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PubMed2000

Effects of selenium dioxide on blood and femoral bone marrow of rats.

This study was undertaken to investigate the effects of selenium dioxide (SeO2) on rat blood and femoral bone-marrow oxidant mechanisms. Treatment with SeO2, 67 microg Se/kg i.p. daily for 14 d, significantly decreased lipid peroxidation and the concentrations of Fe in serum and bone marrow. The concentrations of Se in serum and bone-marrow cells were significantly increased after SeO2 treatment. The activities of glutathione peroxidase (GPx) in blood and bone-marrow cells were markedly increased. The levels of oxyhemoglobin in blood were significantly increased, while the concentrations of methemoglobin were decreased after SeO2 administration. The fragility of erythrocytes membranes was significantly decreased in SeO2-treated rats compared to controls. Data suggest that treatment with a low dose of SeO2 may provide antioxidant nutrients to blood and bone marrow.

Animals↗
PubMed2002

Metabolic pathway for selenium in the body: speciation by HPLC-ICP MS with enriched Se.

Selenium (Se) is an ultramicro essential nutrient and both inorganic (selenite and selenate) and organic (selenocysteine and selenomethionine) forms of Se can be used as nutritional sources. Metabolic pathways for Se in the body were studied for selenite and selenate, with the use of enriched 82Se, by speciation with separation by gel filtration HPLC and detection by element-specific mass spectrometry with ionization with inductively coupled argon plasma (HPLC-ICP MS). The concentrations of 82Se in organs and body fluids and the distributions of their constituents depending on the dose and time after the intravenous administration of 82Se-selenite and -selenate to rats were determined. Selenite was taken up by red blood cells within several minutes, reduced to selenide by glutathione, and then transported to the plasma, bound selectively to albumin and transferred to the liver. Contrary to selenite, intact selenate was either taken up directly by the liver or excreted into the urine. The 82Se of selenite origin and that of selenate origin were detected in the forms of the two Se peak materials in the liver, A and B. The former one was methylated to the latter in vivo and in vitro. The latter one was identical with the major urinary metabolite and it was identified as Se-methyl-N-acetyl-selenohexosamine (selenosugar). The chemical species-specific metabolic pathway for Se was explained by the metabolic regulation through selenide as the assumed common intermediate for the inorganic and organic Se sources and as the checkpoint metabolite between utilization for the selenoprotein synthesis and methylation for the excretion of Se.

Animals↗
PubMed1985

Reactions of selenium dioxide free radicals with amino acids and enzymes.

Pulse radiolysis of selenium dioxide in aqueous solution has shown the presence of three selenite radicals in acid-base equilibrium within well defined pH ranges: (formula; see text) The selenite radicals react selectively with amino acids, preferentially with the aromatic ones in the order tryptophan greater than tyrosine greater than histidine, independently of the acid-base structure of the radical. Kinetic and spectroscopic data on the reaction of selenite radicals with some proteins and parallel inactivation studies generally reflect knowledge on the amino acid residues mainly involved in the radical attack. The investigations at different pH values on the reactivity of selenite radicals with amino acids and proteins and on the transient spectra of the reaction products exhibit different behaviour for the various acid-base structures of the selenite radicals, reflecting the influence of particular ionizable groups in the reacting molecules and the structure modifications at the level of proteins.

Amino Acids↗
PubMed1985

Urinary excretion of selenium by New Zealand and North American human subjects on differing intakes.

Lower renal plasma clearances of selenium (CSe 0.1-0.2 ml min-1), indicating excretion of a smaller proportion of Se presented to the kidneys, were found in New Zealand (NZ) residents with low plasma Se ((Se)p 50-70 ng ml-1) on customary intakes below 30 micrograms d-1 Se. North American subjects consuming 80 micrograms d-1 with (Se)p 120-140 ng ml-1 had CSe between 0.2 and 0.3 ml min-1. Several weeks' supplementation with high-Se bread increased NZ subjects' (Se)p to 120-175 ng ml-1 and CSe to 0.4-0.7 ml min-1. (Se)p remained elevated when supplementation ceased, but CSe returned to the basal range within a few days. Americans' clearances showed no such abrupt decrease when their dietary intake was similarly reduced. The NZ residents thus appeared to excrete selenium more sparingly than others. Rapid alterations in clearance after supplements and single doses were probably due to changes in the proportions of different forms of selenium in the plasma.

