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PubMedDate not supplied

Chemoprevention with triphenylselenonium chloride in selenium-deficient rats.

Cancer chemoprevention by high levels of selenium, including compounds like sodium selenite or selenomethionine, is generally not accompanied by increases in known selenoenzymes. There has been no information on whether selenoenzymes are obligatory mediators of the anticarcinogenic effect of selenium. Our previous experience with triphenylselenonium chloride suggests that it might be an ideal agent for studying selenium chemoprevention while simultaneously precluding the synthesis of selenoenzymes. Triphenylselenonium chloride has excellent tumor inhibitory activity but does not support the repletion of selenoenzymes in animals that have been deprived of a bioavailable form of selenium. In the present experiments, we evaluated the efficacy of mammary cancer protection by this compound in rats fed either a selenite-deficient (< 0.01 ppm Se) or selenite-adequate (0.1 ppm Se) diet. We also measured the activities of liver glutathione peroxidase and thioredoxin reductase as markers of selenium bioavailability in these different treatment conditions. In carcinogen-treated control animals not receiving triphenylselenonium chloride, mammary tumor incidence and the total number of tumors were similar between the selenite-deficient and selenite-adequate groups. Thus the correction of selenium deficiency by the addition of 0.1 ppm Se as selenite did not have detectable anticarcinogenic effects. Supplementation of triphenylselenonium chloride at a level of 30 ppm Se suppressed mammary tumorigenesis by approximately 50% regardless of dietary selenium nutritional status. However, this supplement had little effect on tissue selenium levels and did not increase liver glutathione peroxidase or thioredoxin reductase activities. In contrast, a level of 0.1 ppm Se as selenite did not affect mammary tumorigenesis but markedly increased tissue selenium concentrations and selenoenzyme activities. It is concluded that triphenylselenonium chloride does not release inorganic selenium for selenoprotein synthesis and that its anticancer activity involves mechanisms that are probably intrinsic to the compound. This study also shows for the first time that selenium chemoprevention is possible in an environment of severely depressed selenoenzyme expression. Thus selenium chemoprevention efficacy can be separated experimentally from selenoprotein synthesis using this model system.

Animals↗
PubMed1991

The influence of selenium on the reproduction of rats.

Selenium is a vestigial element indispensable for man and animal, having adverse effects when in bigger quantities. Among the diseases resulting from selenium deficiency in animals the most important are nutritional muscular dystrophy, exudative disthesis (most common in poultry), and nutritional hepatic dystrophy. In the man chronic intoxication occurs most of all, which is observed in selenium bearing regions. Taking into consideration geographic distribution on some of the diseases beneficial influence of selenium is observed in cardiac and vascular diseases, and hypertension. The correlation between selenium deficiency and mortality caused by neoplasm is also notable. It is unquestionable that selenium inhibits the activity of enzymes, especially those containing sulfohydryl groups. The stabilization of lysosomal membranes leads to the presumption that selenium prevents peroxidation processes in tissues and cell membranes. The influence of selenium on reproduction is also worth noticing. Its supply turns out to be effective in cases of infertility of sheep, and partly in rats, pigs, and poultry. The embryo dies in pigs fed on fodder poor in selenium and vitamin E. The degeneration of the ovaries and placenta accretion occur in cows in cases of selenium deficiency. The excess of selenium can affect negatively the reproductive system. The element is thought to be a teratogenic agent. Since it permeates through the placenta and lactic gland easily, the symptoms of selenosis appear in new-born animals; many of them have developmental anomalies occurring at the same time. In birds the decrease in laying eggs and their incubation occur in case of selenium deficiency.

Animals↗
PubMed2006

[Studies of bioavailability of different food sources of selenium in experiment].

The selenium bioavailability in selenium enriched Spirulina (Arthrospira platensis), phycocyanin containing (Se-PC) protein isolate, separated from this micro algae and in sodium selenite was studied and compared in rats. The daily dose of selenium per one animal was 5 microgram in all experimental groups. The average selenium levels in blood serum and liver of animals that received sodium selenite during 14 days were the highest. The average selenium level in blood serum of animals fed with selenium enriched Spirulina platensis after 14 days of receiving was the same with the control group, but the average concentration of selenium in their liver was rather high and close to this parameter of sodium selenite animal group. The animals which were fed with Se-PC showed better results. Their average selenium level in blood serum was higher than in Spirulina group, but lower than in sodium selenite group. The average concentration of selenium in the liver of these animals was the same with sodium selenite animal group. As regards to animals that were fed with selenium enriched Spirulina, Se-PC and sodium selenite for 21 days, the average selenium levels ratio in their blood serum and liver was higher than in control group, but these results were not significantly different among each other. The concentrations of selenium in seminal glands in all groups of animals including control group both after 14 and 21 days feeding were close to each other.

