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PubMed1984

Plasma ascorbate concentrations and blood cell dehydroascorbate transport in patients with diabetes mellitus.

Rates of dehydroascorbate uptake by blood granulocytes and mononuclear cells are slower, and plasma ascorbate concentrations are lower, among persons with diabetes mellitus than in nondiabetic subjects. These measurements do not correlate with one another or with simultaneously measured plasma glucose or glycosylated hemoglobin; they do not differ with type of diabetes or mode of treatment. In those diabetic granulocytes that exhibit slow dehydroascorbate uptake, maximal velocity (Vmax) transport rates for dehydroascorbate, 2-deoxyglucose, and 3-O-methylglucose are decreased, each to the same degree, while Km values for transport of these ligands are not different from those observed in nondiabetic cells. Since diffusion of these ligands is facilitated by a common transporter, these observations may reflect decreased numbers of glucose transporters in the plasma membranes of some diabetic leukocytes.

3-O-Methylglucose↗
PubMed2002

Are diabetic neuropathy, retinopathy and nephropathy caused by hyperglycemic exclusion of dehydroascorbate uptake by glucose transporters?

Vitamin C exists in two major forms. The charged form, ascorbic acid (AA), is taken up into cells via sodium-dependent facilitated transport. The uncharged form, dehydroascorbate (DHA), enters cells via glucose transporters (GLUT) and is then converted back to AA within these cells. Cell types such as certain endothelial and epithelial cells as well as neurons that are particularly prone to damage during diabetes tend to be those that appear to be dependent on GLUT transport of DHA rather than sodium-dependent AA uptake. We hypothesize that diabetic neuropathies, nephropathies and retinopathies develop in part by exclusion of DHA uptake by GLUT transporters when blood glucose levels rise above normal. AA plays a central role in the antioxidant defense system. Exclusion of DHA from cells by hyperglycemia would deprive the cells of the central antioxidant, worsening the hyperglycemia-induced oxidative stress level. Moreover, AA participates in many cellular oxidation-reduction reactions including hydroxylation of polypeptide lysine and proline residues and dopamine that are required for collagen production and metabolism and storage of catecholamines in neurons. Increase in the oxidative stress level and metabolic perturbations can be expected in any tissue or cell type that relies exclusively or mainly on GLUT for co-transport of glucose and DHA including neurons, epithelial cells, and vascular tissues. On the other hand, since DHA represents a significant proportion of total serum ascorbate, by increasing total plasma ascorbate concentrations during hyperglycemia, it should be possible to correct the increase in the oxidative stress level and metabolic perturbations, thereby sparing diabetic patients many of their complications.

Ascorbic Acid↗
PubMed2004

Facilitated glucose and dehydroascorbate transport in plant mitochondria.

Ascorbate, dehydroascorbate, and glucose transport was investigated in plant mitochondria and mitoplasts prepared from cultured BY2 tobacco cells. Using a rapid filtration method with radiolabeled ligands, we observed a specific glucose and dehydroascorbate transport, which was temperature and time dependent and saturable. Inhibition of mitochondrial respiration by KCN and the uncoupler 2,4-dinitrophenol did not influence the transport of the investigated compounds. Dehydroascorbate transport was inhibited by glucose and genistein, while glucose uptake was decreased upon 3-O-methyl-glucose, D-mannose, cytochalasin B or genistein addition. On the other hand, a low affinity low capacity ascorbate transport was found. Oxidizing agents (potassium ferricyanide or ascorbate oxidase) increased ascorbate uptake. The results demonstrate the presence of dehydroascorbate and glucose transport in plant mitochondria and suggest that it is mediated by the same or closely related transporter(s).

Ascorbic Acid↗
PubMed1995

Cell death by oxidative stress and ascorbic acid regeneration in human neuroectodermal cell lines.

In this paper, we show that human neuroectodermal cells exposed to 1-5 mM hydrogen peroxide or 10 nM-1 mM ascorbate die by programmed cell death induced by oxidative stress. The cell death by peroxide occurs within 4 h and involves approximately 80% of B-mel melanoma cells, while ascorbate causes cell death of approximately 86% of B-mel cells within 24 h. SK-N-BE(2) neuroblastoma cells are more resistant, 32% and 43% cell death for peroxide and ascorbate, respectively. In all cases, cell death causes hypodiploic DNA staining, evaluated by flow cytometry. Both cell lines can efficiently metabolise ascorbate due to significant levels of NADH-dependent semidehydroascorbate reductase and glutathione-dependent dehydroascorbate reductase. The cell death observed suggests a pro-oxidant, rather than anti-oxidant, role for ascorbic acid at physiological concentrations under these experimental conditions.

Apoptosis↗
PubMed2003

Role of ascorbate in the regulation of nitric oxide generation by polymorphonuclear leukocytes.

We have recently demonstrated that NO-mediated polymorphonuclear (PMN)-dependent inhibition of rat platelet aggregation is significantly enhanced in the presence of ascorbate. Consequently, the present study was undertaken to elucidate the underlying mechanisms involved in ascorbate-mediated potentiation of NO synthesis in PMNs. We observed that ascorbate or its oxidized product, dehydroascorbate (DHA), enhanced NOS activity, as measured by nitrite content, diaminofluorescein fluorescence or conversion of L-[3H]arginine to L-[3H]citrulline in rat, monkey, and human PMNs. The increase in NO generation following ascorbate treatment was due to the intracellular ascorbate as iodoacetamide-mediated inhibition of DHA to ascorbate conversion attenuated the DHA-mediated increase in NO synthesis. The augmentation of NOS activity in the PMN homogenate by tetrahydrobiopterin was significantly enhanced by ascorbate, while ascorbate alone did not influence the NOS activity. Ascorbate-mediated enhancement of NOS activity in the cultured PMNs was significantly reduced in the presence of biopterin synthesis inhibitors. Ascorbate, thus, seems to regulate the NOS activity in the PMNs through tetrahydrobiopterin.

Animals↗
PubMed1999

Ascorbate and dehydroascorbate modulate nitric oxide-induced vasodilations of rat coronary arteries.

Soluble guanylyl cyclase (GC) is a heme-containing protein that is a predominant target of nitric oxide (NO). This study examined whether the reductant, ascorbate (ASC), the oxidant, dehydroascorbate (DHAA), or other redox agents modulated the sensitivity of isolated rat coronary arteries to NO-induced vasodilations. Based on NO measurements with a NO-sensitive electrode, NO dilated the arteries with a pEC50 of 8.24 +/- 0.05. The potency of NO was significantly enhanced in the presence of ASC (pEC50 = 8.70 +/- 0.02) but was diminished in the presence of DHAA (pEC50 = 7.91 +/- 0.15). The potency of NO was not affected by other redox agents including dithiothreitol, beta-mercaptoethanol, diamide, 1-chloro-2,4-dinitrobenzene, ferricyanide, or ferrocyanide. Experiments involving the cyclic guanosine monophosphate (cGMP) analog, 8-Br-cGMP, and the phosphodiesterase inhibitor, isobutyl-methylxanthine, indicated that neither ASC nor DHAA has an effect on the degradation or potency of cGMP. ASC and DHAA also failed to affect vasodilations induced by diltiazem or forskolin. However, ASC and DHAA affected the potency of NO in human mesenteric arteries. The results are consistent with other evidence that ASC and DHAA affect the redox state of GC, and through this modulate arterial sensitivity to NO. This suggests that the regulation of the redox state of GC may be an additional site of modulation of the NO/cGMP pathway.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Oxidative stress induced by ascorbate causes neuronal damage in an in vitro system.

Of particular physiological interest, ascorbate, the ionized form of ascorbic acid, possesses strong reducing properties. However, it has been shown to induce oxidative stress and lead to apoptosis under certain experimental conditions. Ascorbate in the brain is released during hypoxia, including stroke, and is subsequently oxidized in plasma. The oxidized product (dehydroascorbate) is transported into neurons via a glucose transporter (GLUT) during a reperfusion period. The dehydroascorbate taken up by cells is reduced to ascorbate by both enzymatic and non-enzymatic processes, and the ascorbate is stored in cells. This reduction process causes an oxidative stress, due to coupling of redox reactions, which can induce cellular damage and trigger apoptosis. Ascorbate treatment decreased cellular glutathione (GSH) content, and increased the rates of lipid peroxide production in rat cortical slices. Wortmannin, a specific inhibitor of phosphatidylinositol (PI)-3-kinase (a key enzyme in GLUT translocation), prevented the ascorbate induced-decrease of GSH content, and suppressed ascorbate-induced lipid peroxide production. However, wortmannin was ineffective in reducing hydrogen peroxide (H(2)O(2))-induced oxidative stress. The oxidative stress caused ceramide accumulation, which was proportionally changed with lipid peroxides when the cortical slices were treated with ascorbate. These differential effects support the hypothesis that GLUT efficiently transports the dehydroascorbate into neurons, causing oxidative stress.

Androstadienes↗
PubMed2000

The non-oxidative degradation of ascorbic acid at physiological conditions.

The degradation of L-ascorbate (AsA) and its primary oxidation products, L-dehydroascorbate (DHA) and 2,3-L-diketogulonate (2, 3-DKG) were studied under physiological conditions. Analysis determined that L-erythrulose (ERU) and oxalate were the primary degradation products of ASA regardless of which compound was used as the starting material. The identification of ERU was determined by proton decoupled (13)C-nuclear magnetic resonance spectroscopy, and was quantified by high performance liquid chromatography, and enzymatic analysis. The molar yield of ERU from 2,3-DKG at pH 7.0 37 degrees C and limiting O(2)97%. This novel ketose product of AsA degradation, was additionally qualitatively identified by gas-liquid chromatography, and by thin layer chromatography. ERU is an extremely reactive ketose, which rapidly glycates and crosslinks proteins, and therefore may mediate the AsA-dependent modification of protein (ascorbylation) seen in vitro, and also proposed to occur in vivo in human lens during diabetic and age-onset cataract formation.

2,3-Diketogulonic Acid↗
PubMed1980

Subcellular distribution of ascorbate in bovine adrenal medulla. Evidence for accumulation in chromaffin granules against a concentration gradient.

The subcellular distribution of ascorbate and catecholamines has been studied in homogenates of bovine adrenal medulla and cortex. 1. The recovery of the vitamin was found to be 4.10 +/- 0.22 and 9.57 +/- 1.37 mumol/g wet weight for the medulla and cortex, respectively. A major fraction (34.4%) of the vitamin was recovered in the particulate fraction of the medulla as compared to about 8% in the corresponding fraction of the cortex. In comparison, 78.9% of the catecholamines were found in the particulate fraction of the medulla. 2. Analytical differential centrifugation of medulla homogenates revealed a sedimentation profile of ascorbate which was identical to that obtained for noradrenalin and adrenalin. The co-sedimentation of these compounds indicates that ascorbate is an essential component of the heavy as well as the light population of chromaffin granules. The stoichiometry of catecholamines to ascorbate was approx. 25:1 in both subpopulations. 3. Based on an estimated volume fraction of approximately 13% for the chromaffin granules, as determined morphometrically (Kryvi, H., Flatmark, T. and Terland, O. (1979) Eur. J. Cell Biol. 20, 76-82), a concentration gradient (chromaffin granules:cytosol) of approx. 4 was estimated for ascorbate in the cells of adrenal medulla. 4. No ascorbate 2-sulfate was detected in any of the subcellular fractions isolated, and the content of dehydroascorbate in isolated chromaffin granules was less than 1% of the total ascorbate value.

Adrenal Cortex↗
PubMed1998

Oxidative scission of plant cell wall polysaccharides by ascorbate-induced hydroxyl radicals.

Scission of plant cell wall polysaccharides in vivo has generally been assumed to be enzymic. However, in the presence of l-ascorbate, such polysaccharides are shown to undergo non-enzymic scission under physiologically relevant conditions. Scission of xyloglucan by 1 mM ascorbate had a pH optimum of 4.5, and the maximum scission rate was reached after a 10-25-min delay. Catalase prevented the scission, whereas added H2O2 (0.1-10 mM) increased the scission rate and shortened the delay. Ascorbate caused detectable xyloglucan scission above approx. 5 microM. Dehydroascorbate was much less effective. Added Cu2+ (>0.3 microM) also increased the rate of ascorbate-induced scission; EDTA was inhibitory. The rate of scission in the absence of added metals appeared to be attributable to the traces of Cu (2.8 mg.kg-1) present in the xyloglucan. Ascorbate-induced scission of xyloglucan was inhibited by radical scavengers; their effectiveness was proportional to their rate constants for reaction with hydroxyl radicals (.OH). It is proposed that ascorbate non-enzymically reduces O2 to H2O2, and Cu2+ to Cu+, and that H2O2 and Cu+ react to form .OH, which causes oxidative scission of polysaccharide chains. Evidence is reviewed to suggest that, in the wall of a living plant cell, Cu+ and H2O2 are formed by reactions involving ascorbate and its products, dehydroascorbate and oxalate. Systems may thus be in place to produce apoplastic .OH radicals in vivo. Although .OH radicals are often regarded as detrimental, they are so short-lived that they could act as site-specific oxidants targeted to play a useful role in loosening the cell wall, e.g. during cell expansion, fruit ripening and organ abscission.

Ascorbate Oxidase↗
PubMed2004

Ascorbate distribution during hibernation is independent of ascorbate redox state.

Distribution of ascorbate into tissues is an essential process in ascorbate antioxidant defense. Hibernating animals are studied as a model of tolerance to ischemia-reperfusion because of their tolerance to fluctuations in blood flow associated with prolonged torpor and periodic arousal episodes. Throughout hibernation, plasma ascorbate concentration ([Asc](p)) repetitively increases during torpor, then falls during periodic arousal bouts. We previously proposed that high [Asc](p) provides a ready source of antioxidant protection for distribution to the central nervous system and peripheral tissues during arousal. Here we tested whether deliberate oxidation of plasma ascorbate by intravenous administration of ascorbate oxidase (AO), prior to arousal, compromised tissue levels of ascorbate or the other water-soluble antioxidants, glutathione (GSH) and urate. Although AO decreased [Asc](p) to below the level of detection during torpor and after arousal, ascorbate oxidation did not decrease post-arousal tissue levels of reduced ascorbate, glutathione, or urate in any tissue examined, except liver. The data imply that ascorbate is taken up equally well into brain and other tissues as either ascorbate or its oxidized product dehydroascorbate, with subsequent intracellular reduction of dehydroascorbate. Lack of effect of ascorbate oxidation on tissue levels of GSH or urate indicates that dehydroascorbate uptake and reduction do not compromise tissue concentrations of these other water-soluble antioxidants. Thus, we show equal availability of reduced and oxidized plasma ascorbate during metabolically demanding thermogenesis and reperfusion associated with arousal from hibernation.

Animals↗
PubMed1998

Ascorbate and glutathione homeostasis in vascular smooth muscle cells: cooperation with endothelial cells.

Human umbilical vein smooth muscle cells (HUVSMCs) utilize extracellular cystine, glutathione (GSH), and N-acetylcysteine (NAC) to synthesize cellular GSH. Extracellular cystine was effective from 5 microM, whereas GSH and NAC were required at 100 microM for comparable effects. The efficacy of extracellular GSH was dependent on de novo GSH synthesis, indicating a dependence on cellular gamma-glutamyltransferase (glutamyl transpeptidase). Coculture of syngenetic HUVSMCs and corresponding human umbilical vein endothelial cells (HUVECs) on porous supports restricted cystine- or GSH-stimulated synthesis of HUVSMC GSH when supplied on the "luminal" endothelial side. Thus HUVSMC GSH rapidly attained a steady-state level below that achieved in the absence of interposed HUVECs. HUVSMCs also readily utilize both reduced ascorbate (AA) and oxidized dehydroascorbate (DHAA) over the range 50-500 microM. Phloretin effectively blocked both AA- and DHAA-stimulated assimilation of intracellular AA, indicating a role for a glucose transporter in their transport. Uptake of extracellular AA was also sensitive to extracellular, but not intracellular, thiol depletion. When AA was applied to the endothelial side of the coculture model, assimilation of intracellular AA in HUVSMCs was restricted to a steady-state level below that achieved by free access.

Acetylcysteine↗
PubMed2000

Transport and action of ascorbate at the plant plasma membrane.

The plasmalemma is both a bridge and a barrier between the cytoplasm and the outside world. It is a dynamic interface that perceives and transmits information concerning changes in the environment to the nucleus to modify gene expression. In plants, ascorbate is an essential part of this dialogue. The concentration and ratio of reduced to oxidized ascorbate in the apoplast, for example, possibly modulates cell division and growth. The leaf apoplast contains millimolar amounts of ascorbate that protect the plasmalemma against oxidative damage. The apoplastic ascorbate-dehydroascorbate redox couple is linked to the cytoplasmic ascorbate-dehydroascorbate redox couple by specific transporters for either or both metabolites. Although evidence about the mechanisms driving ascorbate or dehydroascorbate transport remains inconclusive, these carrier proteins potentially regulate the level and redox status of ascorbate in the apoplast. The redox coupling between compartments facilitated by these transport systems allows coordinated control of key physiological responses to environmental cues.

Ascorbic Acid↗
PubMed2002

Effects of glutamate on dehydroascorbate uptake and its enhanced vulnerability to the peroxidation in cerebral cortical slices.

Pro-oxidant properties of ascorbate have been studied with uses of brain tissues and neuronal cells. Here we address potential mechanism of ascorbate coupling with glutamate to generate oxidative stress, and the role which oxidized ascorbate (dehydroascorbate) transport plays in oxidative neuronal injury. Ascorbate in neurones can be depleted by adding glutamate in culture medium since endogenous ascorbate can be exchanged with glutamate, which enhances ascorbate/dehydroascorbate transport by depleting ascorbate in the neurons with the glutamate- heteroexchange. However, ascorbate is known readily being oxidized to dehydroascorbate in the medium. Glutamate enhanced the dehydroascorbate uptake by cells via a glucose transporter (GLUT) from extracellular region, and cytosolic dehydroascorbate enhanced lipid peroxide production and reduced glutathione (GSH) concentrations. Iso-ascorbate, the epimer of ascorbate was ineffective in generating the oxidative stress. These observations support the current concept that the high rates of dehydroascorbate transport via a GLUT after the release of ascorbate by glutamate leads to peroxidation, the role of glutamate on ascorbate/dehydroascorbate recycling being critical to induce neuronal death via an oxidative stress in the brain injury.

Animals↗
PubMed2006

Dehydroascorbate reductase affects leaf growth, development, and function.

Ascorbic acid (Asc) is a major antioxidant in plants that detoxifies reactive oxygen species (ROS) and maintains photosynthetic function. Expression of dehydroascorbate reductase (DHAR), responsible for regenerating Asc from an oxidized state, regulates the cellular Asc redox state, which in turn affects cell responsiveness and tolerance to environmental ROS. Because of its role in Asc recycling, we examined whether DHAR is important for plant growth. Suppression of DHAR expression resulted in a preferential loss of chlorophyll a, a lower steady state of Rubisco as measured by the amount of the large subunit of Rubisco (RbcL), and a lower rate of CO(2) assimilation. As a consequence, a slower rate of leaf expansion and reduced foliar dry weight were observed. In addition, an accelerated rate of loss of chlorophyll, RbcL, light-harvesting complex II, and photosynthetic functioning was observed in mature leaves, resulting in premature leaf aging. