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PubMed1992

Synthesis of 5-methylaminomethyl-2-selenouridine in tRNAs: 31P NMR studies show the labile selenium donor synthesized by the selD gene product contains selenium bonded to phosphorus.

An enzyme preparation from Salmonella typhimurium catalyzes the conversion of 5-methylaminomethyl-2-thiouridine in tRNAs to 5-methylaminomethyl-2-selenouridine when supplemented with selenide and ATP. Similar preparations from a Salmonella mutant strain carrying a defective selD gene fail to catalyze this selenium substitution reaction. However, supplementation of the deficient enzyme preparation with the purified selD gene product (SELD protein) restored synthesis of seleno-tRNAs. In the absence of the complementary enzyme(s), the SELD protein catalyzes the synthesis of a labile selenium donor compound from selenide and ATP. 31P NMR studies show that among the products of this reaction are AMP and a compound containing selenium bonded to phosphorus. The reaction is completely dependent on the addition of both selenide and magnesium. The dependence of reaction velocity on ATP concentration shows sigmoidal kinetics, whereas dependence on selenide concentration obeys Michaelis-Menten kinetics indicating a Km value of 46 microM for selenide.

Adenosine Monophosphate↗

PubMedDate not supplied

Combination of neutron activation analysis, tracer techniques, and biochemical methods in the investigation of selenium metabolism.

In several studies on rats, the metabolism of selenium was investigated. The quantitative determination of the element was carried out by instrumental neutron activation analysis. For in vivo tracer experiments, 75Se-labeled selenium compounds were used. In addition to these methods, procedures for the measurement of the selenoenzyme glutathione peroxidase, and for the investigation of other selenoproteins, were applied. In this way, information on the specific pools and sites of action of the element, on biologically important selenoproteins and the regulation of the selenium metabolism, was obtained.

Animals↗

PubMed2000

Reproductive outcomes in a population exposed long-term to inorganic selenium via drinking water.

Despite being an essential element in mammals and lower animals at very low doses, selenium is recognized as a teratogen and a growth-inhibiting substance in several animal species. Some inorganic selenium compounds have also been shown to be mutagenic and pro-oxidant: however, very little is known about their effects on human reproduction. Between 1972 and 1988, a few thousand residents in the municipality of Reggio Emilia, northern Italy, were accidentally exposed to drinking water with unusually high levels of inorganic selenium (selenate), range 7-9 microg/l, through a local public water supply system. We found no deleterious effect on overall body weight and length of newborns and stillborns delivered by 18 women previously exposed to high-selenium tapwater. Rates of spontaneous abortions, however, were increased slightly (RR = 1.73; 95% CI = 0.62-4.80), compared with rates among unexposed women from the same municipality. From 1980 through 1988 the prevalence of congenital malformations at birth among the exposed population was similar to that expected, but estimates were imprecise owing to small numbers. Results do not suggest marked effects on human reproduction from chronic exposure to selenate in drinking water at < 10 microg/l.

Abortion, Spontaneous↗

PubMed1987

Mammary cancer chemoprevention by inorganic and organic selenium: single agent treatment or in combination with vitamin E and their effects on in vitro immune functions.

The chemopreventive efficacies of selenate, selenite, selenium dioxide, selenomethionine and selenocystine were examined during the promotion phase of carcinogenesis in the 7,12-dimethylbenz[a]anthracene-induced mammary tumor model in rats. Each agent was added to the diet at a final concentration of 3 p.p.m. selenium. In general there was no significant difference in the potency of these five selenium compounds in inhibiting the development of mammary tumors. The interaction of vitamin E (500 p.p.m.) with either selenite or selenomethionine was further characterized in a second carcinogenesis study. Results of this experiment suggested that vitamin E enhanced the protective effect of selenite but not that of selenomethionine. In an attempt to explore the synergistic mechanism of selenium and vitamin E, the effects of these two agents on mitogen-induced blastogenesis and natural killer cytotoxic activity were also investigated. No consistent changes in these in vitro immune functions were detected resulting from supranutritional feeding of either selenite or vitamin E or both. The metabolism of inorganic versus organic selenium was discussed in relation to their role in the control of neoplastic growth as well as to their selective modulation by vitamin E.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1985

Trace elements (copper, zinc, manganese, and selenium) in plasma and erythrocytes in relation to dietary intake during infancy.