Animals↗
PubMed1989

[Usual values of selenium and glutathione peroxidase in a Belgian population].

Several biological parameters for assessing selenium status have been determined in years 1985-1986 in a large Belgian population group, males and females 0 to 92 years old, representative from Brussels and surroundings. In 145 people, 20 to 79 years old, mean concentrations were: 1.06 +/- 0.15 mumol Se/l plasma, 5.0 +/- 1.1 nmol Se/g Hb in erythrocytes and 7.4 +/- 2.0 mu/g Hb for the selenodependent glutathione peroxidase activity measured in erythrocytes (mean +/- standard deviation). Values for urine selenium have a disymmetric distribution and range from 0.05 to 0.65 mumol Se/g creatinine. No difference was evidenced in this group according to sex and age. Children below 20 years and elderly above 80 years have decreased plasma and erythrocyte selenium concentrations but glutathione peroxidase is not modified. These blood selenium concentrations are lower than those determined in a similar population group in years 1980-1981, suggesting a progressive decrease in selenium intake. The concentrations of the biological parameters are not correlated together except in selenium deficient patients having plasma selenium less than 0.75 mumol/l: a significant correlation is observed between plasma selenium and erythrocyte glutathione peroxidase activity, that becomes more intense with decreasing plasma selenium. Finally, two recent investigations are described where a significant response in platelet glutathione peroxidase was obtained during a 60 days selenium supplementation with 100 to 200 micrograms selenium per day, suggesting that usual selenium intake in Belgium (50 micrograms per day) is marginally deficient.

Adolescent↗
PubMed1985

Selenium deficiency and detoxication functions in the rat: effect of chronic dietary cadmium.

Male rats from moderately selenium-deficient dams were fed a Torula yeast-based, selenium-deficient diet for 7 weeks, with or without added supplements of sodium selenite (0.2 ppm selenium) and cadmium chloride (50 ppm cadmium) in the drinking water. Cadmium caused about 10% body-weight loss in selenium-deficient, as well as in supplemented rats. Glutathione peroxidase activity in liver 105,000 g supernatant and in erythrocyte hemolysate from selenium-deficient rats was about 1% and 3%, respectively, of that in supplemented rats. A cadmium-induced decrease of glutathione peroxidase activity was found in erythrocyte and liver preparations from selenium-supplemented rats, while cadmium caused an increase of the liver activity in selenium deficiency. Selenium deficiency per se caused a significant decrease of cytochrome P-450 content, while cadmium treatment did not modify further the content of this enzyme. NADPH-cytochrome c reductase was not changed by selenium regimen or cadmium treatment, while cytochrome b5 was increased on cadmium treatment of the supplemented rat. The microsomal metabolism of N,N-dimethylaniline showed a decrease of the cytochrome P-450-dependent C-oxygenation in selenium-deficient groups. Cadmium treatment had no further significant effect. The flavin-containing monooxygenase, which performs N-oxygenation of N,N-dimethylaniline, was decreased significantly by cadmium treatment in selenium deficiency. Selenium deficiency seems thus to be connected with higher susceptibility to cadmium-induced impairments of liver detoxication functions, although progressive accumulation of cadmium in the liver appears to produce only modest effects.

Aniline Compounds↗
PubMed1985

Effects of selenium on cell proliferation in rat liver and mammalian cells as indicated by cytokinetic and biochemical analysis.

