Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT03226 (vitamin E)
 17,558 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this investigation was to find out whether vitamin E deficiency, apart from influencing the lipid component of cellular membranes, also influences the protein component. For that purpose a number of membrane-bound enzymes in the liver of the Pekin duckling were histochemically, cytochemically, and biochemically examined. Furthermore, cells, cellular membranes, and protein particles in membranes were morphometrically investigated. Histochemically five membrane-bound enzymes appeared to be stimulated in vitamin E deficiency: 5'-nucleotidase, glucose-6-phosphatase, isocitrate dehydrogenase (NADP), tetrazolium reductase (NADH), and tetrazolium reductase (NADPH). 5'-Nucleotidase and glucose-6-phosphatase were also investigated cytochemically and biochemically. The cytochemical localization of these enzymes was identical in control and vitamin E-deficient ducklings. Biochemically, a stimulation of these two enzymes also could be demonstrated. The increase per milligram of DNA appeared to be largest whereas the increase per milligram of protein, per milligram of phospholipid, and per milligram of RNA was only half of the increase per milligram of DNA. This can be explained by the 30 per cent increase of the cell volume in vitamin E deficiency leading to an increase of protein, phospholipid, and RNA per cell. The thickness of membranes and the diameter of protein particles in membranes were measured in liver parenchymal cells. In vitamin E deficiency the thickness of the outer mitochondrial membrane and the diameter of protein particles in this membrane were smaller whereas the thickness of the endoplasmic reticular membrane was larger. The increase of the activities of mitochondrial and microsomal enzymes and the decrease of the thickness of the outer mitochondrial membrane and of its protein particles are interpreted to be the result of the influence of free radicals on membranes with electron transport functions. The increase of 5'-nucleotidase activity in the plasma membrane is likely to have a different cause; it may be related to the transport of nucleotides across this membrane.
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PMID:Cellular membranes and membrane-bound enzymes in vitamin E deficiency. A histochemical, cytochemical, biochemical, and morphologic study of the liver of the Pekin duckling. 16 37

Toxic doses of butylated hydroxytoluene (BHT), a phenolic antioxidant commonly used as a food additive, are known to produce lung damage. In this study, 3 days after a single ip injection of 62.5, 215, or 500 mg/kg BHT in mice there was a dose-dependent increase in lung weight. This concentration dependence with injected BHT was accompanied by increases in lung DNA and nonprotein sulfhydryl levels and in whole lung tissue enzyme activities of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and superoxide dismutase. The increased enzyme activities are considered to correspond to inflammatory and proliferative pulmonary changes resulting from acute lung cell injury and necrosis, which have been described previously, and cannot be construed as evidence for a primary oxidant-induced pulmonary lesion. The mechanism of BHT-induced lung changes may not be related to the antioxidant property of BHT, since vitamin E, n-propyl gallate, ethoxyquin, N,N'-p-phenylenediamine, and the structurally similar compound, butylated hydroxyanisole did not appear to produce the gross anatomical or biochemical lung changes observed with BHT.
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PMID:Effect of butylated hydroxytoluene and other antioxidants on mouse lung metabolism. 59 82

Two sets of experiments were performed to investigate the nonantioxidant functions of alpha-tocopherol. Eighteen rabbits in the first set and 48 rabbits in the second set were equally divided into three groups. The first group received a basal tocopherol-deficient diet supplemented with all-rac-alpha-tocopherol for 3 wk and the second group was fed the basal diet. The third group received vitamin E supplementation for 1 wk after 2 wk of consuming a tocopherol-deficient diet. In the first set of animals, skeletal muscle concentration, metabolism and turnover of various adenine nucleotides were measured by incubating the muscles of the three groups with [8-3H]adenine. The second set of experiments investigated in vivo concentration of various adenine nucleotides before incubation with radioactive substrate and quantity of newly formed adenine nucleotides after incubation with four different specific radioactive substrates: [8-14C]ATP; [8-14C]cAMP; [8-14C]5'AMP and [8-14C]adenosine. The results expressed per milligram of DNA were compared between the tocopherol-supplemented and tocopherol-deficient rabbits. Cyclic-AMP concentration (measured after a 2-h incubation with [8-3H]adenine) was lower and 5'-AMP concentration was very high in the tocopherol-deficient rabbits. The results of incorporation studies indicated that the turnover of ATP + ADP, cAMP, 5'-AMP and adenosine was higher in the tocopherol-deficient rabbits. Administration of tocopherol to tocopherol-deficient rabbits restored the turnover of cAMP to nearly normal values. These observations provided new insights concerning nonantioxidant functions of alpha-tocopherol.
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PMID:Turnover of cyclic adenosine-5'-monophosphate is elevated in skeletal muscle of vitamin E-deficient rabbits. 132 14

