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Effects of selenium deficiency on the formation and detoxification of endogenous electrophiles in rats.

Selenium deficiency could be expected to lead to enhanced lipid peroxidation through loss of selenium-dependent glutathione peroxidase activity. Such a relation has, however, been difficult to verify. In the present study, the influence of selenium deficiency in rats on in vivo doses of some endogenously occurring low-molecular mass aldehydes and epoxides was determined. In vivo doses were measured by mass-spectrometric analysis according the N-alkyl Edman method of reaction products (adducts) with N-terminal valines in hemoglobin. Despite variations between experiments, the adduct levels of acetaldehyde and malonaldehyde were shown to be significantly higher in rats fed a selenium-deficient diet than in controls fed a selenium-adequate diet. No significant effect was found for the other aldehydes measured. In contrast, the in vivo doses of endogenous ethylene oxide and propylene oxide were lowered in selenium-deficient rats, indicating a 1.7-times faster detoxification rate. This was verified by the lower adduct levels in selenium-deficient rats following intraperitoneal administration of these epoxides at moderate doses. In conclusion, the results seem to reflect the complex changes of induced and reduced enzyme activities in response to selenium deficiency. Measurement of reactive compounds through their adducts to hemoglobin has shown its ability to elucidate the effects of selenium deficiency per se.

Journal Article↗

Plasma selenium over time and cognitive decline in the elderly.

BACKGROUND: Because brain oxidative stress is a cause of cognitive impairment, selenium, which is an antioxidant, may protect against cognitive decline. The aim of the study was to examine whether declining selenium levels over time are associated with cognitive decline in a cohort of community-dwelling French elderly. METHODS: During 1991-1993, 1389 subjects (age 60-71 years) were recruited into a 9-year longitudinal study with 6 waves of follow-up. Cognitive functions were evaluated by neuropsychologic tests. To take into account the entire set of cognitive measurements and the within-subject correlations between measures, we analyzed mixed linear and logistic models to study associations between selenium change and cognitive decline. RESULTS: After controlling for potential confounders, cognitive decline was associated with decreases of plasma selenium over time. Among subjects who had a decrease in their plasma selenium levels, the greater the decrease in plasma selenium, the higher the probability of cognitive decline. Among subjects who had an increase in their plasma selenium levels, cognitive decline was greater in subjects with the smallest selenium increase. There was no association between short-term (2-year) selenium change and cognitive changes. CONCLUSION: Selenium status decreases with age and may contribute to declines in neuropsychologic functions among aging people.

Age Factors↗

Selenoprotein metabolism and function: evidence for more than one function for selenoprotein P.

Biological functions of selenium are exerted by selenoproteins that contain selenocysteine in their primary structure. Selenocysteine is synthesized and inserted into proteins cotranslationally by a complex process. Families of selenoproteins include the glutathione peroxidases, the iodothyronine deiodinases and the thioredoxin reductases. These are redox enzymes that take advantage of the chemical properties of selenium to catalyze, respectively, removal of hydroperoxides by glutathione, deiodination of thyroid hormones and support of cellular processes requiring reduction of disulfides. Approximately 10 additional selenoproteins have been identified. One of them, selenoprotein P, is an extracellular protein that contains most of the selenium in plasma. It associates with endothelial cells, probably through its heparin-binding properties. Selenoprotein P has been postulated to protect against oxidative injury and to transport selenium from the liver to peripheral tissues. Selenium-dependent protection against diquat-induced liver necrosis and lipid peroxidation in the rat correlates with the presence of selenoprotein P. Recent results support a transport function. When (75)SeO(3)(2-) was administered intravenously to rats, liver tissue took up (75)Se within minutes, associated with a rapid decline in plasma (75)Se. Brain tissue did not begin accumulating (75)Se until (75)Se-labeled selenoprotein P had begun appearing in the plasma after 30 min. These results suggest that tissues like liver can take up small-molecule forms of selenium whereas presence of the element in selenoprotein P facilitates uptake by tissues like brain. Thus, there is evidence for both antioxidant and selenium transport functions of selenoprotein P.

Animals↗

Effects of a supranutritional dose of selenate compared with selenite on insulin sensitivity in type II diabetic dbdb mice.

