Mercury distribution studies involving complexes of low-molecular weight thiols and methylmercury.
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Animals↗
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Glutathione peroxidase mimics prevent TNFalpha- and neutrophil-induced endothelial alterations.
Based on the assumption that glutathione peroxidase (GPx) activity might be limiting in preventing peroxide-induced impairment of endothelial regulatory functions, we studied the effect of a series of new selenium-containing GPx mimics on endothelial cells exposed to an inflammatory stress. The two compounds that have the highest GPx activity, BXT-51072 and BXT-51077, were shown to be the most efficient inhibitors of leukocyte recruitment by human umbilical vein endothelial cells (HUVEC), upon incubation with neutrophils (10-fold excess over HUVEC) and with 1 ng/ml TNF-alpha for 1 or 3.5 h. When HUVEC were pre- and cotreated with 10 microM of either compound, neutrophil adhesion and endothelial alteration were markedly inhibited, as assessed by immunoassays of myeloperoxidase and von Willebrand factor, respectively. These two GPx mimics were also found to be the most efficient inhibitors of the TNFalpha-induced endothelial expression of P- and E-selectin and of the TNFalpha- or interleukin1-induced endothelial release of interleukin-8. Our results demonstrate that GPx mimics such as BXT-51072 behave as potent antagonists of TNF-alpha and interleukin-1 through the downregulation of endothelial proinflammatory responses.
Antioxidants↗
Comparison of selenite F, Muller-Kauffmann tetrathionate and Rappaport's medium for the isolation of salmonellas from sewage-polluted natural water using a pre-enrichment technique.
Three enrichment broths, selenite F, Muller-Kauffmann tetrathionate and Rappaport, were examined for their efficiency in salmonella isolation. The three media, prepared from single ingredients in the laboratory, were compared with their commercial equivalents. Laboratory-prepared media were more efficient for isolating salmonellas from sewage-polluted natural water samples. A pre-enrichment stage using buffered peptone water was employed throughout the investigation. The size of inoculum from the pre-enrichment medium was relevant to successful salmonella isolation. Inocula studied were 1 ml and one loopful (3 mm diameter loop). The smaller inoculum gave better results with Rappaport, the larger with selenite and tetrathionate. Using the optimal inocula, Rappaport was the most efficient enrichment broth of the three fluid media in this study.
Benzylidene Compounds↗
Effects of diet on mercury metabolism and excretion in mice given methylmercury: role of gut flora.
Mice fed either (1) a pelleted rodent diet, (2) evaporated milk, or (3) a synthetic diet (high protein, low fat) exhibited different rates of whole body mercury elimination and fecal mercury excretion after exposure (per os) to methylmercuric chloride. The percentage of the total mercury body burden present as mercuric mercury was highest (35.3%) in mice fed the synthetic diet (which had the highest rate of mercury elimination) and lowest (6.6%) in the animals having the lowest mercury elimination rate (milk-fed mice). Mice fed the synthetic diet had lower mercury concentrations and had a higher proportion of mercuric mercury in their tissues than the mice from the other dietary groups. Treatment of the mice with antibiotics throughout the experimental period to suppress the gut flora reduced fecal mercury excretion and the dietary differences in whole body retention of mercury. Tissue mercury concentrations and proportion of organic mercury in feces, cecal contents, liver, and kidneys were increased by antibiotic treatment of mice fed the pelleted or synthetic diets. These results are consistent with the theory that demethylation of methylmercury by intestinal microflora is a major factor determining the excretion rate of mercury.
Animal Feed↗
[ON THE DEMONSTRATION AND EFFECT OF SOME SELENIUM-CONTAINING BETA-KETO BASES. 2. ON SELENOPHENOL DERIVATIVES].
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Benzene Derivatives↗
Contrasting patterns of selenium excretion by female CD rats treated with chemically related chemopreventive organic selenocyanate compounds.