The ether lipid antineoplastic agents have no known interaction with DNA, but rather they appear to target membranes. The primary mechanism of action is unknown but effects on membrane biology are documented. We have studied the effect of two ether lipids on membrane lipids and examined the hypothesis that membrane peroxidative damage may be involved in their mechanism of action. With the use of cells having membranes enriched in polyunsaturated fatty acids of the omega-3 family of fatty acids, we have demonstrated that the prototypical ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine and a thioether lipid analogue, 1-O-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine , increase membrane lipid peroxidation and cytotoxicity in a time- and drug concentration-dependent manner. The oxidative cofactors Fe2+ and ascorbic acid were required. The pattern of cell death did not fully correspond to the peroxidation, since cofactors were required for peroxidation but not cytotoxicity. However, the rate of decrease in cell viability after exposure to the drug and cofactors corresponded to the peroxidation rate. In addition, when L1210 cells modified with the monounsaturated fatty acid oleic acid or unmodified cells were used, there was no ether lipid-enhanced peroxidation, and the cells were significantly less sensitive to the drug, with or without cofactors. The lipid-soluble antioxidant vitamin E inhibited 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine peroxidation and cytotoxicity in a concentration-dependent manner in the presence of cofactors but not consistently without them. Depletion of cellular glutathione content of L1210 cells using L-buthionine-(SR)-sulfoximine resulted in 40% augmentation of cofactor-facilitated cytotoxicity of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine and a borderline effect on peroxidation. Another ether lipid, the thio compound 1-O-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine , enhanced peroxidation in the presence of cofactors with kinetics corresponding to those of cytotoxicity. In the presence of ether lipid and cofactors the intensity of ascorbate free radical increased, consistent with oxidative stress. We conclude that the ether lipids stimulate membrane lipid peroxidation in a time- and drug concentration-dependent manner in the presence of oxidative cofactors. Even though peroxidation may not fully explain the cytotoxic effect of the ether lipid class of anticancer drugs, this observation provides further information on the nature of the membrane damage induced by the drugs. Since the ether lipids generate no known free radical intermediates directly, this suggests that membrane damage indirectly results in a process involving a peroxidative reaction.
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PMID:Membrane peroxidative damage enhancement by the ether lipid class of antineoplastic agents. 139 29

The tumor-enhancing effect of hydrogen peroxide (H2O2) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated rainbow trout hepatocarcinogenesis was investigated and correlated with the levels of the mutagenic DNA adduct 8-hydroxy-2'-deoxyguanosine (oh8dG). In addition, the protective role of vitamin E was examined in relation to tumor enhancement and oh8dG levels in liver DNA. Trout were fed diets containing two levels of vitamin E (1000 or 20 mg/kg wet wt), each of which were made up to contain three levels of H2O2 (0, 600 or 3000 p.p.m.). Dietary vitamin E levels had no significant effect on tumor incidence or levels of oh8dG in liver DNA. On the other hand, dietary H2O2 enhanced liver tumors in a dose-dependent manner. Liver tumor incidence correlated significantly with the mean level of liver DNA oh8dG content (r = 0.87). We conclude that the H2O2 tumor-enhancing effect coincides with higher levels of oh8dG in the trout liver genome. Thus, rainbow trout may be a useful model for the study of the relationship of oh8dG levels in vivo to enhancement or promotion of carcinogenesis and its modulation by dietary enhancers and inhibitors of oxidative stress.
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PMID:Dietary hydrogen peroxide enhances hepatocarcinogenesis in trout: correlation with 8-hydroxy-2'-deoxyguanosine levels in liver DNA. 139 49