Studies were conducted in vivo with regenerating liver and in vitro with mammalian cells to determine the effects of selenium on cell proliferation and the stages of the cell cycle affected by selenium. Six ppm selenium as Na2SeO3 fed to weanling male F344 rats for 6 wk significantly reduced the percentage of 3H-labeled hepatocyte nuclei by one-half compared to 0.1 ppm selenium when [methyl-3H]thymidine was injected at 23 h post-two-thirds hepatectomy. Sampling was done at 30 h post-hepatectomy. A trend towards decreased 3H per DNA per labeled cell was also observed, suggesting that selenium decreased the rate of DNA synthesis as well as delaying the entry of cells into S phase (i.e., increasing the duration of G0-G1). Studies in vitro with H-4 "minimal deviation" hepatomas and 3T3 mouse fibroblasts demonstrated that selenium decreased the growth of these cells in a dose-dependent manner, and this inhibition was reversible upon removal of selenium from the growth medium. Cytokinetic analysis using fluorescence flow cytometry and microscopic techniques indicated that selenium treatment increased the duration of G1, S, and G2 phases of the cell cycle, while having no effect on mitosis under the conditions of our experiments. Biochemical analyses of H-4 cells demonstrated that selenium treatment caused a significant dose-dependent increase in oxidized and reduced glutathione (GSSG and GSH) as well as in the GSSG:GSH ratio as was previously observed in liver in vivo. In addition, glutathione reductase activity as well as the oxidized nicotinamide adenine dinucleotide phosphate:reduced nicotinamide adenine dinucleotide phosphate ratio was significantly increased with selenium treatment. These results indicate that selenium affects all "synthetic" stages of the cell cycle, and elevated GSSG or the GSSG:GSH ratio may explain the antiproliferative effects of selenium on cells.

Animals↗
PubMed1984

The effect of vitamin E or selenium on the oxidant-antioxidant balance in rats.

Vitamin E and selenium are two components which contribute to the antioxidant potential of plasma and tissues. In the present study we aimed to define the type of tissue toxicity deriving from chronic deficiency of either vitamin E or selenium and to evaluate the reliability of peripheral markers of tissue toxicity in these conditions. We studied rats fed a vitamin E or selenium-deficient diet for 3 or 7 months and a selenium-supplemented diet. The effectiveness of the dietary treatment was confirmed by measuring vitamin E and selenium in plasma. Heart and kidney malondialdehyde (MDA), a typical product of lipid peroxidation, was significantly increased after the 3-month diet in both vitamin E- and selenium-deficient rats. The iron-binding capacity of plasma, an activity ascribed to plasma transferrin, was reduced in selenium-deficient and increased in selenium-supplemented animals. In red cells globular resistance (resistance to osmotic haemolysis) was low in vitamin E- and selenium-deficient, but high in selenium-supplemented animals. Glutathione peroxidase was also increased in selenium-supplemented rats. Platelet count did not differ from controls in any of the three conditions studied. Platelet MDA formation induced by arachidonic acid was raised in both selenium-deficient and, particularly, vitamin E-deficient groups. This can be regarded as a peripheral marker of reduced antioxidant defence at tissue level.

Animals↗
PubMedDate not supplied

[The selenium content of milk].

The selenium content in milk of dairy cows from different countries varies between 2 and 60 micrograms/kg, because of differences in the selenium content in the feeds. With an increasing selenium content in the feed a decreasing part is secreted into the milk. A bigger part is utilized from natural selenium compounds in the feed than from selenite. In own investigations milk from Swedish cows had significantly lower selenium content during summer and autumn than during winter and spring (p less than 0,0001). The LS-means between different regions also differed significantly (p less than 0,0001). From the autumn of 1980 the feed manufacturers have been allowed to add sodium-selenite to concentrates and mineral feeds in amounts permitting a selenium content of 0,1 mg/kg DM in the total ration of dairy cows. The year after the selenium fortification was allowed, the LS-means for the selenium content of milk were 1 microgram/kg higher than the year before (p less than 0,001). In the southern parts of Sweden the selenium content was 8-10 and in the central and northern parts 7-9 micrograms/kg. These means were substantially lower than the figure of 15 micrograms/kg which was reported from the central part of Sweden two decades ago. The low selenium content in the milk during summer in some parts of Sweden could possibly mean that there is still a risk of selenium deficiency among the cattle. Anyhow the milk will not always cover the selenium requirement of the sucking or milkfed calf.

Animal Feed↗
PubMed1983

Considerations in the design of selenium bioavailability studies.

