Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation of ascorbate radicals, identified by ESR experiments, was observed in the ascorbate peroxidase reaction by thyroid microsomes. The steady-state concentration of ascorbate radicals decreased in the presence of NADH. The oxidation of NADH was followed optically. Using the ascorbic acid oxidase system, NADH-dependent electron transport in thyroid microsomes was examined. Ascorbate radicals competed with bound cytochrome b5 for the reaction with reduced NADH-cytochrome b5 reductase. The NADH-ascorbate radical reductase activity of thyroid microsomes was calculated to be 0.17 mumol/mg.s at 3.3 microM ascorbate radicals. Kinetic results show that the properties of NADH-cytochrome b5 reductase in thyroid microsomes were similar to those of the enzyme in liver microsomes. The formation of ascorbate radicals by thyroid microsomes was stimulated by the addition of thyroxine, and the stimulation was decreased also by NADH. The thyroxine-mediated oxidation of ascorbate is explained in terms of consecutive one-electron transfers initiated by bound thyroid peroxidase. These results, along with those described in our previous paper (M. Nakamura, I. Yamazaki, and S. Ohtaki, 1990, J. Biochem. 108, 804-810), support the idea that ascorbate protects thyroid hormones from oxidative degradation through the NADH-cytochrome b5 reductase system.
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PMID:Formation and reduction of ascorbate radicals by hog thyroid microsomes. 839 46

The one-electron oxidation of a reduced nitroxide (2,2,6,6-tetramethyl-1,4-dihydroxypiperidine, TOLH), detected by ESR, was used to resolve and quantify oxidants arising from the reaction of heme proteins with hydroperoxides, including chelatable iron released subsequent to oxidative cleavage of the porphyrin ring. Released iron was distinguished from protein radicals and ferryl heme by analyzing TOLH oxidation in the presence of different chelating agents. Metmyoglobin (metMb) treatment with one mole of H2O2 per mole of heme produced protein-bound oxidants that oxidized about two molecules of TOLH per heme. Some of the oxidizing species responsible for TOLH oxidation were highly persistent (t1/2 for the decay was 3 hrs at 25 degrees C). Iron release, metMb bleaching and the catalysis of Fenton-type chemistry were compared in metMb solutions treated with tert-butyl hydroperoxide (tBH). Iron release required about five-fold higher hydroperoxide concentrations than did metMb bleaching. Alkoxyl and methyl radical production was catalyzed by iron released from metMb but not by protein-bound iron in oxidized metMb solutions treated with tBH and ascorbic acid. The results suggest that ascorbate-mediated hydroxyl and alkoxyl radical production by hydroperoxide-treated metMb is due to released iron and that the protein-bound non-heme iron that arises during bleaching is at most a weak Fenton reagent.
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PMID:Hydroxyl and alkoxyl radical production by oxidation products of metmyoglobin. 839 72

SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared. (1) SR 4233 did not affect hepatocyte viability (as determined by plasma membrane disruption) or glutathione levels under aerobic conditions. SR 4233 however induced cyanide-resistant respiration, an indicator of redox cycling mediated oxidative stress and became cytotoxic if hepatocyte catalase or glutathione reductase was inactivated. Glutathione oxidation occurred well before cytotoxicity ensued. Addition of ascorbate markedly enhanced SR 4233 cytotoxicity to these compromised hepatocytes. (2) In contrast, SR 4233 was highly toxic to hypoxic hepatocytes. Addition of ascorbate to enhance SR 4233 reduction also caused a marked increase in hepatocyte toxicity and an SR 4233 radical was detected with ESR spectroscopy. SR 4233 cellular reduction and toxicity was prevented with fructose or inhibitors of NADPH:cytochrome P-450 reductase. Inactivation of catalase or glutathione reductase had no effect on SR 4233 toxicity and hepatocyte GSH was not oxidised indicating oxidative stress did not occur during hypoxic SR 4233 hepatocyte toxicity. (3) The lack of SR 4233 cytotoxicity under aerobic conditions could probably be attributed to the detoxification of the SR 4233 radical by mitochondrial oxidation as SR 4233, but not its metabolite SR 4317 markedly increased state III and IV mitochondrial respiration in the presence of NADH. The increased respiration was inhibited by the respiratory inhibitors KCN and antimycin A but not by rotenone. Furthermore SR 4233 cytotoxicity under aerobic conditions was markedly increased by partially inhibiting hepatocytes respiration with cyanide but not rotenone.
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PMID:Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions. 839 29