All determinations of copper, zinc, manganese, and selenium were performed with a flameless atomic absorption spectrophotometer. Seventy-three full-term infants aged 1 to 52 weeks were divided into three age groups. Each age group contained two subgroups, breast-fed and formula-fed. No statistically significant differences between formula-fed and breast-fed subgroups were found in regard to the levels of copper and zinc in plasma and erythrocytes. At 1 to 5 weeks of age, the manganese concentration of erythrocytes was higher in formula-fed than in breast-fed infants (p less than 0.001). This might be due to the high dietary intake of this element in the formula-fed subgroup. On the other hand, plasma selenium concentrations were significantly higher in breast-fed than in formula-fed infants of all ages (p less than 0.01 at 1 to 5 weeks and p less than 0.05 at 6 to 52 weeks). This suggests that selenium compounds are biologically more available for infant nutrition in breast milk than in formula.

Copper↗

PubMed2006

Selenocompounds can serve as oxidoreductants with the methionine sulfoxide reductase enzymes.

In a recent study on the reducing requirement for the methionine sulfoxide reductases (Msr) (Sagher, D., Brunell, D., Hejtmancik, J. F., Kantorow, M., Brot, N. & Weissbach, H. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 8656-8661), we have shown that thioredoxin, although an excellent reducing system for Escherichia coli MsrA and MsrB and bovine MsrA, is not an efficient reducing agent for either human MsrB2 (hMsrB2) or human MsrB3 (hMsrB3). In a search for another reducing agent for hMsrB2 and hMsrB3, it was recently found that thionein, the reduced, metal-free form of metallothionein, could function as a reducing system for hMsrB3, with weaker activity using hMsrB2. In the present study, we provide evidence that some selenium compounds are potent reducing agents for both hMsrB2 and hMsrB3.

Animals↗

PubMed1992

Selenoprotein synthesis in E. coli. Purification and characterisation of the enzyme catalysing selenium activation.

The product of the selD gene from Escherichia coli catalyses the formation of an activated selenium compound which is required for the synthesis of Sec-tRNA (Sec, selenocysteine) from Ser-tRNA and for the formation of the unusual nucleoside 5-methylaminomethyl-2-selenouridine in several tRNA species. selD was overexpressed in a T7 promoter/polymerase system and purified to apparent homogeneity. Purified SELD protein is a monomer of 37 kDa in its native state and catalyses a selenium-dependent ATP-cleavage reaction delivering AMP and releasing the beta-phosphate as orthophosphate. The gamma-phosphate group of ATP was not liberated in a form able to form a complex with molybdate. It was precluded that any putative covalent or non-covalent ligand of SELD not removed during purification participated in the reaction. In a double-labelling experiment employing [75Se]selenite plus dithiothreitol and [gamma-32P]ATP the 75Se and 32P radioactivities co-chromatographed on a poly(ethyleneimine)-cellulose column. No radioactivity originating from ATP eluted in this position when [alpha-32P]ATP or [beta-32P]ATP or [14C]ATP were offered as substrates. The results support the speculation that the product of SELD is a phosphoselenoate with the phosphate moiety derived phosphoselenoate from the gamma-phosphate group of ATP. The alpha,beta cleavage of ATP is also supported by the finding that neither adenosine 5'-[alpha,beta-methylene]triphosphate nor adenosine 5'-[beta,gamma-methylene]triphosphate served as substrates in the reaction.

Adenosine Triphosphate↗

PubMed2001

[Selenium as an essential and deficient factor in the nutrition of Russian population].

The paper presents summarized data on the metabolism of selenium and approaches to justifying physiological requirements for this micronutrient. The studies dealing with the levels of selenium in different foodstuffs have indicated that they are lower in the foods made in Russia than in those made in foreign countries, which leads to its insufficient dietary intake in Russia's population, in poor ecological regions in particular. Experimental studies have revealed that organic selenium compounds exert a beneficial effect on the metabolism of priority food pollutants, such as mycotoxins and N-nitrosoamines.

Adolescent↗

PubMed2002

Speciation of Cu, Se, Zn and Fe in blood serum of hemodialysed patients.