Adaptation, Physiological↗
PubMed1989

Ascorbic acid-selenite interactions in humans studied with an oral dose of 74SeO3(2-).

The interaction between dietary ascorbic acid at extremes of ascorbic acid intake and selenium in young adult male humans was investigated with a stable-isotope approach using 74Se-selenite. Measurements were made of 74Se in plasma, urine, and feces with neutron-activation analysis after oral administration of 74SeO3(2-). Urine excretion and total body retention of isotope and the selenite-exchangeable metabolic pool (Se-EMP) were calculated. Limiting dietary ascorbic acid to about 20 mg/d appeared to reduce the time-related retention of absorbed selenite and the size of Se-EMP. Compared with a diet providing 1 g ascorbic acid/d the low ascorbic acid intake was associated with a lower fractional absorption of the isotope, a reduced retention of the label, and a smaller Se-EMP. These data and those previously obtained in subjects with more usual ascorbic acid intakes point to a possible important role for ascorbic acid in the maintenance of Se homeostasis.

Absorption↗
PubMed1997

Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells.

Methylselenocysteine (MSC), an organic selenium compound has significant anticarcinogenic activity against mammary tumorigenesis. Previous experiments have demonstrated that MSC and inorganic selenite inhibit mammary cell (TM6 cell line) growth through different pathways. The present investigation demonstrated that MSC arrested cells in S phase during the TM6 cell cycle, which was followed by cells entering apoptosis at 48 h. Methylselenocysteine specifically affected the cdk2 kinase activity of the TM6 cells (54% reduction) at 16 h after release from growth arrest. The cdk4 kinase activity did not change during the cell cycle, confirming that cells had passed the G1 checkpoint and had entered S phase. The amount of cyclin E associated with cdk2 was increased by MSC by the 12 h time point, thereby facilitating entry of cells into S phase. Afterwards, cyclin E and cyclin A associated with cdk2 did not change for the remainder of the cell cycle. The data demonstrate that inhibition of mammary cell growth by MSC is mediated by alterations in progression of cells through S phase. The decrease in cdk2 kinase activity is coincident with prolonged arrest in S phase. One consequence of prolonged arrest may be apoptosis.

Animals↗
PubMed2000

Inhibition of ebselen on aflatoxin B(1)-induced hepatocarcinogenesis in Fischer 344 rats.

Aflatoxin B(1) (AFB(1)), a potent hepatocarcinogen, enhances ROS formation and causes oxidative DNA damage, which may play a role in its carcinogenicity. We have demonstrated recently that ebselen, an organic selenium compound, protects against the cytotoxicity of AFB(1) through its antioxidant capability. The present study was designed to investigate the effect of ebselen on AFB(1)-induced hepatocarcinogenesis in an animal model. Fischer 344 rats were first treated with either deionized water or ebselen (5 mg/kg, 5 days/week) via gavage for 4 weeks, then given AFB(1) (0.4 mg/kg, gavage, once a week) or AFB(1) plus ebselen (5 mg/kg, 5 days/week) for another 24 weeks. The results showed that the hepatocarcinogenicity of AFB(1) in rats was significantly reduced by ebselen treatment as indicated by a decrease in: (i) serum gamma-glutamyl transpeptidase activity; (ii) expression of mRNAs of liver alpha-fetoprotein and the placental form of glutathione S-transferase (GST-P); and (iii) the area and mean density of staining of liver GST-P foci. Ebselen treatment significantly reduced the formation of hepatic AFB(1)-DNA adducts and 8-hydroxydeoxyguanosine caused by AFB(1) exposure. These findings suggest that ebselen can inhibit the carcinogenicity of AFB(1). In addition to the reduction of AFB(1)-DNA adduct formation, the protective effect of ebselen against AFB(1)-induced oxidative DNA damage may also, at least in part, contribute to its anticarcinogenic property.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1982

Effects of copper deficiency on the activity of the selenoenzyme glutathione peroxidase and on excretion and tissue retention of 75SeO3(2-).