Recommendations for safe and adequate dietary intakes of selenium were recently established. The recommendations were based largely on data from animals, because few data for humans were available. Some information regarding the dietary selenium intake required by humans to replace excretory losses has now appeared, but the bioavailability to humans of selenium from different dietary sources has not been determined. Selenium bioavailability depends on several metabolic processes, including not only absorption but also conversion into a biochemically active form. Of the different forms of selenium in foods, probably not all are converted to biologically active selenium with equal ease. Therefore, determination of selenium absorption may not in itself yield an accurate estimate of selenium bioavailability. Rather, functional tests, such as measurement of the selenoenzyme glutathione peroxidase, apparently are more valid for determining selenium bioavailability. Various food sources of selenium for humans differ widely in their ability to restore hepatic glutathione peroxidase activity in selenium-depleted rats. Platelet glutathione peroxidase activity seems to be particularly promising for bioavailability studies because platelets are a convenient biopsy material and the platelet enzyme is sensitive to changes in dietary selenium intake. Work in progress should establish the feasibility of this approach for future research in this area.

Animal Nutritional Physiological Phenomena↗
PubMed1983

Roles of selenium and sulfur-containing amino acids in protection against oxygen toxicity.

Tolerance and adaptation to hyperoxia have been correlated with increases in antioxidant enzymes. This study evaluated whether selenium deficiency would prevent an increase in glutathione peroxidase (GSHPX), a selenium-containing enzyme, during oxygen exposure, and, thus, inhibit adaptation. Because the Torula yeast-based diet, which was used to produce selenium deficiency, was also deficient in cysteine and methionine, the effects of these deficiencies were also evaluated. When rats were exposed to 80% oxygen for 1 week, mortality was 80% for rats deficient in both selenium and the sulfur-containing amino acids, 40% for selenium-deficient rats, 35% for cysteine- and methionine-deficient rats, and 0% for rats fed either a standard laboratory diet or a selenium, cysteine-, and methionine-supplemented Torula yeast diet. However, only one of the six surviving rats with low selenium and none of the rats from any other dietary group died during a subsequent 96 hours of 98% oxygen, indicating adaptation to hyperoxia (LD50 for unadapted rats is 72 hours.) GSHPX activity (per gram of dry weight) was decreased 85% in lungs from unexposed rats fed the low selenium diets. After oxygen exposure, lung GSHPX activity was elevated in all dietary groups. Rats fed the high selenium diets had a 47% increase in enzyme activity, whereas rats with high selenium had a 214% increase. Although hyperoxia caused a relatively high percentage increase in the low Se rats, the resulting absolute GSHPX activity was only 34 to 70% of that of unexposed high selenium rats. The results indicate that both selenium and sulfur-containing amino acids contribute to antioxidant defense. However, although the stress of hyperoxic exposure produces an increase in glutathione peroxidase activity, the absolute lung GSHPX activity is better correlated with tolerance than with adaptation to hyperoxia.

Adaptation, Physiological↗
PubMed1995

Liver and kidney necrosis in selenium-deficient rats depleted of glutathione.

BACKGROUND: Selenium and glutathione have interrelated oxidant defense roles in vivo. Experiments were carried out to determine the effect of glutathione depletion in selenium-deficient rats. EXPERIMENTAL DESIGN: Selenium-deficient and control rats were injected with phorone to deplete glutathione. Histologic assessment of liver and kidney injury was performed at 24 hours. In another experiment, glutathione depletion, lipid peroxidation, and liver injury were measured for 12 hours after phorone administration to determine their relationships with one another. In a final experiment, selenoproteins were correlated with protection against lipid peroxidation and liver necrosis. Selenium-deficient rats were injected with vehicle alone and with 5, 10, or 25 micrograms of selenium/kg. Twelve hours later, selenoproteins were measured in some of the rats, and phorone was injected into others. Liver injury and lipid peroxidation were assessed 6 hours after the phorone injection. RESULTS: Twenty-four hours after phorone administration (125 mg/kg), centrilobular hepatic necrosis and renal tubular necrosis were evident in selenium-deficient rats but not in controls. The time-course experiment revealed that phorone (250 mg/kg) caused sharp decreases in liver and kidney glutathione levels in both groups within 2 to 4 hours. Lipid peroxidation, as assessed by F2 isoprostane concentrations, in selenium-deficient animals. Liver necrosis, indicated by a rise in plasma ALT, took place in selenium-deficient rats but not in controls. Selenium injections into selenium-deficient rats increased selenoprotein P concentrations from 4% of control to as high as 39% but had little effect on glutathione peroxidase activities. Six hours after phorone administration, rats that had received selenium had no rise in ALT, and the rises in F2 isoprostanes were abolished or attenuated. CONCLUSIONS: We conclude that depletion of glutathione in selenium-deficient liver and kidney leads to necrosis in those organs associated with evidence of lipid peroxidation. Protection against this injury by selenium correlates with selenoprotein P concentration in plasma but not with glutathione peroxidase activity in tissues or in plasma. These findings raise the possibility that selenoprotein P protects cell membranes against oxidant injury and that glutathione is involved in that protection.