The speciation of trace elements in serum samples of hemodialysed patients was investigated using on-line connection of SEC and ICP-MS. The 0.02 mol/l TRIS-HCl buffer of pH 7.5 was used as mobile phase. The results of speciation as well as the total concentration data were compared with those of control group of healthy person. Alterations of total concentration were observed in case of selenium and zinc only. Iron was present in form of transferrin and ferritin, main amount of copper was bound to ceruloplasmin and selenium compounds were identified as selenoproteine P and glutathione peroxidase. The latter compound was detected in samples of control group only. The chromatograms of the other elements were similar and no substantial changes between both investigated groups were observed.

Copper↗

PubMed2005

Attenuation of estrogen receptor alpha (ERalpha) signaling by selenium in breast cancer cells via downregulation of ERalpha gene expression.

Numerous studies have shown that selenium provides beneficial effects as a cancer chemoprevention agent. Although long-term intervention trials failed to confirm selenium protection against breast cancer in humans because of insufficient cases, the evidence of effective selenium chemoprevention in animal mammary tumor models or human breast cancer cells is substantial and convincing. The present study demonstrates that the selenium compound methylseleninic acid (MSA) inhibits estrogen receptor alpha (ERalpha) signaling in ER-positive MCF-7 breast cancer cells as evidenced by decreased estradiol-dependent cell growth and gene expression. MSA diminishes estradiol induction of endogenous ER-regulated pS2 and c-myc genes as well as the expression of an ER-regulated reporter gene. A major mode of MSA action on ER signaling is through a downregulation of ERalpha gene expression that precedes a decrease in ERalpha protein level. This study provides a mechanism driven rationale for using selenium as a chemopreventive agent for women at high risk for developing breast cancer or as a therapeutic strategy for ER-positive breast cancer.

Breast Neoplasms↗

PubMedDate not supplied

Utilization of selenium from different chemical entities for selenoprotein biosynthesis by mammalian cell lines.

Four different cell lines (Hep G2, THP-1, EL 4 6.1, and ECV 304) were grown in a selenium-deficient standard medium (5% fetal calf serum in RPMI 1640 resulting in 5.5 nM selenium of unknown bioavailability) and supplemented with increasing concentration of selenium in the form of sodium selenite, selenomethionine and serum-bound selenium. The activities of two types of glutathione peroxidases (cGPx and PHGPx) were measured to estimate the availability of selenium for selenoprotein synthesis. Only sodium selenite between 1 and 100 nM was found to consistently induce GPx activity in all cell lines, whereas selenomethionine in equal concentrations was practically ineffective. Only THP-1 cells were able to utilize selenium from serum as efficiently as sodium selenite. PHGPx activity similarly responded to selenium supplementation, but was not increased in EL 4 6.1 cells. Our data demonstrate that conventional tissue culture media require selenium supplementation to guarantee adequate selenoprotein biosynthesis in cultured cells. The chemical nature of the selenium compound used for such supplement is as critical for in vitro cultivated cells as for dietary intake.

Animals↗

PubMed2002

Induction of caspase-mediated apoptosis and cell-cycle G1 arrest by selenium metabolite methylselenol.

Previous work based on mono-methyl selenium compounds that are putative precursors of methylselenol has strongly implicated this metabolite in the induction of caspase-mediated apoptosis of human prostate carcinoma and leukemia cells and G1 arrest in human vascular endothelial and cancer epithelial cells. To test the hypothesis that methylselenol itself is responsible for exerting these cellular effects, we examined the apoptotic action on DU145 human prostate cancer cells and the G1 arrest effect on the human umbilical vein endothelial cells (HUVECs) of methylselenol generated with seleno-L-methionine as a substrate for L-methionine-alpha-deamino-gamma-mercaptomethane lyase (EC4.4.1.11, also known as methioninase). Exposure of DU145 cells to methylselenol so generated in the sub-micromolar range led to caspase-mediated cleavage of poly(ADP-ribose) polymerase, nucleosomal DNA fragmentation, and morphologic apoptosis and resulted in a profile of biochemical effects similar to that of methylseleninic acid (MSeA) exposure as exemplified by the inhibition of phosphorylation of protein kinase AKT and extracellularly regulated kinases 1/2. In HUVEC, methylselenol exposure recapitulated the G1 arrest action of MSeA in mitogen-stimulated G1 progression during mid-G1 to late G1. This stage specificity was mimicked by inhibitors of phosphatidylinositol 3-kinase. The results support methylselenol as an active selenium metabolite for inducing caspase-mediated apoptosis and cell-cycle G1 arrest. This cell-free methylselenol-generation system is expected to have significant usefulness for studying the biochemical and molecular targeting mechanisms of this critical metabolite and may constitute the basis of a novel therapeutic approach for cancer, using seleno-L-methionine as a prodrug.