We previously demonstrated that while both benzyl selenocyanate (BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) have high efficacy as cancer chemopreventive agents in several animal tumor models, p-XSC is less toxic. Using atomic absorption spectrophotometry, we compared the urinary and fecal excretion of total selenium derived from p-XSC and BSC in female CD rats. The results indicate that there exist distinct differences in the selenium excretion patterns when these compounds are administered orally, but not when they are administered i.p. In terms of the percent dose, the total selenium excreted in the 5 days following equimolar dosing (50 mumol/kg) of p-XSC or BSC, respectively, was as follows: after gavage, 68% or 3% in the feces and 6% or 18% in the urine; after i.p. administration, 9% or 4% in feces and 16% or 20% in urine. These results indicate that while most of the BSC administered orally is absorbed in the gastrointestinal tract, most of the p-XSC given the same way is not absorbed. This difference would account for the significantly lower tissue levels of selenium derived from orally administered p-XSC compared to BSC, and accounts, in part, for the lower oral toxicity of p-XSC compared to BSC. Subsequent studies employing o- and m-XSC, isomers of p-XSC, demonstrate that the excretion patterns of selenium are significantly different, depending on the position of substitution. In vitro studies suggest that the differences among BSC and the three XSC isomers with regard to absorption is probably due to different extent of binding to components of the gut contents. The results of these studies are useful for the future design of less toxic and more effective chemopreventive organic seleno-cyanates.
Animals↗
The selenium metabolite methylselenol inhibits the migration and invasion potential of HT1080 tumor cells.
There is increasing evidence for the efficacy of certain forms of selenium as cancer-chemopreventive compounds. Methylselenol has been hypothesized to be a critical selenium metabolite for anticancer activity in vivo. To determine whether tumor cell migration, invasion, and cell cycle characteristics are inhibited by methylselenol, we exposed HT1080 cells to methylselenol. Methylselenol was generated with seleno-L-methionine (a substrate for methioninase). Submicromolar methylselenol exposure led to an increase in the G1 and G2 fractions with a concomitant drop in the S-phase, indicating slower cell growth. Furthermore, methylselenol inhibited the migration and invasion rate of the tumor cells by up to 53 and 76%, respectively, when compared with the control tumor cells. Although all cells had increased matrix metalloproteinase (MMP) enzyme activities of pro-MMP-2 and pro-MMP-9, the active form of MMP-2 was decreased in HT1080 cells cultured with methylselenol. In addition, methylselenol increased the protein levels of antimetastasic tissue inhibitor metalloproteinase (TIMP)-1 and TIMP-2. Collectively, these results demonstrate that submicromolar concentrations of methylselenol increase both prometastasis MMP-2 and MMP-9 and antimetastasis TIMP-1 and TIMP-2 expression. The apparent net effect of these changes is the inhibition of pro-MMP-2 activation and carcinogenic potential or activity.
Cell Cycle↗
Methionine, vitamin E, and selenium toxicity.
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Aniline Compounds↗
Analysis of trimethylselenonium ion in urine by high-performance liquid chromatography.
A rapid and simple method for the separation of trimethylselenonium ion and other cationic forms of selenium in urine by HPLC on a strong cation exchanger is described. Most of the inorganic salts in urine are removed prior to chromatography by means of ethanolic precipitation, thus minimizing interferences. Following sample loading and elution with 0.003 M ammonium phosphate (pH 4), a linear gradient to 0.33 M ammonium phosphate (pH 4) is employed. Complete separation of the trimethylselenonium ion from four other selenonium compounds was achieved, and good recovery of the compounds was obtained for the desalting and chromatographic procedures. The procedure was successfully employed to demonstrate that dimethylselenocysteineselenonium iodide and Se-methylselenomethionineselenonium iodide are extensively metabolized when administered to rats, and that trimethylselenonium ion is a major urinary metabolite of both compounds.
Animals↗
The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis.
This paper describes the effects of the thiol compounds glutathione and N-acetylcysteine and the seleno-organic agent Ebselen on the development of Sephadex-induced lung edema and cell infiltration in the rat. Neither thiol had any effect upon the development of the edema when administered in large, repeated doses. In contrast, when Ebselen was co-administered with the thiols, there was a dose-dependent inhibition of the development of the edema, but lung weights could not be returned to normal values. However, when the thiols were omitted and Ebselen was administered alone, the development of the edema was totally blocked. In addition, in Ebselen-only treated animals there was a selective inhibition of the infiltration of lymphocytes, basophils and eosinophils into the lung lumen without affecting the populations of macrophages and neutrophils. Again, the Ebselen-induced effect was reduced by coadministration of either thiol. These findings are discussed in terms of the potential mechanism of action of Ebselen in vivo and of the possibility of Ebselen being of therapeutic potential in cases of diffuse pulmonary inflammation in humans.
Animals↗
Allylic selenosulfide rearrangement: a method for chemical ligation to cysteine and other thiols.
Alkylation of potassium selenosulfate with allylic halides gives Se-allyl seleno Bunte salts. On reaction with thiols at room temperature, these afford mixed dialkyl selenosulfides, which undergo 2,3-sigmatropic rearrangement with loss of selenium, either spontaneously or with assistance by triphenylphosphine, thereby providing mixed dialkyl sulfides and a new permanent chemical ligation method. The process is illustrated through the lipidation of cysteine-containing tripeptides and by the allylation of 1-thioglucose tetraacetate.
Allyl Compounds↗
Pharmacokinetics of selol, a new agent containing selenium, in rats.
The pharmacokinetic properties of selol, a new organoselenium compound, were evaluated in rats. Each animal was given a single oral or subcutaneous dose of selol 12 mg/kg. The selenium concentration was determined in whole blood and tissues by non flame carbon furnace atomic-absorption spectrometry. The pharmacokinetic parameters Cmax and tmax differed statistically between oral (p.o.) and subcutaneous (s.c.) treatment. The selenium average peak concentrations in the blood were 494 +/- 8 ng/ml after oral and 322 +/- 5 ng/ml after subcutaneous administration. They were reached after 1.9 +/- 0.1 h and 2.4 +/- 0.1 h, respectively. For the AUC0 mean values of 1373 +/- 56 ng.h/ml (p.o.) and 1273 +/- 137 ng.h/ml (s.c.) were found. The mean residence time (MRT) was significantly longer after subcutaneous administration. Selenium distributes quickly to the main organs with prevalence to the adrenal gland. Moreover, its concentrations in the examined organ were evidently higher after subcutaneous treatment as compared to the oral route. Our data suggest that Selol may be used as a possible source of selenium for the treatment of selenium-deficient patients, particularly via the subcutaneous route.
Administration, Oral↗
A purified selenophosphate-dependent enzyme from Salmonella typhimurium catalyzes the replacement of sulfur in 2-thiouridine residues in tRNAs with selenium.
A tRNA-modifying enzyme tentatively termed tRNA 2-selenouridine synthase was purified by a five-step procedure that resulted in 50-60% pure preparations. This enzyme catalyzes the conversion of a 5-methylaminomethyl-2-thiouridine residue in the tRNA substrate to 5-methylaminomethyl-2-selenouridine. The selenium donor substrate for this reaction is shown to be selenophosphate which is formed from ATP and selenide by selenophosphate synthetase. Replacement of sulfur with selenium in tRNAs catalyzed by tRNA 2-selenouridine synthase occurs in the absence of ATP. The dependence of reaction velocity on selenophosphate concentration obeys Michaelis-Menten kinetics indicating an apparent Km value of 17.1 microM. Bulk thio-tRNA preparations from Escherichia coli and Salmonella typhimurium are equally effective as substrates for the selenium incorporation reaction. An intact 3' end of the tRNA molecule does not seem to be essential for selenium incorporation. Identity of the product of the reaction was confirmed by HPLC analysis of digests of [75Se]seleno-tRNAs labeled by incubation with the purified enzyme. A labeled compound in the nucleoside mixture was coeluted with authentic 5-methylaminomethyl-2-selenouridine.
Chromatography, Gel↗
Isotope effects and the mechanism of allylic hydroxylation of alkenes with selenium dioxide.
The mechanism of the allylic oxidation of 2-methyl-2-butene with selenium dioxide was explored by a combination of experimental and theoretical studies. A comparison of the experimental (13)C and (2)H kinetic isotope effects with predicted values shows that the observed isotope effects are consistent with an initial concerted ene step mediated by SeO(2). However, this comparison also does not rule out the involvement of a selenous ester in the ene reaction or a stepwise reaction involving reversible electrophilic addition of HSeO(2)(+) followed by rate-limiting proton abstraction. Becke3LYP calculations strongly favor SeO(2) over a selenous ester as the active oxidant, with the predicted barrier for reaction of 2-methyl-2-butene with SeO(2) being 21-24 kcal/mol lower than that for reaction with H(2)SeO(3). The possibility of a selenous ester being the active oxidant is also disfavored by the observation of oxidations in non-hydroxylic solvents. The involvement of HSeO(2)(+) does not appear consistent with a lack of dependence of the reaction on the basicity of the reaction mixture. A concerted ene reaction with SeO(2) as the active oxidant appears to be the major mechanistic pathway operative in these reactions.
Alkenes↗
Organoselenium compounds as potential therapeutic and chemopreventive agents: a review.
Selenium is an essential trace element. It is, however toxic at concentration little above which is required for health. Selenium is incorporated into proteins as selenocysteine, the 21(st) amino acid. Selenoproteins are found in bacteria, archaea and eukaryotes. Biochemical and physicochemical properties of selenium result in the unique redox characteristics of selenocysteine and its use in antioxidant enzymes. In this context of a redox reaction is the reduction of reactive oxygen metabolites by glutathione peroxidases, helping to maintain membrane integrity, reduces the oxidative damage to lipids, lipoproteins, and DNA. Selenium has structural and enzymatic roles. Selenium influences a number of endocrine processes, most notably, those involved in thyroid hormone synthesis and metabolism. Se is needed for the proper functioning of the immune system, a role in viral suppression, AIDS, and also is implicated in delaying the aging process. Its deficiency has been linked to a number of disorders such as heart disease, diabetes, and diseases of the liver, and it is required for sperm motility and may reduce the risk of miscarriage. Se supplementation has recently moved from the realm of correcting nutritional deficiencies to one of pharmacological intervention, especially in the clinical domain of cancer chemoprevention. During the last few years, a tremendous effort has been directed toward the synthesis of stable organoselenium compounds that could be used as antioxidants, enzyme modulators, antitumor, antimicrobials, antihypertensive agents, antivirals and cytokine inducers. The biochemistry and pharmacology of selenium-based compounds are subjects of intense current interest, especially from the point of view of public heath. The purpose of this review is to discuss the recent pharmacological applications of organoselenium compounds as therapeutic agents in the treatment of several diseases.
Animals↗
Antifungal activity of dermatological shampoos.
The effect of several "medicated" shampoos on the growth of a variety of fungi was determined. Shampoos with as low as 0.5% coal tar were inhibitory to all strains, 2.5% selenium sulfide and 1 and 2% zinc pyrithione were significantly more inhibitory. Since these shampoos have substantivity for the human scalp, they may be useful as adjunctive therapy to griseofulvin in the treatment of scalp infections and minimize the risk of spread of viable spores to others in the environment.
Coal Tar↗
Ebselen prevents inositol (1,4,5)-trisphosphate binding to its receptor.
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Anilides↗
Identification of selenium-containing glutathione S-conjugates in a yeast extract by two-dimensional liquid chromatography with inductively coupled plasma MS and nanoelectrospray MS/MS detection.
An approach for the identification of unknown selenium-containing biomolecules was developed, enabling the identification of selenodiglutathione (GS-Se-SG) and the mixed selenotrisulfide of glutathione and cysteinylglycine (GS-Se-SCG) in aqueous yeast extracts. The method consists of two-dimensional liquid chromatography, inductively coupled plasma mass spectrometry (ICPMS) and nanoelectrospray tandem mass spectrometry. Analytes were separated by size-exclusion chromatography followed by preconcentration and separation on a porous graphitic carbon HPLC column. The HPLC effluent was monitored for selenium by ICPMS, and two selenium-containing fractions were isolated and analyzed by nanoelectrospray MS. The nanoelectrospray technique has a low sample consumption of approximately 80 nL/min, enabling a preconcentration of the sample to a few microliters. Mass spectra of the two fractions showed the characteristic Se isotopic pattern centered at m/z 693.1 and 564.0 for the [M + H]+ 80Se ions. MS/MS spectra of adjacent parent ions confirmed the presence of Se. The two selenium species were identified as GS-Se-SG and GS-Se-SCG by collision induced dissociation (CID). The accurately measured masses of the most abundant 691 and 693 u parent ions are in good agreement (differences = 3 ppm) with the theoretical masses. To our knowledge, this is the first identification of GS-Se-SG and GS-Se-SCG in biological matrixes by MS/MS.
Chromatography, High Pressure Liquid↗