Tocopherols and tocotrienols (vitamin E) and ascorbic acid (vitamin C) as well as the carotenoids react with free radicals, notably peroxyl radicals, and with singlet molecular oxygen (1O2), this being the basis of their function as antioxidants. RRR-alpha-tocopherol is the major peroxyl radical scavenger in biological lipid phases such as membranes or low-density lipoproteins (LDL). L-Ascorbate is present in aqueous compartments (e.g. cytosol, plasma, and other body fluids) and can reduce the tocopheroxyl radical; it also has a number of metabolically important cofactor functions in enzyme reactions, notably hydroxylations. Upon oxidation, these micronutrients need to be regenerated in the biological setting, hence the need for further coupling to nonradical reducing systems such as glutathione/glutathione disulfide, dihydrolipoate/lipoate, or NADPH/NADP+ and NADH/NAD+. Carotenoids, notably beta-carotene and lycopene as well as oxycarotenoids (e.g. zeaxanthin and lutein), exert antioxidant functions in lipid phases by free-radical or 1O2 quenching. There are pronounced differences in tissue carotenoid patterns, extending also to the distribution between the all-trans and various cis isomers of the respective carotenoids. Antioxidant functions are associated with lowering DNA damage, malignant transformation, and other parameters of cell damage in vitro as well as epidemiologically with lowered incidence of certain types of cancer and degenerative diseases, such as ischemic heart disease and cataract. They are of importance in the process of aging. Reactive oxygen species occur in tissues and cells and can damage DNA, proteins, carbohydrates, and lipids. These potentially deleterious reactions are controlled in part by antioxidants that eliminate prooxidants and scavenge free radicals. Their ability as antioxidants to quench radicals and 1O2 may explain some anticancer properties of the carotenoids independent of their provitamin A activity, but other functions may play a role as well. Tocopherols are the most abundant and efficient scavengers of peroxyl radicals in biological membranes. The water-soluble antioxidant vitamin C can reduce tocopheroxyl radicals directly or indirectly and thus support the antioxidant activity of vitamin E; such functions can be performed also by other appropriate reducing compounds such as glutathione (GSH) or dihydrolipoate. The biological efficacy of the antioxidants is also determined by their biokinetics.
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PMID:Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. 144 60

The effect of pretreatment with vitamin E on cytotoxicity, DNA single strand breaks, and chromosomal aberrations as well as on mutation induced by ultraviolet-B light (UV-B) was investigated in Chinese hamster V-79 cells. Cellular pretreatment with non-toxic levels of 25 microM alpha-tocopherol succinate (vitamin E) for 24 h prior to exposure resulted in a 10-fold increase in cellular levels of alpha-tocopherol. Using a colony-forming assay, this pretreatment decreased the cytotoxicity of UV-B light. However, alkaline elution assays demonstrated that pretreatment with vitamin E did not affect the number of DNA single strand breaks caused by UV-B light. In addition, UV-B exposure produced a dose-dependent induction of chromosomal aberrations and mutations at the HGPRT locus, and neither of these actions of UV-B was influenced by pretreatment with the vitamin. These results suggest that vitamin E protects cells from UV-B-induced cytotoxicity, possibly through its ability to scavenge free radicals. The results also suggest that the extent of genotoxicity induced by UV-B light may not correlate directly with the cytotoxic action of this wavelength region in sunlight.
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PMID:Effect of vitamin E on cytotoxicity, DNA single strand breaks, chromosomal aberrations, and mutation in Chinese hamster V-79 cells exposed to ultraviolet-B light. 150 80

Feeding rainbow trout for 16 weeks a diet in which the levels of vitamin E were reduced 70-fold resulted in marked depletion (18-fold) of vitamin E levels in liver microsomes from these fish. The susceptibility of hepatic microsomes to lipid peroxidation in vitro and the levels of plasma and liver microsomal lipid hydroperoxides generated in vivo were markedly elevated in vitamin E-depleted trout. No appreciable alterations were observed in the liver microsomal cytochrome P450-dependent mixed-function oxidase system or in the fatty acid composition of trout liver microsomal membranes. Livers from rats fed a vitamin E-deficient diet for 10 weeks also had significantly lower levels of microsomal vitamin E. In addition, total cytochrome P450 levels were depressed (15%) and cytosolic glutathione was enhanced (40%) in livers from rats fed the vitamin E-depleted diet. Covalent binding of [3H]-(+)-benzo[a]pyrene-7,8-dihydrodiol to exogenous DNA in vitro was enhanced with liver microsomes from vitamin E-deficient trout and these fish were much more sensitive to the acute toxicity of this carcinogenic polycyclic aromatic hydrocarbon. These results indicate that trout may be a useful model for studying the significance of peroxidative pathways in carcinogenesis and their manipulation by dietary antioxidants.
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PMID:Alterations in lipid peroxidation, antioxidant enzymes, and carcinogen metabolism in liver microsomes of vitamin E-deficient trout and rat. 152 56

