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PubMedDate not supplied

Adverse health effects of selenium in humans.

Epidemiologic studies and case reports have shown that chronic exposure to selenium compounds is associated with several adverse health effects in humans. An early toxic effect of selenium is on endocrine function, particularly on the synthesis of thyroid hormones following dietary exposure of around 300 micrograms Se/d, and on the metabolism of growth hormone and insulin-like growth factor-1. Other adverse effects of selenium exposure can be the impairment of natural killer cells activity and at higher levels, hepatotoxicity and gastrointestinal disturbances. Dermatologic effects, such as nail and hair loss and dermatitis, occur after exposure to high levels of environmental selenium. Assessing the toxicity and morbidity after long-term exposure to environmental selenium is difficult: neurotoxicity, particularly the degeneration of motor neurons leading to increased risk of amyotrophic lateral sclerosis, might occur after chronic exposure to both organic and inorganic selenium compounds. The results of laboratory investigations and cohort studies suggest that selenium species exhibit a bivalent effect in cancer, either increasing or decreasing risk. Current environmental selenium exposure limits appear to be inadequate for averting adverse health effects.

Biomarkers↗
PubMed1979

Is the selenium drinking water standard justified?

Four cases are presented which suggest that the present U.S.E.P.A. drinking water standard for selenium of 10 micrograms/L in inappropriate. The rationale upon which this standard is based is that selenium is carcinogenic, induces dental caries formation, and is highly toxic to animals. However, a critical assessment of this literature can not support these claims. Case no. 1 demonstrates that there is insufficient evidence to classify selenium as a carcinogen. Data derived from the three respective groups of researchers claiming a carcinogenic effect induced by selenium are obscure due to 1) the inability to accurately identify malignancies, 2) the apparent opposite effects of different selenium compounds, and 3) the lack of proper controls. Case no. 2 reviews recent evidence that selenium reduces the incidence of cancer in laboratory animals and in man, an effect which can probably be attributed to the antioxidant properties of selenium compounds. Case no. 3 provides evidence which does not permit the classification of selenium as a cariogenic element. Epidemiological studies supporting such a claim are inadequate since they lack properly matched control groups. Animal data do not support this link as well. Case no. 4 is a review of studies which clearly demonstrate the essentiality of selenium, an aspect of selenium metabolism that was not considered when the 10 micrograms/L standard was promulgated. In light of the four cases presented and an assessment of selenium toxicity in man, it is concluded that the 10 micrograms/L standard can not be justified. Instead, it is suggested that 50 micrograms/L selenium should provide sufficient protection from the toxic effects of this element. This is consistent with the current state of knowledge with respect to the potential adverse health effects associated with selenium.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Evaluation of organoselenium compounds for potential chemopreventive properties in colon carcinogenesis.

As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium, we have evaluated benzyl selenocyanate (BSC) and its o-, m-, p-nitro and -methoxy isomers, o-, m-, and p-isomers of phenylenebis(methylene)selenocyanate (XSC), dibenzyl diselenide (DDS), and 2,2'-diselenobis[((N,N-dimethylamino)methyl)- benzene]bis(hydrochloride salt) (DSBDB) for their potential colon tumor inhibitory properties using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), a preneoplastic lesion, in male F344 rats prior to preclinical efficacy study. In the first experiment, the effect of these agents administered during initiation and postinitiation periods of carcinogenesis was investigated. Male F344 rats were fed diets containing 8 ppm Na2SeO3 or 10 ppm of each BSC and its analogues, DDS and DSBDB or 20 ppm of each XSC analogue, two weeks prior to AOM (15 mg/kg body wt., once weekly for two weeks, s.c.) administration and during and until 8 weeks after AOM treatment. Formalin-fixed and methylene blue stained colons were scored for AOM-induced ACF using the light microscope. Taking body weight gains and multiplicity of 4 or more AC/focus, the inhibitory effects of Na2SeO3, o-, m- and p-methoxy-BSC, p-XSC and DDS were much greater than those of the other selenium compounds. In the second study, the effects of these agents when administered during the initiation or postinitiation periods were investigated. The results indicated that o-, m-, and p-methoxy-BSC, DDS and p-XSC significantly inhibited crypt multiplicity during the initiation period whereas o-, and p-methoxy-BSC, p-XSC and DDS suppressed crypt multiplicity during the postinitiation period. It is concluded that o-, and p-methoxy-BSC, p-XSC and DDS possess potential chemopreventive properties in colon cancer. Further studies are warranted to evaluated these agents for chemopreventive properties in preclinical efficacy studies.