Apoptosis↗

PubMed2005

Medicinal mushroom modulators of molecular targets as cancer therapeutics.

Empirical approaches to discover anticancer drugs and cancer treatments have made limited progress in the past several decades in finding a cure for cancer. The expanded knowledge of the molecular basis of tumorigenesis and metastasis, together with the inherently vast structural diversity of natural compounds found in mushrooms, provided unique opportunities for discovering new drugs that rationally target the abnormal molecular and biochemical signals leading to cancer. This review focuses on mushroom low-molecular-weight secondary metabolites targeting processes such as apoptosis, angiogenesis, metastasis, cell cycle regulation, and signal transduction cascades. Also discussed in this review are high-molecular-weight polysaccharides or polysaccharide-protein complexes from mushrooms that appear to enhance innate and cell-mediated immune responses, exhibit antitumor activities in animals and humans, and demonstrate the anticancer properties of selenium compounds accumulated in mushrooms.

Agaricales↗

PubMed1994

Enrichment of selenium in allium vegetables for cancer prevention.

We previously reported that garlic cultivated with selenium fertilization is superior to regular garlic in mammary cancer prevention in the rat 7,12-dimethylbenz[a]anthracene (DMBA) model (Nutr. Cancer, 17, 279-286, 1992). A new crop of high-selenium garlic was harvested in 1992 and was used in a dose-response study to confirm the reproducibility of the product and the bioassay. Supplementation of 1 or 2 p.p.m. Se in the diet from the high-selenium garlic produced a 56% or 75% reduction respectively in the total tumor yield. Since both garlic and onion belong to the same allium family of vegetables, we were also interested in finding out whether our experience with garlic could be similarly applied to onion. A high-selenium onion crop was grown in the same season and location and with the same schedule of selenium fertilization. Two distinct differences were noted with the high-selenium onion regarding its capacity to accumulate selenium and its efficacy in cancer prevention. First, the selenium concentration in onion was considerably lower (28 p.p.m. Se dry wt) as compared to that found in garlic (110-150 p.p.m. Se). Second, given the same levels of selenium supplementation, the high-selenium onion was apparently not as powerful as the high-selenium garlic in mammary cancer inhibition. Thus different plants, even those of the same genus, may respond in their unique way to selenium fertilization and the biological benefits of selenium enrichment may vary depending on the species. Additional information from our study indicated that the high-selenium garlic/onion might provide an ideal system for delivering selenium-substituted analogs in a food form for cancer prevention: (i) they expressed a good range of anticancer activity and could be easily adapted for human consumption on a regular basis; (ii) their ingestion did not result in an excessive accumulation of tissue selenium, a concern that is associated with the standard selenium compounds such as selenite and selenomethionine; (iii) no perturbation in the maintenance of functional selenoenzymes were observed even at high levels of supplementation.

Allium↗

PubMed1991

Selenium antagonizes the induction of human heme oxygenase by arsenite and cadmium ions.

Effects of selenium compounds on the induction of heme oxygenase in human cells exposed to sodium arsenite or cadmium chloride have been investigated by an immunoblotting technique. Exposure of HeLa cells to arsenite or cadmium ions caused a marked increase in the synthesis of heme oxygenase, and the presence of sodium selenite suppressed the induction. DL-Selenocystine was an effective suppressor, and sodium selenate was less effective. DL-Selenomethionine had no effect. Northern blot analysis showed that selenite abolished the induction of heme oxygenase mRNA in the cells exposed to arsenite or cadmium ions. These results indicated that selenium antagonizes the induction of heme oxygenase by heavy metals ions.

