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PubMed2000

A comparison of vancomycin and sulfated beta-cyclodextrin as chiral selectors for enantiomeric separations of selenoamino acids using capillary electrophoresis with UV absorbance detection.

The enantiomeric separation of three selenoamino acids, D,L-selenomethionine, D,L-selenoethionine and D,L-selenocystine is described. Both sulfated beta-cyclodextrin and vancomycin have been successfully used to separate all enantiomers of the compounds with UV detection. Reproducible separations, in terms of peak area and migration time were obtained using sulfated beta-cyclodextrin with reversed polarity and UV detection. With vancomycin as a chiral selector, reversed polarity was found to be more reproducible than positive polarity in terms of peak migration times.

Cystine↗
PubMed1992

Some properties of murine selenocysteine synthase.

Selenocysteine (Scy) was synthesized on natural opal suppressor tRNA(Ser) by conversion from seryl-tRNA. We studied the mechanisms of the synthesis of mammalian Scy-tRNA using hydro[75Se]selenide (H75Se-). We found Scy synthase activity in the 105,000 g supernatant of a murine liver extract. The supernatant was chromatographed on DEAE-cellulose, and the activity was eluted at 0.12 M-KCl. The reaction mixture for synthesis of Scy-tRNA contained suppressor tRNA, serine, ATP, seryl-tRNA synthetase (SerRS), HSe- and the enzyme to synthesize Scy-tRNA. These are all essential for the synthesis of Scy-tRNA. Scy in the tRNA product was confirmed by five t.l.c. systems. The conversion from seryl-tRNA to Scy-tRNA was also confirmed with the use of [14C]- and [3H]-serine. The apparent Km values for the substrates serine, tRNA, ATP and HSe- were 30 microM, 140 nM, 2 mM and 40 nM respectively. The active eluates from DEAE-cellulose contained no tRNA kinase. This result showed that Scy-tRNA was not synthesized through phosphoseryl-tRNA. ATP was necessary when Scy-tRNA was synthesized from seryl-tRNA and HSe-. Therefore ATP is used for not only the synthesis of seryl-tRNA but also for the synthesis of Scy-tRNA from seryl-tRNA. The active fraction from DEAE-cellulose was chromatographed on Sephacryl S-300, but the activity disappeared. However, the activity was recovered by mixing the eluates corresponding to proteins of 500 kDa and 20 kDa. In order to examine the binding of HSe- to proteins, a mixture of the active fraction, H75Se- and ATP was analysed by chromatography on Sephacryl S-300. The 75Se radioactivity was found at the position of a 20 kDa protein in the presence of ATP. Thus the 20 kDa protein plays a role in binding HSe- in the presence of ATP. The 500 kDa protein must have a role in the synthesis of Scy-tRNA. There are two natural suppressor serine tRNAs, tRNA(NCA) and tRNA(CmCA), in cell cytosol. The present paper shows that the suppressor tRNA fraction, eluted later on benzoylated DEAE-(BD-)cellulose, is a better substrate with which to synthesize Scy-tRNA. Thus we consider that murine Scy-tRNA is synthesized from a suppressor seryl-tRNA on the 500 kDa protein with the activated HSe-, which is synthesized with ATP on the 20 kDa protein. This mammalian mechanism used to synthesize Scy is similar to that seen in Escherichia coli.

Animals↗
PubMed1999

Prostaglandin D2 and sleep--a molecular genetic approach.

Prostaglandin (PG) D2 is the major prostanoid in the mammalian brain, and is the endogenous sleep-promoting substance in mice, rats, and monkeys, and probably in humans as well. When PGD synthase (PGDS), the enzyme responsible for the biosynthesis of PGD2 in the brain, was inhibited in vivo by its selective inhibitors, tetravalent selenium compounds, both slow-wave sleep and rapid-eye-movement sleep were reduced almost completely but reversibly, indicating that PGDS is a key enzyme in sleep regulation. Experiments with transgenic mice also support this contention. In situ hybridization, immunoperoxidase staining, and direct enzyme assay of tissue samples revealed that PGDS is mainly, if not exclusively, localized in the arachnoid membrane and choroid plexus, from which it is secreted into the cerebrospinal fluid to become beta-trace protein. PGD2 exerts its somnogenic activity by binding with PGD2 receptors, exclusively localized at the ventro-rostral surface of the basal forebrain. CGS21680, an adenosine A2a agonist, mimicked the somnogenic activity of PGD2 when applied to the PGD2-sensitive zone. This effect was dose-dependently and selectively abolished by the prior i.p. application of the adenosine A2a antagonist KF17837. Furthermore, the somnogenic activity of PGD2 was also dose-dependently and selectively attenuated by KF17837, indicating the possibility that the sleep induction by PGD2 may be mediated by adenosine through A2a receptors under these conditions. When PGD2 was infused into the subarachnoid space below the rostral basal forebrain, concurrent with sleep induction, striking expression of Fos immunoreactivity was observed in the ventrolateral preoptic area. Fos expression in the ventrolateral preoptic area was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus. PGD2 also increased Fos IR in the basal leptomeninges and several regions implicated in autonomic regulation. These observations suggest that PGD2 may induce sleep via leptomeningeal PGD2 receptors with subsequent activation of the ventrolateral preoptic area neurons.