Animals↗
PubMed1993

Increase in serum selenium levels in Finnish children and young adults during 1980-1986: a correlation between the serum levels and the estimated intake.

Serum selenium concentrations of Finnish children and adolescents (ages: 3, 6, 9, 12, 15 and 18 years) were analysed in 1980. The sample included 1706 subjects from five different areas, each containing rural and urban sectors. The serum selenium concentration levels were compared to the intakes of energy, selenium, protein, fat and carbohydrate estimated by a dietary survey (in a total of 1090 subjects from the 1706). In 1986 corresponding data were obtained from 280 of the subjects from the 1980 sample. The mean intake of selenium from food in 1980 ranged from 12 to 23 micrograms per day for the different age groups. In 1986, after the addition of selenium to fertilizers, the mean daily intake of selenium ranged from 69 to 82 micrograms per day for the groups of subjects, who were 9, 12, 15, 18, 21 and 24 years old by that time. In 1980, the children aged 3 and 6 years had lower selenium concentrations in their sera compared to the other age groups. However, serum selenium levels were higher in the Tampere and Oulu areas. In 1986 the selenium concentrations in sera increased with age (9-21-year-olds) and no regional differences were found. The selenium levels in sera were higher in 1986 than in 1980 due to the increased intake after the addition of selenium to fertilizers used in Finland. The increase in selenium levels between the 1980 and 1986 studies were, on the average, 45%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

[Selenium, glutathione peroxidase, peroxides and platelet functions].

In the last five years, there has been a renewal of interest in the protective role of selenium in vascular disorders, inspired by experimental evidence that this trace element could modulate leukotriene and prostaglandin synthesis in both endothelial cells and platelets. In people living in low-selenium areas, a relationship has been established between a decrease in plasma selenium and an increase in the risk of coronary disease, atherosclerosis, platelet hyperaggregability and synthesis of proaggregant and proinflammatory compounds like thromboxane A2 and leukotrienes. Selenium, as an essential part of glutathione peroxidase, takes part in the reduction of hydrogen peroxides and lipid peroxides. The concentration of these peroxides, in turn, regulates the activities of cyclooxygenase and lipooxygenase pathways, ultimately influencing the production of eicosanoids and modulating the balance between a proaggregatory and antiaggregatory state. Recent evidence shows that selenium, via its action on glutathione peroxidase activity, may be primarily responsible for the regulation of the endogenous hydroperoxide level. In human platelets, the activity of glutathione peroxidase is particularly high and is very sensitive to the requirement of selenium. This sensitivity could explain why platelets of selenium-deficient subjects show increased aggregation, thromboxane B2 production and synthesis of the lipoxygenase-derived compounds. In these deficient subjects, selenium administration increases platelet glutathione peroxidase activity and inhibits platelet hyperaggregation and leukotriene synthesis. These results support the hypothesis that selenium supplementation has a positive effect on platelet aggregation in selenium-deficient subjects. In France, more than 10% of the population is selenium-deficient and long-term supplementation with low doses of selenium could have a beneficial effect on the prevention of both thrombosis and coronary heart disease in these subjects.

Animals↗
PubMed1997

Chemopreventive and growth inhibitory effects of selenium.