Arsenic↗

PubMed1994

Activity of triphenylselenonium chloride in mammary cancer prevention.

The present study was designed to evaluate the tolerance and cancer chemopreventive activity of triphenylselenonium chloride in female Sprague-Dawley rats. No information is available in the literature on the anticarcinogenic efficacy of a lipophilic cationic selenium compound as exemplified by the triphenylselenonium ion. A short-term preliminary study indicated that it was well tolerated via the dietary route. Supplementation at levels up to 200 p.p.m. Se did not produce any apparent adverse effect in the animals. In the dimethylbenzanthracene mammary cancer model, a level of 30 p.p.m. Se in the diet reduced the total tumor yield by approximately 70% when treatment was applied during either the initiation phase or the post-initiation phase. In the MNU mammary cancer model, the inhibitory response was expressed only during the post-initiation phase. These findings suggest that the triphenylselenonium ion may have multiple modes of action in suppressing the development of neoplasia. Tissue analysis confirmed that there was minimal accumulation of total selenium until the level of supplementation reached 100 p.p.m. Se or above. Our study therefore convincingly demonstrates that triphenylselenonium chloride fits the criteria of an effective and desirable anticancer agent with a distinct separation between the chemopreventive dose range and the toxic dose range.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1992

Characterization of selenocysteine lyase in human tissues and its relationship to tissue selenium concentrations.

The characterization of human selenocysteine lyase, an enzyme that specifically catalyzes the decomposition of L-selenocysteine to L-alanine and hydrogen selenide, is described. The enzyme is the first described that acts exclusively on a selenium compound. The enzyme from human tissues, analogous to that from pig tissues and bacteria, requires pyridoxal 5-phosphate as a cofactor. L-selenocysteine is the sole substrate with a Km = 0.50 mM. L-cysteine is a noncompetitive inhibitor of the enzyme with a Ki = 5.85 mM. The following amino acids and purines are inert: L-cysteine, selenocystamine, seleno-DL-methionine, 6-selenopurine, and 6-selenoguanosine. The enzyme was found in liver, kidney, heart, adrenal and muscle in decreasing order of specific activity. The enzyme activity in liver was found not to be related to tissue selenium concentration or glutathione peroxidase activity.

Glutathione Peroxidase↗

PubMed1976

Cancer diagnosis. The role of tumor-imaging radiopharmaceuticals.

Several radiopharmaceuticals have recently been shown to have a considerable affinity for malignant tissue. All the tumor-seeking radiopharmaceuticals in current use are nonspecific and may also be picked up by benign tumors and infectious processes, including abscess and granuloma. The sensitivity of the tumor-imaging procedure depends on the radiopharmaceutical employed, the type of tumor, its size and location, and previous or current treatment. Gallium-67 citrate (67Ga), the most widely used tumor-seeking radiopharmaceutical, seems to have its greatest value in detecting bronchogenic carcinomas irrespective of cell type. The sensitivity for lung cancer in 489 studies was 93 per cent. Gallium-67 is also of great value in the staging of Hodgkin's disease, in which its sensitivity is 87 per cent. Non-Hdgkin's lymphomas are detected with only slightly lower sensitivity. There is, in fact, evidence that 67Ga is at least complemenatry, if not more sensitive than lymphangiography, in the staging of lymphoma. However, adenocarcinomas originating in the gastrointestinal tract are detected by 67Ga with a sensitivity of only about 40 per cent, whereas various chelates of bleomycin (including 111In-Bleo, 99mTc-Bleo and 57Co-Bleo) detect adenocarcinoma of the gastrointestinal tract with considerably higher sensitivity. In the few studies available comparing bleomycin chelates, 57Co-Bleo and 99mTc-Bleo appear to be more sensitive in detecting tumor than 111In-Bleo. Other tumor-seeking radiopharmaceuticasl which have been employed with somewhat less success include selenium compounds, labeled pyrimidines, several inorganic cations, lanthanide chelates and labeled proteins. Yet to be evaulated clinically is the efficacy of radiolabeled antibodies which are specific for tumor antigens, such as 131I-anti-CEA (carcinoembryonic antigen).

Antibodies, Neoplasm↗