Animals↗
PubMedDate not supplied

Inhibition of colony formation of Hela cells by naturally occurring and synthetic agents.

The present study compared the effects of naturally occurring extracts or compound in combination with synthetic selenium compounds on the colony formation and nucleic acid synthesis of cultured human cervical epitheloid carcinoma cells (Hela). Crude extract of bean (Phaseolus vulgaris) or purified lectin from red kidney bean (Phaseolus vulgaris) in combination with selenomethionine were more effective in inhibiting the colony formation of Hela cells than when these cells were treated with these agents alone. Extracts of saffron (Crocus sativus) and selenite have previously been shown to inhibit the colony formation and nucleic acid synthesis by Hela cells in vitro. In the present study we examined the effects of saffron extract in combination with selenite on the colony formation and DNA and RNA synthesis in Hela cells. We found that the treatment of tumor Hela cells with saffron extract in combination with selenite increased the level of inhibition of the colony formation and nucleic acid synthesis in comparison with cells that were treated with only one of these agents. The inhibitory effect of saffron extract in combination with selenite was modified by intracellular sulfhydryl compounds.

Cell Division↗
PubMed1988

Efficacy of trimethylselenonium versus selenite in cancer chemoprevention and its modulation by arsenite.

Selenite, which has been demonstrated to be an effective prophylactic agent in experimental carcinogenesis, is metabolized to trimethylselenonium as an excretory product. Previous reports in the literature have shown that arsenite decreases the toxicity of selenite but increases that of trimethylselenonium. The present study was designed to compare the anti-carcinogenic efficacy of selenite and trimethylselenonium and their interactions with arsenite in chemoprevention, using the dimethylbenz[a]anthracene-induced mammary tumor model in rats. The results of this experiment indicated that supplementation of selenite (3 p.p.m. Se) alone produced approximately 50% reduction in tumor yield, and arsenite (5 p.p.m. As) reduced the response to selenite. In contrast, arsenite greatly enhanced the protective effect of trimethylselenonium (40 p.p.m. Se); this combination was nearly as effective as selenite, although either trimethylselenonium or arsenite alone was inactive. Thus, arsenite has the capacity to influence the anti-carcinogenic action of selenium, and can either potentiate or attenuate the protective effect depending on the methylation state of the selenium compound. The metabolism of selenium and its perturbation by arsenite are discussed in relation to the above findings.

Animals↗
PubMed2002

Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease.

Keshan disease is a cardiomyopathy of unknown origin reported in some areas of China. Because of epidemiologic features, this disease was ascribed to an infectious agent, likely a Coxsackie virus, but it has also been thought to depend on selenium deficiency, mainly because selenite is effective in its prophylaxis. We examined the hypothesis that pharmacological activity of selenite on Coxsackie virus growth was associated with prevention of Keshan disease. We studied the antiviral effects of three selenium compounds on Coxsackie virus B5 replication: five microM selenite reduced viral replication, whilst 10 microM selenate and selenomethionine did not exhibit any antiviral activity. The inhibitory activity of selenite on viral replication was due to its toxicity following its interaction with thiols, as that activity could be blocked by dithiothreitol, a sulfhydryl-protecting agent known to reverse several toxic effect of selenite. Zinc, another inhibitor of selenite toxicity, also counteracted the antiviral effect of selenite. The selenium compounds showed only limited activity against herpes simplex 1 virus and IHD strain of vaccinia virus. A direct inhibitory effect of selenite on Coxsackie virus replication might explain the efficacy demonstrated by this compound in the prophylaxis of Keshan disease.

Animals↗
PubMed1979

The influence of selinium on methyl mercury toxicity in rat hepatoma cells, human embryonic fibroblasts and human lymphocytes in culture.

The effect of methyl mercury and two selenium compounds have been studied in cell cultures. Methyl mercury in concentrations above 1 microM had a pronounced inhibiting effect on the growth of rat Morris hepatoma cells. Glucose and lactate uptake in relation to cell protein was appreciably stimulated by the organic mercury compound. Selenite in low concentration (0.5 microM) and seleno-di-N-acetyl glycine in thousandfold higher concentrations offered considerable protection against these effects of methyl mercury. The same selenite concentration (0.5 microM), which did not affect cell growth, caused an appreciable protection against methyl mercury (6 microM), even if it was added 3 days after methyl mercury. The methyl mercury inhibited the growth of human embryonic fibroblasts and the DNA-synthesis in the human lymphocytes. However, no protective effect of selenite were observed in these cell types. These results suggest that selenium compounds exert their protective effect through cell specific processes rather than by a direct chemical reaction between selenite and methyl mercury.