Since the introduction of paraquat (PQ) as a herbicide in 1963, there have been many speculations concerning the critical lesion in PQ toxicity. Damage to membrane lipids might be an initial event leading to PQ-induced cell killing. The ability of PQ to induce lipid peroxidation was tested in liver homogenates of the mouse. Lipid peroxidation was indeed induced by PQ and shown to be dose dependent, starting to be significant at 2.5 mM. Subsequently, a possible correlation between lipid peroxidation and PQ-induced cell death was investigated in mouse fibroblasts (LM) and Ehrlich ascites tumour (EAT) cells using a clonogenic assay. It was found that in order to be cytotoxic PQ needs enzymatic activation (incubation at 37 degrees). In both cell lines, PQ-induced cell killing appeared to be dose dependent, starting at a dose of 0.5 mM. Supplementation of LM cells with the antioxidant vitamin E had no effect on PQ-induced cell killing and modification of the membranes of LM cells by incorporation of the polyunsaturated fatty acid 20:4 (arachidonic acid) did not sensitize the cells to PQ toxicity. PQ had no effect on the glutathione (GSH) level in EAT cells and complete GSH depletion by DL-buthionine-(SR)-sulfoximine could not sensitize the cells to PQ toxicity. In LM cells PQ-induced cell killing was enhanced after complete GSH depletion by DEM. This sensitization might, however, be attributed to the binding of DEM to proteins. From these results it seems unlikely that lipid peroxidation is the primary cause for PQ-induced cell killing. Another critical target in PQ toxicity is DNA. This possibility was investigated in EAT cells. PQ was found to induce DNA damage (detected by the alkaline unwinding assay) in the same dose range that caused cell death. A good correlation was obtained for cell killing after PQ treatment and DNA damage measured 2 hr after 37 degrees post-incubation. A proposed possible interaction between PQ and X-rays was also investigated. In EAT cells, X-ray-induced cell death was significantly enhanced by pre-incubation with PQ at doses of 0.5 mM and above. At the level of 10% survival an enhancement factor of 1.6 could be observed by treatment with 1 mM PQ when cell killing by PQ is not taken into account. Induction as well as processing of radiation-induced DNA damage seems to be unaffected by pre-incubation with PQ. The mechanism of radiosensitization by PQ is yet unclear.
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PMID:Role of lipid peroxidation and DNA damage in paraquat toxicity and the interaction of paraquat with ionizing radiation. 154 Feb 24

The roles of glutathione (GSH), cysteine, vitamin C, liposome-encapsulated superoxide dismutase (L-SOD) and vitamin E in preventing oxidative DNA damage and cytotoxicity in the rat kidney after administration of potassium bromate (KBrO3) to male F344 rats were investigated by measuring 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative DNA product, lipid peroxidation (LPO) levels and relative kidney weight (RKW). Combined pre- and posttreatment of animals with 2 x 800 mg/kg GSH i.p. inhibited the increase of 8-OH-dG, LPO levels and RKW caused by 80 mg/kg KBrO3 i.p. administration. In contrast, pretreatment with 0.3 ml/kg diethylmaleate (DEM) i.p., a depletor of tissue GSH, was associated with elevation of 8-OH-dG, LPO levels and RKW after a 20 mg/kg KBrO3 i.p. treatment, which itself caused no change. Administration of KBrO3 itself reduced renal non-protein thiol levels, but this was inhibited by the two doses of exogenous GSH. Combined treatment with DEM and KBrO3 lowered the non-protein thiol level in the kidney more than did DEM treatment alone. Protective effects against the oxidative damage caused by KBrO3 were also observed for pre- and posttreatment with 400 mg/kg cysteine i.p., another sulfhydryl compound, and daily i.g. application of 200 mg/kg vitamin C for 5 days. However, no influence was evident after pre- and posttreatment with 18,000 U/kg L-SOD i.p. or daily i.g. 100 mg/kg of vitamin E for 5 days. The results suggest that intracellular GSH plays an essential protective role against renal oxidative DNA damage and nephrotoxicity caused by KBrO3.
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PMID:The protective role of glutathione, cysteine and vitamin C against oxidative DNA damage induced in rat kidney by potassium bromate. 154 73


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