Sodium 5,6-benzylidene ascorbate (SBA) is a conjugate of ascorbic acid (Asc) with benzyaldehyde. It has been found that the antioxidant activity of SBA is more stable and has a longer lifetime in living cells and organs than Asc. In this study, we investigated the effect of SBA on the induction of melanin in cultured melanoma (B-16) cells irradiated by UV-A. Melanin content of B-16 cells was significantly increased by UV-A irradiation. The induction was abolished by mannitol and particularly by superoxide dismutase, suggesting the involvement of O2- in the biosynthesis of melanin in cultured melanoma cells. This was theorized by the fact that the induction was also observed in B-16 cells treated with superoxide anion radicals chemically generated in the hypoxanthine/xanthine oxidase-reaction system, instead of UV-A irradiation. The induction of melanin caused by UV-A irradiation was suppressed by SBA in a dose-dependent manner. To elucidate the mechanism of this suppressive effect, the scavenging activity against O2-, and the inhibitory effect of SBA on tyrosinase activity were examined. ESR spectrometric analysis showed that SBA strongly scavenged O2-, and the presence of SBA in the medium remarkably inhibited the tyrosinase activity in cultured B-16 melanoma cells. It can be concluded that SBA effectively inhibits the melanin biosynthesis in B-16 melanoma cells induced by reactive oxygen species (ROS) generated by UV-A irradiation via tyrosinase.
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PMID:Inhibitory effect of sodium 5,6-benzylidene ascorbate (SBA) on the elevation of melanin biosynthesis induced by ultraviolet-A (UV-A) light in cultured B-16 melanoma cells. 853 99

Isolated rat-liver nuclei were incubated with a series of membrane-permeable metal-ion-complexing agents and examined for DNA damage. Of the reagents tested, only 1,10-phenanthroline (OP) and neocuproine (NC) were found to induce DNA fragmentation. Agarose-gel electrophoresis of the DNA fragments generated in the presence of OP revealed internucleosomal cleavage, which is widely considered to be a hallmark for the enzymic DNA digestion that occurs during apoptosis. Ascorbate, particularly in the presence of hydrogen peroxide, increased the levels of fragmentation induced by OP. As well as undergoing fragmentation, the DNA from nuclei was also found to contain 8-hydroxydeoxyguanosine, which indicates attack (oxidation) by the hydroxyl radical. Complementary experiments in vitro involving ESR determinations of hydroxyl radical formation and measurements of DNA oxidation under biomimetic conditions demonstrated that Cu2+, but not Fe3+, forms a complex with either OP or NC (but not the other complexing agents tested) that stimulates hydroxyl radical formation and DNA damage in the presence of hydrogen peroxide and ascorbate. It is therefore proposed that OP in the nuclei incubations binds to Cu2+, which exists naturally in chromosomes, forming a complex that promotes hydroxyl-radical-dependent DNA fragmentation. These findings demonstrate the promotion of hydroxyl-radical-mediated DNA damage by endogenous Cu2+ and, perhaps more significantly, demonstrate that the internucleosomal DNA 'laddering' that is often used as an indicator of apoptosis may also result from DNA fragmentation by non-enzymic processes.
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PMID:1,10-Phenanthroline stimulates internucleosomal DNA fragmentation in isolated rat-liver nuclei by promoting the redox activity of endogenous copper ions. 854 78

Oxidative DNA damage by NAD(P)H in the presence of metal ions has been characterized by using 32P 5' end-labeled DNA fragments obtained from human p53 tumor suppressor gene and c-Ha-ras-1 protooncogene. NADH, as well as other endogenous reductants, induced DNA damage in the presence of Cu(II). The order of inducing effect on Cu(II)-dependent DNA damage was ascorbate > reduced glutathione (GSH) > NADH > NADPH. Although NADH caused no or little DNA damage in the presence of Fe(III)-EDTA, the addition of H2O2 induced the DNA damage. The Cu(II)-mediated DNA damage induced by NADH was inhibited by catalase and bathocuproine, a Cu(I)-specific chelator; but not by scavengers of hydroxyl free radical (.OH), suggesting the involvement of active species derived from hydrogen peroxide (H2O2) and Cu(I) rather than .OH. The predominant cleavage sites were thymine residues located 5' and/or 3' to guanine. The cleavage pattern was similar to that induced by Cu(II) plus GSH, Cu(II) plus ascorbate, or Cu(I) plus H2O2. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine by NADH increased with its concentration in the presence of Cu(II). UV-visible spectroscopy indicated the facilitation of reduction of Cu(II) by NADH under some conditions. ESR spin-trapping experiments and mass spectrometry showed that the carbon-centered radical was formed during the reaction of NADH with Cu(II). These results suggest that optimal molar ratios of DNA/metal ion yield copper with a high redox potential which catalyzes NADH autoxidation to NAD. being further oxidized to NAD+ with generation of superoxide radical and that H2O2 reacts with Cu(I) to form active oxygen species such as copper(I)-peroxide complex causing DNA damage.
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PMID:Site-specific DNA damage induced by NADH in the presence of copper(II): role of active oxygen species. 860 9