Adenosine↗
PubMed1998

Control of zinc transfer between thionein, metallothionein, and zinc proteins.

Metallothionein (MT), despite its high metal binding constant (KZn = 3.2 x 10(13) M-1 at pH 7.4), can transfer zinc to the apoforms of zinc enzymes that have inherently lower stability constants. To gain insight into this paradox, we have studied zinc transfer between zinc enzymes and MT. Zinc can be transferred in both directions-i.e., from the enzymes to thionein (the apoform of MT) and from MT to the apoenzymes. Agents that mediate or enhance zinc transfer have been identified that provide kinetic pathways in either direction. MT does not transfer all of its seven zinc atoms to an apoenzyme, but apparently contains at least one that is more prone to transfer than the others. Modification of thiol ligands in MT zinc clusters increases the total number of zinc ions released and, hence, the extent of transfer. Aside from disulfide reagents, we show that selenium compounds are potential cellular enhancers of zinc transfer from MT to apoenzymes. Zinc transfer from zinc enzymes to thionein, on the other hand, is mediated by zinc-chelating agents such as Tris buffer, citrate, or glutathione. Redox agents are asymmetrically involved in both directions of zinc transfer. For example, reduced glutathione mediates zinc transfer from enzymes to thionein, whereas glutathione disulfide oxidizes MT with enhanced release of zinc and transfer of zinc to apoenzymes. Therefore, the cellular redox state as well as the concentration of other biological chelating agents might well determine the direction of zinc transfer and ultimately affect zinc distribution.

Animals↗
PubMed1999

Inhibitory sites in enzymes: zinc removal and reactivation by thionein.

Thionein (T) has not been isolated previously from biological material. However, it is generated transiently in situ by removal of zinc from metallothionein under oxidoreductive conditions, particularly in the presence of selenium compounds. T very rapidly activates a group of enzymes in which zinc is bound at an inhibitory site. The reaction is selective, as is apparent from the fact that T does not remove zinc from the catalytic sites of zinc metalloenzymes. T instantaneously reverses the zinc inhibition with a stoichiometry commensurate with its known capacity to bind seven zinc atoms in the form of clusters in metallothionein. The zinc inhibition is much more pronounced than was previously reported, with dissociation constants in the low nanomolar range. Thus, T is an effective, endogenous chelating agent, suggesting the existence of a hitherto unknown and unrecognized biological regulatory system. T removes the metal from an inhibitory zinc-specific enzymatic site with a resultant marked increase of activity. The potential significance of this system is supported by the demonstration of its operations in enzymes involved in glycolysis and signal transduction.

Aldehyde Dehydrogenase↗
PubMed1984

Short-term dietary selenium restriction in young adults: quantitative studies with the stable isotope 74SeO3(2-).

A 45 d metabolic study was carried out in four young adult male North American residents consuming a controlled diet based on an amino acid mixture. During the initial 10 d, total daily selenium intake was adjusted to 107.7 (SE 0.1) microgram/d, which was reduced to 11.4 (SE 0.1) microgram/d for the remaining 35 d. Two doses of a stable isotope (74SeO3(2-)) were administered orally in the post-absorptive state on days 4 and 39 of the study. Se balance (faecal + urinary excretion) as well as stable isotope excretion studies were carried out for the entire 45 d period; blood plasma and erythrocyte Se concentrations were also monitored. Plasma Se concentrations (microgram/ml) fell progressively from the initial value of 0.132 (SE 0.007) to 0.083 (SE 0.008) at the end of the study. The erythrocyte concentrations of Se did not vary in a consistent manner (average value for the entire study 0.147 (SE 0.002) microgram/ml). Faecal excretion of unenriched Se decreased from 66 (SE 6) microgram/d for days 1-10 to 10.2 (SE 0.8) microgram/d for days 14-40. Mean urinary excretions of the unenriched Se were 43.9 (SE 2.8) microgram/d (days 1-10) and 26.9 (SE 4.6) microgram/d (days 14-40). Total balance (intake-faecal excretion-urinary excretion) for unenriched Se was (microgram/d):-18 (SE 7) days 10-19, -17 (SE 2) days 19-39, -5 (SE 1) days 38-45. Fractional absorption of the ingested label was 0.529 (SE 0.032) and 0.542 (SE 0.038) for the Se-adequate and Se-restricted phases of the study. However, urinary excretion of the absorbed label was reduced from 6.57 (SE 0.73)% for day 1 of the Se-adequate phase to only 3.32 (SE 0.26)% for day 1 of the Se-restricted phase. Similar observations were also made for day 7 of each phase. These findings indicate that immediate contribution of ingested Se to the urinary Se pool is small.

Adult↗
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↗
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↗