterized by reverse phase chromatography. SIV-infected monkeys show a decrease in blood selenium levels similar to that observed in AIDS with development of SAIDS. Cells infected with SIV in vitro exhibit reduced selenoprotein levels and an accumulation of small molecular weight selenium compounds relative to uninfected cells. Examination of the selenocysteine tRNA isoforms in HIV-infected KK1 cells or SIV-infected CEMx174 cells reveals an isoform distribution characteristic of selenium-deficient cells. Furthermore, transfection of Jurkat E6 cells with the Tat gene selectively altered selenoprotein synthesis, with GPX4 and Sep15 being the most inhibited and TR1 the most enhanced. Taken together, the data show that monkeys infected with SIV in vivo and cells infected with SIV in vitro will provide appropriate models for investigating the mechanism(s) responsible for reduced selenium levels that accompany the progression of AIDS in HIV disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Rheumatoid arthritis and metal compounds--perspectives on the role of oxygen radical detoxification.

Rheumatoid arthritis (RA) is characterised by migration of activated phagocytes and other leukocytes into synovial and periarticular tissue. Activated oxygen species and other mediating substances from triggered phagocytes appear to exacerbate and perpetuate the rheumatoid condition. Iron excesses are capable of aggravating the arthritic inflammation, probably through their pro-oxidant potentials. In contrast, therapeutically given gold salts, through a lysosomal loading of the metal, inhibit the triggered cells, thereby reducing the toxic oxygen production. Pharmacological doses of zinc also may immobilise macrophages. Furthermore, the copper-zinc-containing enzyme SOD (superoxide dismutase) can act as a scavenger of toxic oxygen in the tissues. Therapeutic remission of RA has been obtained following intraarticular administration of SOD. Intramuscular administration of copper complexes has induced remission in about 60% of RA patients in open studies. Another drug, penicillamine, that protects cellular membranes against toxic oxygen in vitro, is presumed to act as an antirheumatic via the SOD mimetic activity of its copper complex. Thiomalate and other thiols may possess similar activities. Selenium compounds also may act as oxygen radical scavengers. A significant alleviation of articular pain and morning stiffness was obtained following selenium and vitamin E supplementation in a double-blind study on RA patients. The observations reviewed here indicate that metal compounds and other antioxidants can reduce the rheumatic inflammation by reducing the cellular production and/or concentration of toxic oxygen species.

Arthritis, Rheumatoid↗
PubMed1992

Selenodiglutathione is a highly efficient oxidant of reduced thioredoxin and a substrate for mammalian thioredoxin reductase.

Selenium compounds like selenite (SeO3(2-) may form a covalent adduct with glutathione (GSH) in the form of selenodiglutathione (GS-Se-SG), which is assumed to be important in the metabolism of selenium. We have isolated GS-Se-SG and studied its reactions with NADPH and thioredoxin reductase from calf thymus or with thioredoxin reductase and thioredoxin from Escherichia coli. Incubation of 0.1 microM calf thymus thioredoxin reductase or 0.1 microM thioredoxin reductase and 1 microM thioredoxin from E. coli with 5, 10, or 20 microM GS-Se-SG resulted in a fast initial reaction, followed by a large and continued oxidation of NADPH. However, anaerobic incubation of 0.1 microM calf thymus thioredoxin reductase and 20 microM GS-Se-SG resulted only in oxidation of a stoichiometric amount of NADPH; admission of oxygen started continuous NADPH oxidation. Contrary to the mammalian enzyme, GS-Se-SG was not a substrate for thioredoxin reductase from E. coli. The rate of the oxygen-dependent reaction between calf thymus thioredoxin reductase and GS-Se-SG was increased 2-fold in the presence of 4 mM GSH, indicating that HSe- was the reactive intermediate. Glutathione reductase from rat liver reduced GS-Se-SG with a very slow continued oxidation of NADPH, and the presence of the enzyme did not affect the oxygen-dependent nonstoichiometric oxidation of NADPH by GS-Se-SG and thioredoxin reductase. Fluorescence spectroscopy showed GS-Se-SG to be a very efficient oxidant of reduced thioredoxin from E. coli and kinetically superior to insulin disulfides. Thioredoxin-dependent reduction of CDP to dCDP by ribonucleotide reductase was effectively inhibited by GS-Se-SG.

Animals↗