Animals↗
PubMed1986

Mercury, silver, and gold inhibition of selenium-accelerated cysteine oxidation.

In vivo, cysteine in proteins or glutathione is the major amino acid involved in sulfhydryl oxidation-reduction reactions. An in vitro model of cysteine oxidation accelerated by selenium compounds was used to study the interaction of selenocystine and sodium selenite with metal ions. The interaction of metal ions with selenium compounds inhibited cysteine oxidation. The ionic forms of three toxic soft-acid metals, mercury, silver, and gold, were the most effective inhibitors. The antiarthritic gold drugs, aurothiomalate and aurothioglucose, were of particular interest as they inhibit the activity of selenium-glutathione peroxidase. The effect of gold ligands on gold(I) inhibition of selenocystine-accelerated cysteine oxidation was tested. Sodium cyanide partially reversed inhibition and potassium iodide had no effect. Inhibition of selenium-accelerated oxidation-reduction reactions by soft-acid metal ions may be of biological relevance during toxicities or during antiarthritic gold therapy.

Cysteine↗
PubMed1989

Susceptibility of methicillin-resistant Staphylococcus aureus to the selenium-containing compound 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (PZ51).

The growth of Staphylococcus aureus 209P was inhibited by 0.20 micrograms of 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (PZ51) per ml, while strains of the family Enterobacteriaceae were more resistant to the drug. The MIC for 90% of methicillin-resistant S. aureus strains was 1.56 micrograms/ml, and the drug was bactericidal. The selenium in PZ51 was essential, since its sulfur analog (PZ25) lost the antibacterial activity.

Azoles↗
PubMed2001

Antigenotoxic properties of selenium: studies in the wing spot test in Drosophila.

The genotoxic activity of three selenium compounds (sodium selenite, sodium selenate, and selenious acid) and the antigenotoxic effects of sodium selenite in combination with the chromium compound potassium dichromate were studied using the wing spot test of Drosophila melanogaster. This assay is based on the principle that the loss of heterozygosity of suitable recessive markers, multiple wing hairs (mwh) and flare-3 (flr[3]), can lead to the formation of mutant clones of larval cells, which are then expressed as spots on the wings of the adult flies. Pretreatment and chronic cotreatment was comparatively used for the antigenotoxicity study. From the results obtained, it was evident that all selenium compounds are unable to increase the frequency of any of the three categories of spots recorded (small, large, and twin spots). Nevertheless, the antigenotoxic effects of sodium selenite were clearly demonstrated, in both cotreatment and pretreatment, by a complete suppression of those clones induced by potassium dichromate. Therefore, the D. melanogaster wing spot test was revealed to be a good assay, not only for evaluating genotoxic activity but also for detecting antigenotoxic effects in vivo.

Animals↗
PubMed1976

Fluoride-selenium interaction in the hard and soft tissues of the rat.

The interaction of dietary fluoride and selenium in the hard and soft tissues of rats was studied by providing drinking solutions containing 50 ppm F, as NaF, alone or plus 1 or 3 ppm Se as one of the following selenium compounds: NaSeO3, Na2SeO4, DL-selenomethionine, or DL-selenocystine. The following parameters were measured: symptoms of selenium toxicity, soft tissue uptake of fluoride and selenium, histology of liver and kidney tissues, fluoride uptake into growing femur bones, and fluoride uptake onto calcified molar enamel. No evidence was found that fluoride interacted with any of the four selenium compounds.

Animals↗
PubMed1996

Chiral Diselenides in the Total Synthesis of (+)-Samin.

Chiral selenium compounds are applied to stoichiometric as well as to catalytic reactions in the synthesis of substituted tetrahydrofuran derivatives: The selenium compound 1 was used in catalytic amounts for a rapid access to chiral diselenide 3. The efficient stereoselective addition to alkene 5 yields product 8 with a selenium functionality as a precursor for an intramolecular radical cyclization. In this way a short total synthesis of (+)-samin (11), a naturally occurring furofuran lignan, was achieved.

Journal Article↗
PubMed2001

The protective role of selenium on genetic damage and on cancer.