The present study was performed to examine the mechanism by which selenate ameliorates the insulin sensitivity in type II diabetic dbdb mice. Therefore, 21-adult female dbdb mice were randomly assigned to three experimental groups (0Se, SeIV and SeVI) with seven animals per group. Mice of group 0Se were fed with a selenium-deficient diet (<0.02 mg Se/kg) based on wheat and torula yeast for 8 weeks whereas the mice of groups SeIV (selenite) and SeVI (selenate) were fed with sodium selenite and sodium selenate (up to 35% of the LD(50) for mice in eighth week), in addition to the diet by daily tube feeding. Eight weeks of selenate application led to significantly elevated insulin sensitivity in comparison with selenium deficiency and selenite application. The activity of cytosolic protein tyrosine phosphatases (PTPs) as important negative regulators of insulin signalling was reduced from 53.8% to 22.5% in the liver and skeletal muscle of selenate-treated mice in comparison with the selenium deficient and selenite-treated controls, suggesting an inhibition of PTPs by intermediary selenate metabolites. In an additional in vitro inhibition study, selenate (oxidation state +VI) did not inhibit PTP activity. Selenium metabolites in the oxidation state +IV were found to be the actual inhibitors of PTP activity. In conclusion, the results of the present study show that one possible mechanism by which supranutritional selenate doses enhance insulin sensitivity in type II diabetic dbdb mice is based on the inhibition of PTPS as negative regulators of insulin signalling. Moreover the cellular metabolism of selenate including its intermediary reduction to the oxidation state +IV seems to play a crucial role during this process.

Animals↗

Evidence of hepatic endogenous hydrogen peroxide in bile of selenium-deficient rats.

Hepatic endogenous hydrogen peroxide (H(2)O(2)) in bile of selenium-deficient rats (SeD) was for the first time found using the electron spin resonance (ESR) spin-trap technique, and the relationship between glutathione peroxidase (GPX) activity and H(2)O(2) amount is discussed. Normal rats and four groups of rats fed a selenium-deficient diet with different feeding periods were examined. The results showed that the GPX activity decreased depending on the feeding period with the selenium-deficient diet and that the hepatic endogenous H(2)O(2) amount in the bile of the rats fed the selenium-deficient diet for the longest period (a week before birth to 8 weeks old) was drastically higher than those in other groups of rats (P < 0.005). We found that generation of H(2)O(2) due to the decrease in the GPX activity has a threshold value. The results suggest that an exposure to selenium deficiency for long term will cause oxidative stress.

Animals↗

Cardiovascular risk factors in non-insulin-dependent diabetics compared to non-diabetic controls: a population-based survey among Asians in Singapore.

Cardiovascular risk factors were compared between 126 people with non-insulin-dependent diabetes mellitus (NIDDM) and 530 non-diabetics (controls), in a random sample of people (Chinese, Malays, and Asian Indians) aged 40-69 years from the general population of Singapore. Data were adjusted for age and ethnicity. For both genders, people with NIDDM had higher mean body mass indices, waist-hip ratios and abdominal diameters. They also had a higher prevalence of hypertension, higher mean levels of fasting serum triglyceride, slightly lower mean levels of serum high-density-lipoprotein cholesterol, and higher mean levels of plasma plasminogen activator inhibitor-1 and tissue plasminogen activator (antigen). These factors are components of syndrome X (metabolic syndrome) and increase the risk of atherosclerosis and thrombosis. In contrast, there were no important differences for cigarette smoking, serum total and low-density-lipoprotein cholesterol, serum apolipoproteins A1 and B, plasma factor VIIc and plasma prothrombin fragment 1 + 2. Females with NIDDM, but not males, had a higher mean serum fibrinogen level than non-diabetics, which could explain why NIDDM has a greater cardiovascular effect in females than males. Serum lipoprotein(a) concentrations were lower in people with NIDDM. Mean levels of serum ferritin, a pro-oxidant, were higher in people with NIDDM than controls, but there were no important differences for plasma vitamins A, C and E, and serum selenium, which are anti-oxidants.

Arteriosclerosis↗

Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies.

