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The effect of vitamin E on the oxidation state of selenium in rat liver.

ABSTRACT: 1. (75)Se as Na(2) (75)SeO(3) was administered orally to rats under different nutritional conditions. 2. The selenium found in the liver subcellular organelle fractions was present in at least three oxidation states: acid-volatile selenium, assumed to be selenide, zinc-hydrochloric acid-reducible selenium, assumed to be selenite, and higher oxidation states of selenium and organic derivatives, called selenate for convenience. 3. The proportion of the total selenium present as selenide present as selenide is susceptible to oxidation in vitro, which can be prevented by the addition of antioxidants in vitro. 4. The proportion of selenide is also directly related to the vitamin E status of the rats, and treatment of vitamin E-deficient rats with vitamin E results in an increase in the proportion of selenide. 5. Freezing the liver in situ before preparation of the organelle fractions did not alter the susceptibility of the selenide proportion to dietary vitamin E, indicating that the observed effects occur in vivo and not as a result of oxidation post mortem. 6. Intravenous administration of Na(2) (75)SeO(3), to rats whose alimentary tract was partially sterilized by neomycin treatment, gave a similar result to that in paragraph 4, indicating that the reduction of selenite to selenide probably occurs in vivo, and that intestinal micro-organisms are not responsible. 7. Treatment of vitamin E-deficient rats with silver produced a fall in the total (75)Se content of the liver, an effect only partially reversed by vitamin E administration. The proportion of the total selenium present as selenide was also lowered by the treatments with silver, and vitamin E significantly reversed this trend in most cases. 8. These results are consistent with the hypothesis that the active form of Se may be selenide and that the selenide may form part of the active centre of an uncharacterized class of catalytically active non-haem-iron proteins that are protected from oxidation in vivo by vitamin E.

SUBMITTER: Diplock AT

PROVIDER: S-EPMC1177073 | biostudies-other | 1971 Aug

REPOSITORIES: biostudies-other

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Project description:1. The liver intracellular distribution of (75)Se, (75)Se(2-) and (75)SeO(3) (2-) formed from orally administered Na(2) (75)SeO(3) was studied in rats given four different dietary treatments. 2. Subcellular fractionation was done by using sucrose density gradients in a B XIV zonal centrifuge rotor, and conditions were established so that separation of lysosomal, mitochondrial, smooth- and rough-surfaced endoplasmic reticulum, and soluble fractions was achieved. 3. Marker enzymes acid phosphatase, succinate-2 - p - iodophenyl - 3 - p -nitrophenyl - 5 - phenyltetrazolium reductase and glucose 6-phosphatase were used, together with electron microscopy, to establish the identity of the fractions. 4. The dietary treatments investigated were: (a) vitamin E-deficient diet for 3 months, re-fed with vitamin E during the terminal 5 days; (b) vitamin E-deficient diet; (c) adequate diet; (d) vitamin E- and selenium-deficient diet, re-fed with vitamin E during the terminal 5 days. 5. In adequately fed rats, selenide was particularly associated with the mitochondrial fractions; in vitamin E-deficient rats, little selenide was found and the buoyant density of the mitochondria was increased, whereas re-feeding with vitamin E showed a restoration of the normal pattern. In vitamin E- and selenium-deficient rats, re-fed with vitamin E, there was no tendency for selenide to be localized in the mitochondria. 6. In the microsomal regions of the gradients, adequately fed rats showed a concentration of selenide, particularly in the smooth endoplasmic reticulum fractions, and to a lesser extent in the rough endoplasmic reticulum fractions. This was not observed in vitamin E-deficient rats, and the normal pattern was restored on re-feeding with vitamin E, both in rats given the vitamin E-deficient diet and the vitamin E- and selenium-deficient diet. 7. Some selenide was also found in the soluble fractions, when vitamin E was present, and a substantial proportion of this selenide was found to pass through a dialysis membrane. 8. These results are taken to support our hypothesis that the active form of selenium may be selenide located in non-haem iron-containing proteins, and that the function of vitamin E may be to protect the selenide from oxidation.

Project description:Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10-100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and phase II drug-metabolizing systems, i.e. the AhR/Cyp1a1/Nrf2 pathway in hepatocytes.

Project description:In order to understand the molecular mechanism responsible for the therapeutic potential of vitamin D, we conducted an analysis of the liver transcriptome – a central place of metabolic changes. The experiment was carried out on adult female rats (about one year old), n=18, divided into three experimental subjects, receiving different doses of vitamin D for three months: group I - 0, group II - 1000 U/Kg, group III - 5000 U/Kg. After the experiment, the biochemical and haematological parameters of the blood were evaluated. RNA-seq was used to analyze the changes in the liver transcriptome, and Gene Set Enrichment Analysis (GSEA) was used to identify enrichments in gene expression profiles of experimental groups. qPCR was employed to evaluate the expression of several genes connected to cholesterol biosynthesis, metallothioneins, vitamin D metabolism and others. At the end of the experiment, 25(OH) vitamin D concentrations were as follows: group I: 29 ng/ml, group II 43: ng/ml, group III: 70 ng/mL. Considering blood parameters, we observed a lower platelet count (p<0,008) and significantly higher (p<0.02) number of WBC in rats supplemented with 1000 U/Kg than in rats from group III (5000 U/Kg), but no difference between rats from group I and III were detected in these parameters. Moreover, we noted a trend (p<0.06 ) in total cholesterol concentration, suggesting a linear decrease with increasing doses of vitamin D. RNA-seq analysis did not identify any differentially expressed genes with FDR<0.05 in any of the three comparisons. However, GSEA revealed significant activation of the number of processes and pathways. In the I vs III comparison, the most enriched were the genes from the “metallothionein, and TspO/MBR family” (Enrichment Score=8,170, FDR= 0.00006), the genes associated with “glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity” (Enrichment Score=5.13, FDR<00049) and the genes associated with “Negative regulation of tumour necrosis factor production” (Enrichment score=1.26, FDR0.0064. qPCR analysis identified significant upregulation of Mt1, Mt2 and Orm1 genes in animals receiving high doses of vitamin D (p<0.025, p<0.025, p<0009, respectively). Moreover, significant downregulation of Srebp2 and Insig2 was observed in both experimental groups when compared to the control group (p<0.003, p<0.036, respectively). Our results support the potential of vitamin D supplementation in ameliorating oxidative stress, inflammation and high blood cholesterol and underlie the need for further studies aimed at identifying optimal vitamin D doses with therapeutic effects.

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The effect of vitamin E on the oxidation state of selenium in rat liver.

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