Collectively, results from epidemiologic studies, laboratory bioassays, and human clinical intervention trials clearly support a protective role of selenium against cancer development. Several hypotheses have been proposed to explain these observations. Increased genomic instability, either inherent or induced by exogenous agents (mutagens or carcinogens), has been considered as a primary event leading to neoplastic transformation. This report deals specifically with the evidence for a role of selenium in the inhibition of carcinogen-induced covalent DNA adduct formation and retardation of oxidative damage to DNA, lipids and proteins, and for modulating cellular and molecular events that are critical in cell growth inhibition and in the multi-step carcinogenesis process. At present, the bulk of our knowledge on the role of selenium on genetic stability is based primarily on animal data and from studies conducted in in vitro systems. Studies performed in vitro showed that the dose and form of selenium compounds are critical factors with regard to cellular responses. Inorganic (at doses up to 10microM) and organic selenium compounds (at doses equal to or greater than 10microM) elicit distinctly different cellular responses. The recommended daily allowance (RDA) is 50-70 microgramSe per day for healthy adults; with 40 microgramSe as minimum requirement. Less than 11 microgramSe will definitely put people at risk of deficiency that would be expected to cause genetic damage. Daily doses of 100-200 microgramSe inhibited genetic damage and cancer development in humans. About 400 microgramSe per day is considered an upper limit. Clearly, doses above the RDA are needed to inhibit genetic damage and cancer. However, it has been hypothesized that the intake of excessive doses of selenium may cause oxidative damage, leading to genomic instability. The use of a cocktail consisting of selenium, and other vitamins and minerals appears to be a promising approach to inhibit genetic damage and the development of cancer. It is the author's recommendation that development of mechanism-based hypotheses that can be tested in pilot studies in different populations prior to a large-scale clinical trial in humans, is of paramount importance in order to better understand the role of selenium on genetic stability and cancer.

Animals↗
PubMed1994

Screening for agents inhibiting the mutagenicity of extracts and constituents of tobacco products.

The aim of this study was to screen for potential agents affecting the mutagenicity of tobacco products. The influence of a number of compounds which have been suggested to be antimutagenic some of which are present in tobacco products, was investigated on the mutagenicity of a cigarette smoke condensate (CSC) and, in some cases, an extract of oral Swedish moist snuff (SNUS), using a screening procedure of the Ames Salmonella/microsome assay (STY). For some of the compounds the V79/hprt mutagenicity assay with benzo[a]pyrene metabolites as mutagens was used to obtain complementary and confirmatory information on mammalian cells. The antimutagens used included two selenium compounds, sodium selenite and ebselen; the flavonoids and polyphenols, ellagic acid, (+)-catechin hydrate, scopoletin, chlorogenic acid and rutin trihydrate; the porphyrin derivatives, bovine hemin, biliverdine dihydrochloride, chlorophyllin and a plant extract containing chlorophyll; the terpenoids, beta-carotene, retinol and a mixture of the two epimers (4R) and (4S) of (1S,2E,6R,7E,11E)-cembra-2,7,11-triene-4,6-diols (CBD); and cyclohexanol and ubiquinone. Screening of antimutagenic activities using the STY involves problems with toxicity. In several cases in this study mutagenicity was decreased below the control level without signs of toxicity in the background growth of bacteria. Since the survival of mutants and slight bacteriostatic effects on the background growth cannot be determined accurately in the STY, a reduction in mutagenicity may simply be due to toxicity. Only in cases where a dose-response curve declines to a level at or above the background and then levels off, can toxicity be excluded. An antimutagenic effect determined using this test system is therefore often not sufficient for classifying a compound as antimutagenic until these findings are confirmed in other test systems and, preferably, the mechanism behind this effect is clarified. The results obtained with the selenium compounds were considered to be inconclusive since the reduction in the mutation rate declined below the background level and might only reflect the toxic effects of these compounds. For ellagic acid an almost complete inhibition of the mutagenicity of CSC and SNUS in STY was indicated. This indication of antimutagenicity was confirmed in V79 cells using two metabolites of the CSC constituent benzo[a]pyrene, i.e., trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and (+)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE). Chlorogenic acid and (+)--catechin reduced the mutagenicity of CSC and chlorogenic acid also strongly inhibited SNUS mutagenicity. Scopoletin and rutin trihydrate inhibited the mutagenicity of CSC, but showed confounding effects with SNUS.(ABSTRACT TRUNCATED AT 400 WORDS)

Antimutagenic Agents↗
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↗