Quinolinic acid (QUIN), a well known excitotoxin that produces a pharmacological model of Huntington's disease in rats and primates, has been shown to evoke degenerative events in nerve tissue via NMDA receptor (NMDAr) overactivation and oxidative stress. In this study, the antioxidant selenium (as sodium selenite) was tested against different markers of QUIN-induced neurotoxicity under both in vitro and in vivo conditions. In the in vitro experiments, a concentration-dependent effect of selenium was evaluated on the regional peroxidative action of QUIN as an index of oxidative toxicity in rat brain synaptosomes. In the in vivo experiments, selenium (0.625 mg per kg per day, i.p.) was administered to rats for 5 days, and 2 h later animals received a single unilateral striatal injection of QUIN (240 nmol/ micro L). Rats were killed 2 h after the induction of lesions with QUIN to measure lipid peroxidation and glutathione peroxidase (GPx) activity in striatal tissue. In other groups, the rotation behavior, GABA content, morphologic alterations, and the corresponding ratio of neuronal damage were all evaluated as additional markers of QUIN-induced striatal toxicity 7 days after the intrastriatal injection of QUIN. Selenium decreased the peroxidative action of QUIN in synaptosomes both from whole rat brain and from the striatum and hippocampus, but not in the cortex. A protective concentration-dependent effect of selenium was observed in QUIN-exposed synaptosomes from whole brain and hippocampus. Selenium pre-treatment decreased the in vivo lipid peroxidation and increased the GPx activity in QUIN-treated rats. Selenium also significantly attenuated the QUIN-induced circling behavior, the striatal GABA depletion, the ratio of neuronal damage, and partially prevented the morphologic alterations in rats. These data suggest that major features of QUIN-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that selenium partially protects against QUIN toxicity.

Animals↗

Metal-ion-mediated oxidative stress in the gill homogenate of rainbow trout (Oncorhynchus mykiss): antioxidant potential of manganese, selenium, and albumin.

Human activities play a major role in toxic and carcinogenic metal pollution of the environment. This study was undertaken to evaluate the effects of copper and mercury at the 400- to 1000-microM concentration range on some biochemical markers of oxidative stress, such as lipid peroxidation (LPO), glutathione-S-transferase (GST) activity, and reduced glutathione (GSH) content in the rainbow trout gill homogenates with or without supplementation of manganese, selenium, and bovine serum albumin (BSA). The integrity of DNA was also measured to assess metal ion toxicity. The results showed that the LPO and specific activity of GST were elevated. This indicated that cell-protecting antioxidant mechanisms were overtaxed and could not prevent membrane peroxidation. Following the addition of metals, the GSH content was also significantly reduced in a concentration-dependent manner. Mercury was found to be more effective than copper. The application of antioxidants proved beneficial in inhibiting LPO, reducing GST activity, and elevating the GSH levels in the gill samples. Manganese was more effective than selenium and BSA. Surprisingly, when BSA (1.0%) was added to the gill homogenates treated with a 1000-microM concentration of metal ions, instead of alleviating malondialdehyde (MDA) generation, a drastic elevation in the MDA levels, alleviation in GST activity, and a further decrease in glutathione (GSH) levels were observed, which were most likely the result of pro-oxidant activity of BSA. The results also indicated that mercury and copper functioned as genotoxic pollutants, which altered the DNA integrity by inducing the single- and double-stranded DNA breaks in the gill cell nuclei. Collectively, toxicity of metal ions is related to the depletion of GSH content and inhibition of antioxidant enzyme GST, resulting in the propagation of LPO and DNA damage.

Animals↗

Red blood cell and plasma glutathione peroxidase activities and selenium concentration in patients with chronic kidney disease: a review.

The metabolism of oxygen in aerobic organisms leads to generation of reactive oxygen species (ROS). These entities are able to oxidize almost all classes of macromolecules, including proteins, lipids and nucleic acids. The physiological level of ROS is usually regulated by antioxidant defense mechanisms. There are at least three groups of antioxidant enzymes: superoxide dismutases, catalases and glutathione peroxidases (GSH-Pxs) which neutralize ROS. The trace elements (copper, zinc and selenium) bound to the active sites of the above listed enzymes play an important role in the antioxidant defense system. In mammals, a major function of selenium (Se) and Se-dependent GSH-Pxs is to protect cells from oxidative stress. Selenium concentrations and GSH-Px activities are altered in blood components of chronic kidney disease (CKD) patients. The Se level is frequently lower than in healthy subjects and the concentration very often decreases gradually with advancing stage of the disease. Studies on red cell GSH-Px activity in CKD patients reported its values significantly lower, significantly higher and lower or higher, but not significantly as compared with healthy subjects. On the other hand, all authors who studied plasma GSH-Px activity have shown significantly lower values than in healthy subjects. The degree of the reduction decreases gradually with the progression of the disease. High inverse correlations were seen between plasma GSH-Px activity and creatinine level. A gradual decrease in plasma GSH-Px activity in CKD patients is due to the fact that this enzyme is synthesized predominantly in the kidney and thus the impairment of this organ is the cause of the enzyme's lower activity. Se supplementation to CKD patients has a slightly positive effect in the incipient stage of the disease, but usually no effect was observed in end-stage CKD. Presently, kidney transplantation is the only treatment that may restore plasma Se level and GSH-Px activity in patients suffering from end-stage CKD. A few studies have shown that in kidney recipients, plasma Se concentration and GSH-Px activity are restored to normal values within a period of 2 weeks to 3 months following surgery and thus it can be acknowledged that Se supplementation to those patients has a positive effect on plasma GSH-Px activity.