Nitric-oxide (NO) can act as both a pro- or an antioxidant, yielding either cytotoxic or protective effects, respectively. The previously unrecognized redox interactions of NO with antioxidants, and not solely its well-known reactions with oxygen radicals, peroxyl radicals and transition metal centers, may be essential for its dual mechanisms in cells. Since the alpha-tocopherol/ascorbate redox cycle is central to antioxidant protection, we studied the direct effects of NO on alpha-tocopherol, ascorbate and combinations thereof in aqueous, micellar environments using ESR spectral and HPLC quantitative techniques. We found that NO does not directly oxidize ascorbate under anaerobic conditions. alpha-Tocopherol, however, in the presence of NO and under anaerobic conditions, was oxidized to the alpha-tocopheroxyl radical. Under conditions where NO oxidized alpha-tocopherol, the subsequent production of the alpha-tocopheroxyl radical depleted ascorbate, yielding the semidehydroascorbyl radical and regenerating alpha-tocopherol. Thus, NO interacts with the redox cycle involving alpha-tocopherol and ascorbate in a pro-oxidant manner.
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PMID:NO-redox paradox: direct oxidation of alpha-tocopherol and alpha-tocopherol-mediated oxidation of ascorbate. 864 66

The spin-trapping technique in conjunction with a low-frequency electron paramagnetic (or spin) resonance (EPR or ESR) spectrometer was used to detect the hemoglobin thiyl free radical in living rats using a whole body resonator. The hemoglobin thiyl free radical was formed following the intragastric administration of phenylhydrazine at the LD50 dose of 188 mg/kg. The hemoglobin thiyl free radical was then trapped by preinjected 5,5-dimethyl-1-pyrroline N-oxide (DMPO), which formed the DMPO/hemoglobin thiyl-free radical adduct in the blood. The time course of the in vivo formation and disappearance of the spin adduct was followed. The DMPO/hemoglobin thiyl free radical was detected in blood samples using 9.5 GHz (X-band) and 1.1 GHz (L-band) EPR at room temperature and 77 K. Pretreatment of rats with ascorbate and diethylmaleate (DEM) decreased the signal intensity of the DMPO/hemoglobin thiyl free radical spin adduct. The incubation of ascorbate or DEM at 37 degrees C with rat blood containing preformed DMPO/hemoglobin thiyl radical adduct showed that there was no effect of DEM on the free radical concentration, while ascorbate reduced the radical adduct. This study provided direct evidence of the formation of the DMPO/hemoglobin thiyl free radical in vivo and enabled us to study this formation in living animals free of any artifacts that can occur when using ex vivo methods.
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PMID:Detection of free radical metabolite formation using in vivo EPR spectroscopy: evidence of rat hemoglobin thiyl radical formation following administration of phenylhydrazine. 866 Jun 55

ESR spectroscopy revealed that both the radical intensity and degradation rate of sodium ascorbate were increased with increasing pH. Gallic acid significantly reduced the radical intensity of sodium ascorbate, which in turn reduced the radical intensity of gallic acid. Sodium ascorbate inhibited the apoptosis-inducing activity of gallic acid, and gallic acid inhibited the intracellular incorporation of ascorbic acid. These data suggest that interaction between sodium ascorbate and gallic acid might modify their biological activity.
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PMID:The interaction between two antioxidants, sodium ascorbate and gallic acid: radical intensity and apoptosis induction. 870 42

Sodium ascorbate induced cytotoxicity against human glioblastoma T98G cells in RPMI1640 medium supplemented with fetal bovine serum or human serum samples was studied. Several human serum samples significantly reduced the cytotoxic activity of sodium ascorbate, regardless of sex, age or the disease of the serum donor with or without heat-inactivation of the serum. ESR spectroscopy revealed that this serum effect was not simply due to the alteration of the ascorbyl radical intensity, produced from sodium ascorbate. The present study suggests that the apoptosis-inducing activity of sodium ascorbate might be significantly affected by human serum.
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PMID:Effect of the type of serum in the medium on sodium ascorbate-induced cytotoxicity. 871 24


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