There is very convincing evidence that a high dietary level of selenium substantially reduces the incidence of a wide variety of animal cancers. The human epidemiological evidence is less clear cut, but overall suggests that selenium may be protective: the evidence is strongest in men in relation to gastro-intestinal cancers. There is evidence that dietary selenium compounds reduce the formation of DNA adducts by carcinogens. Selenium compounds also inhibit growth in vitro and induce apoptosis. In general, there is a good correlation between the effectiveness of selenium compounds in chemoprevention and growth inhibition, implying that the mechanisms of growth inhibition and chemoprevention may be similar and that a major factor in the chemopreventive effects of selenium compounds in vivo is their ability to retard outgrowth of pre-malignant cells. Various hypotheses have been advanced as to how selenium compounds might prevent tumour cell growth. One is that they cause apoptosis by inducing oxidative stress. However, we have shown that the most potent selenium compound, selenodiglutathione (SDG), a natural metabolite of selenite, does not induce oxidative stress, at least not in the same way as other oxidants such as H2O2 and diamide. Firstly, a partially selenium-resistant variant cell line does not show increased resistance to H2O2. Moreover, SDG does not induce widespread tyrosine phosphorylation, including MAP and SAP kinases, like other oxidants such as H2O2 and diamide and its effects are not reversed by pretreatment with the tyrosine kinase inhibitor, herbimycin. Our experiments with the selenium-resistant variant suggest that a novel selenium-binding protein may be involved in growth inhibition by selenium.

Anticarcinogenic Agents↗
PubMed1999

Selenium-based drug design: rationale and therapeutic potential.

The wide media coverage given recently to a study correlating higher selenium levels with a reduced risk of advanced prostate cancer is but the latest addition to a growing body of epidemiological findings which link dietary selenium deficiency to diseases as diverse as cancer, heart disease, arthritis and AIDS. Indeed, selenium has a long history of association with human health and disease. Moreover, direct evidence is now emerging for specific beneficial effects of dietary selenium supplementation. Thus, the pharmacology, biology and biochemistry of selenium metabolism have become subjects of intense current interest. At the molecular level, selenium (as selenocysteine) is an essential component of the active sites of the enzymes glutathione peroxidase, iodothyronine 5'-deiodinase and mammalian thioredoxin reductase, and is also present in several other mammalian selenoproteins. Both glutathione peroxidase and thioredoxin reductase catalyse reactions essential to the protection of cellular components against oxidative and free radical damage. As a consequence of the growing recognition of the important biological role of selenium, a number of novel pharmaceutical agents, either selenium-based or which target specific aspects of selenium metabolism, are under development. Among these are orally active selenium-based antihypertensive agents, anticancer, antiviral, immunosuppressive and antimicrobial agents, and organoselenium compounds which reduce oxidative tissue damage and oedema. It can be anticipated that as our understanding of the basic biology and biochemistry of selenium increases, future efforts will uncover even more sophisticated approaches for the rational development of new selenium-based pharmaceutical agents.

Journal Article↗
PubMed2001

Plasma selenium in specific and non-specific forms.

Selenium is present in plasma and tissues in specific and non-specific forms. The experiments reported here were carried out to clarify some factors that affect these forms of the element in plasma. A selenium-replete human subject was given 400 microg of selenium daily for 28 days as selenomethionine and, in a separate experiment, as selenate. The selenomethionine raised plasma and albumin selenium concentrations. Selenate did neither. The molar ratio of methionine to selenium in albumin was approximately 8000 under basal and selenate-supplemented conditions but 2800 after selenomethionine supplementation. This demonstrates that selenium from selenomethionine, but not selenium from selenate, can be incorporated into albumin, presumably as selenomethionine in the methionine pool. Selenocysteine incorporation into albumin was studied in rats using (75)Se-selenocysteine. No evidence was obtained for incorporation of (75)Se into albumin after exogenous administration or endogenous synthesis of (75)Se-selenocysteine. Thus, selenocysteine does not appear to be incorporated non-specifically into proteins as is selenomethionine. These findings are in support of selenomethionine being a non-specific form of selenium that is metabolized as a constituent of the methionine pool and is unaffected by specific selenium metabolic processes. No evidence was found for non-specific incorporation of selenium into plasma proteins when it was administered as selenate or as selenocysteine. These forms of the element appear to be metabolized by specific selenium metabolic processes.

Adult↗
PubMed1996

Mechanisms of selenium methylation and toxicity in mice treated with selenocystine.