Liver and lung activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were determined in control and copper-deficient rats. Decreased activity of SOD was found in liver and decreased activity of the selenoenzyme GSH-Px was found in liver and lung in the copper-deficient animals. The decreased liver activity of GSH-Px could be partially corrected by daily supplementation of the basal diet with sodium selenite. Urinary, fecal and biliary excretion of 75SeO3(2-) were determined in controls and copper-deficient rats in order to assess selenium losses. Urinary excretion of 75Se was not different in the two groups. Fecal loss of 75Se was increased in the copper-deficient animals when compared to controls and biliary excretion was decreased. Tissue retention of 75Se was also determined in both groups. Retention of 75Se in the copper-deficient rats was increased in brain and lung and decreased in liver. This pattern of tissue retention of 75Se is similar to that which occurs in selenium-deficient rats. Copper deficiency in rats results in decreased liver activity of both the copper-containing enzyme SOD and the selenoenzyme GSH-Px. The mechanism of decreased GSH-Px activity is unknown.

Animals↗
PubMed1983

Protection against acute paraquat toxicity by dietary selenium in the chick.

Experiments were conducted to determine whether both dietary vitamin E and selenium (Se) affect the acute toxicity of paraquat in the chick. Paraquat significantly stimulated the rate of NADPH-supported consumption of oxygen by the microsomal fractions of chick liver and lung, and this stimulation was decreased by addition of superoxide dismutase and/or catalase. The acute oral LD50 of paraquat in the 8-day-old vitamin E- and Se-deficient chick (131 mg/kg body weight) was increased more than threefold by supplementing the diet with 0.10 ppm Se as Na2SeO3, (419 mg/kg body weight) but was not significantly affected by supplementing the diet with vitamin E (148 mg/kg body weight). A high fat (20%) diet did not alter the protective effect of Se against the acute toxicity of paraquat; however exposure to an oxygen-enriched atmosphere did reduce the protection by dietary Se. Dietary Se at 0.01 ppm protected against acute paraquat toxicity, whereas 0.08 ppm Se produced detectable increases in the Se-dependent glutathione peroxidase. These results indicate that the acute toxicity of paraquat in the chick is highly responsive to nutritional Se status and not vitamin E status.

Animals↗
PubMed2001

Inhibition of mitotic cyclin B and cdc2 kinase activity by selenomethionine in synchronized colon cancer cells.

Selenomethionine (SeMet), an organic selenium compound, has been demonstrated to have significant chemopreventive activity. However, the mechanism of action of SeMet has yet to be identified. Previously, our laboratory found that treatment of cells with SeMet induced apoptosis and altered the cell cycle. These observations have led to further analysis of the cell cycle effects of SeMet in colon cancer cells. Synchronized HCT 116 colon cancer cells treated with 100 microM SeMet for 66 h were found to have a transient delay in G2/M phase of the cell cycle at 18 and 24 h after treatment. With this was observed an inhibition of cell growth. Coincidentally with this delay was a decrease in mitotic cyclin B RNA expression at 18 h after treatment. In addition, the cdc2 kinase activity of HCT 116 cells was decreased at 18 h. Morphological studies indicate an increase in the number of treated cells (45%) undergoing apoptosis at 66 h compared to control cells (27%). These studies demonstrate that modulation of mitotic cyclin expression and cdc2 kinase activity play a role in the ability of SeMet to inhibit tumor cell growth. A consequence of this prolonged arrest is apoptosis.

Apoptosis↗
PubMed2004

Inhibition of DMBA/croton oil-induced two-stage mouse skin carcinogenesis by diphenylmethyl selenocyanate.

Selenium, an essential micronutrient, is associated with antioxidant functions, physiological defence mechanisms against different diseases including several types of cancers. Search for new selenium compounds with more chemopreventive activities and lesser toxicities are in progress. In the present study, the antioxidative roles of a synthetic organoselenium compound, diphenylmethyl selenocyanate, were evaluated against 7,12-dimethylbenz(a)anthracene (DMBA)/croton oil-induced two-stage mouse skin carcinogenesis model. The compound was administered orally in carcinogen-induced mice in two different non-toxic doses: 2 mg/kg body weight and 3 mg/kg body weight. Significant inhibition in the incidence of papilloma formation (58-80%) as well as in the cumulative number of papilloma per papilloma-bearing mouse were observed in the treated groups as compared with the carcinogen control group. The compound was also found to significantly upregulate different phase II detoxifying enzymes in liver cytosol such as glutathione-S-transferase (P<0.01), catalase (P<0.01) and superoxide dismutase (SOD) (P<0.01) when measured after 15 days and also after 12 weeks of first DMBA treatment. Lipid peroxidation measured as the thiobarbituric acid reactive substances in liver microsomes was significantly inhibited (P<0.05) in a dose-dependent manner by diphenylmethyl selenocyanate. Thus the compound exerts its chemopreventive activity by reducing papilloma formation during chemically induced carcinogenesis, which in turn, may be through modulating the level of lipid peroxidation and phase II detoxifying enzyme system at the doses evaluated.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Molecular mechanisms of sleep-wake regulation: a role of prostaglandin D2.

Prostaglandin (PG) D2 is a major prostanoid in the brains of rats and other mammals, including humans. When PGD synthase (PGDS), the enzyme that produces PGD2 in the brain, was inhibited by the intracerebroventricular infusion of its selective inhibitors, i.e. tetravalent selenium compounds, the amount of sleep decreased both time and dose dependently. The amount of sleep of transgenic mice, in which the human PGDS gene had been incorporated, increased several fold under appropriate conditions. These data indicate that PGDS is a key enzyme in sleep regulation. In situ hybridization, immunoperoxidase staining and direct enzyme activity determination of tissue samples revealed that PGDS is hardly detectable in the brain parenchyma but is localized in the membrane systems surrounding the brain, namely, the arachnoid membrane and choroid plexus, from which it is secreted into the cerebrospinal fluid (CSF) to become beta-trace, a major protein component of the CSF. PGD2 exerts its somnogenic activity by binding to PGD2 receptors exclusively localized at the ventrorostral surface of the basal forebrain. When PGD2 was infused into the subarachnoid space below the rostral basal forebrain, striking expression of proto-oncogene Fos immunoreactivity (FosIR) was observed in the ventrolateral preoptic area (VLPO), a putative sleep centre, concurrent with sleep induction. Fos expression in the VLPO was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus (TMN), a putative wake centre. These observations suggest that PGD2 may induce sleep via leptomeningeal PGD2 receptors with subsequent activation of the VLPO neurons and downregulation of the wake neurons in the TMN area. Adenosine may be involved in the signal transduction associated with PGD2.

Animals↗
PubMed2004

Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonine-68 and down-regulation of Cdc6 expression.

Methylselenocysteine (MSC) is an organic selenium compound in preventative clinical trials involving prostate, lung, and colon carcinoma. We found that methioninase-activated MSC potentiates 7-ethyl-10-hydroxycamptothecin (SN-38)-induced cell lethality in vitro in the p53-defective human head and neck carcinoma A253 cells. Activated MSC increases chk2 phosphorylation at threonine-68 induced by SN-38, with no significant effect on chk1 phosphorylation. Cell cycle arrest induced by SN-38, however, was not abrogated or potentiated by MSC. These results suggest that the enhanced cellular lethality of SN-38 by MSC was not associated with cell cycle regulation pathways. Because chk2, in addition to its role in cell cycle arrest, can induce apoptosis by phosphorylation/activation, we examined whether increased chk2 phosphorylation could induce preapoptotic DNA fragmentation. DNA damage analysis showed that megabase DNA fragmentation is decreased, accompanied by the increased 30 to 300 kilobase pairs of DNA fragmentation after exposure to SN-38 with MSC, compared with SN-38 alone. No significant changes in the amount of DNA fragments were observed in cells treated with SN-38 or MSC alone. Moreover, proteolytic destruction of DNA replication-associated proteins cdc6, MCM2, and cdc25A may induce a DNA damage checkpoint response. The observed down-regulation of DNA replication proteins cdc6, MCM2, and cdc25A after exposure to SN-38 with MSC further indicates a relationship between drug response and DNA damage. Exposure to SN-38 with MSC resulted in a significant increase of poly(ADP-ribose) polymerasecleavage and caspase 3 activation. All together, the data support the hypothesis that enhanced lethality of this combination is associated with increased chk2 phosphorylation at Thr68 and down-regulation of specific DNA replication-associated proteins, which result in poly(ADP-ribose) polymerase cleavage, caspase 3 activation, and the induction of 30 to 300 kilobase pairs of DNA fragmentation.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Molecular rulers for scaling down nanostructures.

A method of constructing <30-nanometer structures in close proximity with precise spacings is presented that uses the step-by-step application of organic molecules and metal ions as size-controlled resists on predetermined patterns, such as those formed by electron-beam lithography. The organic molecules serve as a ruler for scaling down a larger "parent" structure. After metal deposition and lift-off of the organic multilayer resist, an isolated smaller structure remains on the surface. This approach is used to form thin parallel wires (15 to 70 nanometers in width and 1 micrometer long) of controlled thickness and spacing. The structures obtained were imaged with field emission scanning electron microscopy. A variety of nanostructures could be scaled down, including structures with hollow patterns.

Journal Article↗
PubMed1983

Purine and glycine metabolism by purinolytic clostridia.

Cell extracts of Clostridium acidiurici, C. cylindrosporum, and C. purinolyticum converted purine, hypoxanthine, 2-hydroxypurine, 6,8-dihydroxypurine, and uric acid into xanthine by the shortest possible route. Adenine was transformed to xanthine only by C. purinolyticum, whereas the other two species formed 6-amino-8-hydroxypurine, which was neither deaminated nor hydroxylated further. 8-Hydroxypurine was formed from purine by all three species. Xanthine dehydrogenase activity was constitutively expressed by C. purinolyticum. Due to the lability of the enzyme activity, comparative studies could not be done with a purified preparation. All enzymes reported to be involved in formiminoglycine metabolism of C. acidiurici and C. cylindrosporum were present in C. purinolyticum. However, glycine was reduced directly to acetate in all three species, as indicated by radiochemical data and by the detection of glycine reductase in cell extracts of C. cylindrosporum and C. purinolyticum. The expression of glycine reductase and the high ratio of glycine fermented to uric acid present points to an energetic advantage for the glycine reductase system, which is expressed when selenium compounds are added to the growth media.

Clostridium↗
PubMed1980

Stable isotope fractionation by Clostridium pasteurianum. 3. Effect of SeO32- on the physiology and associated sulfur isotope fractionation during SO32- and SO42- reductions.

Increased SeO32- concentration reduced H2S evolution from SO32- during whole cell and cell-free extract reductions by Clostridium pasteurianum. H2S production from SO42- was completely inhibited by SeO32- in stationary phase cells. Generation times increased with greater SeO32- concentration, the increase with 1 mM SeO32- being a factor of 2.5 for 1 mM SO32-, and over 3 for 1 mM SO42- reductions. In vitro and in vivo experiments with proposed intermediates of the SO32- reduction pathway show that SeO32- inhibited both the S3O62- to S2O32- and S2O32- to S2- reaction sequences with the latter being more pronounced in growth experiments. Both extracts and whole cells reduced SeO32- to Se0 but Se0 granules were not found in the cell's cytoplasm. The formation of S2O32- by an extracellular chemical mechanism appears not to have occurred in these experiments. Increased SeO32- concentration had the effect of compressing the isotopic release pattern for H2S along the H2S production axis and did not significantly alter the maximum and minimum values of delta 34S. Thus, inhibition by SeO32- limited the conversions of sulfur species without altering the isotopic selectivity of rate-controlling steps in the pathway.

Cell-Free System↗