Erythrocytes↗

Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer.

Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer.

Adult↗

Expression of c-fos and oxidative stress on brain of rats reared on food from mercury-selenium coexisting mining area.

Wanshan mercury mine is the largest mercury deposit in Guizhou Province of China, but there were few reports on mercury toxic effect in the mining area. In order to study the neurotoxicity of food from Wanshan mercury mine area and probe into the effect of food from Wanshan mercury miner area on the changes of brain oxidative damage and expression of c-fos gene. The rats were exposed to mercury contaminated food for 20 d. The content of malondialdehyde (MDA), superoxide dismutase (SOD), GSH-peroxidase (GSH-px) and Glutathione (GSH) in rat brain was measured, and the effect of mercury contaminated rice on the expression of c-fos mRNA in rat brain and the expression of c-FOS protein in cortex, hippocampus were observed using reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemical methods. The results showed the levels of GSH, MDA, SOD and of GSH-dependent enzymes in the rat brain changed between exposure groups and control group; The mercury polluted rice induced significantly the expression of c-fos mRNA; the c-FOS positive cells in hippocampus and cortex of exposure groups were significant different from control group (P<0.01). It could be concluded that oxidative stress signals could contribute to the induction of immediate early genes (IEGs); free radicals and their by-products might not only cause oxidative damage, but also influenced gene expression; IEGs c-fos participated in the toxicity process of brain injury by mercury polluted food.

Animals↗

Selenium supplementation and diet induced hypercholesterolemia in the rat: changes in lipid levels, malonyldialdehyde production and the nitric oxide synthase activity.

Male Sprague Dawley rats were divided into three groups, viz (I) Controls, (II) High fat diet (HFD) fed, (III) HFD fed+selenium supplemented. After three months of treatment, there were significant increases in serum cholesterol and triglycerides in HFD fed group as compared to control. However, in Se supplemented group, the levels of serum cholesterol and triglycerides were significantly less as compared to group II. Selenium-dependent glutathione peroxidase (GSH-Px) activity in the liver and the aorta increased significantly in HFD fed animals and also showed additional significant increase on selenium supplementation. Malonyldialdehyde (MDA) concentrations in serum, liver and aorta and the activity of nitric oxide synthase (NOS; evident from reactive nitrogen intermediates and citrulline levels) in plasma showed significant increases in HFD fed group. However, supplementation of selenium led to a significant reduction in the levels of these parameters vis-a-vis HFD fed animals except in MDA levels in the serum and the liver where this decrease was non-significant. The important finding of this study is that selenium supplementation modulates the sequences favoring pathogenesis of atherosclerosis.

Animals↗

Selenium is effective in inducing lymphocyte progression through cell cycle in cancer patients: potential mechanisms for its activity.

Epidemiologic evidence in humans suggests a role for selenium in reducing cancer incidence and mortality. The aim of the present study was that to assess the ability of selenium dioxide (SeO2) to enhance the lymphocyte progression through the cell cycle in patients with advanced (stage IV) cancer. Ten patients (mean age 51.9 years, range: 32-74; M/F ratio: 3/7) with tumors at different sites were included in the study. The addition into culture of SeO2 1.5 microM enhanced significantly the progression into S phase of PBMCs isolated from cancer patients, whilst no significant effect was observed on PBMCs isolated from controls. ROS levels were significantly higher, whereas GPx activity was significantly lower in cancer patients than controls. Serum levels of IL-6 and TNFalpha were significantly higher in cancer patients than controls. Our results show the ability of selenium to induce a progression of PBMCs from cancer patients into the cell cycle, which is an essential prerequisite for the physiological functioning of the immune system and thus positively influence the immune status of advanced cancer patients. The mechanism of action of selenium could be to downregulate the production and release of proinflammatory cytokines, which have a role in cancer progression and particularly in the onset of cachexia.

Adult↗

Effect of dietary selenium on the induction of altered hepatic foci and hepatic tumors by the peroxisome proliferator ciprofibrate.

The purpose of this study was to determine if the dietary antioxidant selenium could inhibit hepatocarcinogenesis induced by peroxisome proliferators, which are hypothesized to induce tumors by increased production of hydrogen peroxide or other reactive oxygen species. Rats were fed diets containing the peroxisome proliferator ciprofibrate and one of three concentrations (0.04, 0.2, or 1.0 ppm) of selenium for 6 or 21 months. The incidence of hepatic tumors and the number and volume of gamma-glutamyl transpeptidase-positive, ATPase-negative, glucose-6-phosphatase-negative, and glucose-6-phosphatase-positive foci at 21 months were lower in rats fed higher levels of selenium (no foci or tumors were seen at 6 mo). Indices of oxidative damage in the liver (thiobarbituric acid reactants, conjugated dienes, and lipid-soluble fluorescence products), however, were not decreased in rats fed the high-selenium diet. Therefore, selenium was protective against ciprofibrate-induced hepatocarcinogenesis, but not by reducing the degree of oxidative damage. The liver selenium and glutathione concentrations, and liver selenium-dependent glutathione peroxidase activity, increased as dietary selenium increased. Therefore, inhibition of carcinogenesis by selenium was correlated with increased levels of glutathione and glutathione peroxidase, but these did not inhibit the indices of oxidative damage. Peroxisomal beta-oxidation also increased with the dietary selenium content; it therefore does not appear to be a factor in the inhibition of hepatocarcinogenesis in rats fed higher levels of selenium.

Analysis of Variance↗

Protection of vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, coenzyme Q0, coenzyme Q10, beta-carotene, canthaxanthin, and (+)-catechin against oxidative damage to rat blood and tissues in vivo.

Male Sprague-Dawley rats were fed either a vitamin E and selenium deficient diet, a diet supplemented with vitamin E and selenium, or a diet supplemented with vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, Beta-carotene, canthaxanthin, coenzyme Q0, coenzyme Q10, and (+)-catechin. Rats were injected with CBrCl3 (0.05 mmol/100 g body weight) intraperitoneally. Oxidative damage to tissues was measured by formation of oxidized heme proteins (OHP) in blood, liver, kidney, heart, lung, and spleen. Diets supplemented with antioxidants showed protection against oxidative damage caused by CBrCl3. The protection was dependent on the diversity and quantity of antioxidants in the diet. In general, diets supplemented with both fat soluble and water soluble antioxidants provided better protection than diets supplemented only with vitamin E and selenium or with vitamin E, selenium, and fat soluble antioxidants.

Acetylcysteine↗

[Selenium concentration and activity of glutathione peroxidase in lysate of human erythrocytes].

The concentration of selenium in human red cells was measured by a fluorometric determination method after wet digestion of the biological material. In the red cells from the same blood samples the activity of the selenoenzyem glutathione peroxidase (EC 1.11.1.9) was determined with tertiary butyl hydroperoxide as acceptor substrate. The results show that only 10% of the total selenium content of human red cells is fixed to the enzyme. No correlation between the enzyme activity and the selenium concentration could be found. On the basis of these results can be presumed that the protective effect of selenium in glutathione peroxidase against oxidant damage of cells is not the only biological function of this element.

Erythrocytes↗

4-Hydroxynonenal is markedly higher in patients on a standard long-term home parenteral nutrition.

Parenteral nutrition, a commonly used procedure in patients with gastrointestinal disorders, may lead with time to liver steatosis and fibrosis, whose pathogenesis has yet to be elucidated. Oxidative stress and particularly lipid peroxidation likely contribute to the expression of such hepatobiliary complications, by means of their recognized proinflammatory and profibrogenic effects. To evaluate the adequacy against oxidative insult of a standard micronutrient supplementation in patients under long term parenteral nutrition, a comprehensive patterns of redox indices has been determined on peripheral blood samples from forty one adults in comparison to fifty eight blood donors taken as controls. A sustained oxidative stress in peripheral blood of home parenteral patients was observed. Of the two lipid peroxidation markers found to be markedly increased, namely fluorescent plasma protein adducts with malondialdehyde and 4-hydroxynonenal, respectively, only the second was statistically correlated with all the antioxidant-related changes consistently detected in the patients, namely decreased plasma alpha-tocopherol and selenium intake and higher erythrocyte oxidized glutathione. Plasma level of 4-hydroxynonenal-protein adducts appears to be a reliable and easily measurable marker of oxidative status, particularly indicated to monitor the adequacy of dietary regimen during parenteral nutrition.

Adult↗