Mechanisms of selenium methylation and toxicity were investigated in the liver of ICR male mice treated with selenocystine. To elucidate the selenium methylation mechanism, animals received a single oral administration of selenocystine (Se-Cys; 5, 10, 20, 30, 40, or 50 mg/kg). In the liver, both accumulation of total selenium and production of trimethylselenonium (TMSe) as the end-product of methylation were increased by the dose of Se-Cys. A negative correlation was found between production of TMSe and level of S-adenosylmethionine (SAM) as methyl donor. The relationship between Se-Cys toxicity and selenium methylation was determined by giving mice repeated oral administration of Se-Cys (10 or 20 mg/kg) for 10 days. The animals exposed only to the high dose showed a significant rise of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in plasma. Urinary total selenium increased with Se-Cys dose. TMSe content in urine represented 85% of total selenium at the low dose and 25% at the high dose. The potential of Se-methylation and activity of methionine adenosyltransferase, the enzyme responsible for SAM synthesis, and the level of SAM in the liver were determined. The high dose resulted in inactivation of Se-methylation and decrease in SAM level due to the inhibition of methionine adenosyltransferase activity. To learn whether hepatic toxicity is induced by depressing selenium methylation ability, mice were injected intraperitoneally with periodate-oxidized adenosine (100 mumol/kg), a known potent inhibitor of the SAM-dependent methyltransferase, at 30 min before oral treatment of Se-Cys (10, 20, of 50 mg/kg). Liver toxicity induced by selenocystine was enhanced by inhibition of selenium methylation. These results suggest that TMSe was produced by SAM-dependent methyltransferases, which are identical with those involved in the methylation of inorganic selenium compounds such as selenite, in the liver of mice orally administered Se-Cys. Depression of selenium methylation ability resulting from inactivation of methionine adenosyltransferase and Se-methylation via enzymic reaction was also found in mice following repeated oral administration of a toxic dose of Se-Cys. The excess selenides accumulating during the depression of selenium methylation ability may be involved in the liver toxicity caused by Se-Cys.

Adenosine↗
PubMed2005

Selenium metabolites in human urine after ingestion of selenite, L-selenomethionine, or DL-selenomethionine: a quantitative case study by HPLC/ICPMS.

To obtain quantitative information on human metabolism of selenium, we have performed selenium speciation analysis by HPLC/ICPMS on samples of human urine from one volunteer over a 48-hour period after ingestion of selenium (1.0 mg) as sodium selenite, L-selenomethionine, or DL-selenomethionine. The three separate experiments were performed in duplicate. Normal background urine from the volunteer contained total selenium concentrations of 8-30 microg Se/L (n=22) but, depending on the chromatographic conditions, only about 30-70% could be quantified by HPLC/ICPMS. The major species in background urine were two selenosugars, namely methyl-2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside (selenosugar 1) and its deacylated analog methyl-2-amino-2-deoxy-1-seleno-beta-D-galactopyranoside (selenosugar 3). Selenium was rapidly excreted after ingestion of the selenium compounds: the peak concentrations (approximately 250-400 microg Se/L, normalized concentrations) were recorded within 5-9 hours, and concentrations had returned to close to background levels within 48 hours, by which time 25-40% of the ingested selenium, depending on the species ingested, had been accounted for in the urine. In all experiments, the major metabolite was selenosugar 1, constituting either approximately 80% of the total selenium excreted over the first 24 hours after ingestion of selenite or L-selenomethionine or approximately 65% after ingestion of DL-selenomethionine. Selenite was not present at significant levels (<1 microg Se/L) in any of the samples; selenomethionine was present in only trace amounts (approximately 1 microg/L, equivalent to less than 0.5% of the total Se) following ingestion of L-selenomethionine, but it constituted about 20% of the excreted selenium (first 24 hours) after ingestion of DL-selenomethionine, presumably because the D form was not efficiently metabolized. Trimethylselenonium ion, a commonly reported urine metabolite, could not be detected (<1 microg/L) in the urine samples after ingestion of selenite or selenomethionine. Cytotoxicity studies on selenosugar 1 and its glucosamine isomer (selenosugar 2, methyl-2-acetamido-2-deoxy-1-seleno-beta-D-glucosopyranoside) were performed with HepG2 cells derived from human hepatocarcinoma, and these showed that both compounds had low toxicity (about 1000-fold less toxic than sodium selenite). The results support earlier studies showing that selenosugar 1 is the major urinary metabolite after increased selenium intake, and they suggest that previously accepted pathways for human metabolism of selenium involving trimethylselenonium ion as the excretionary end product may need to be re-evaluated.

Cell Line, Tumor↗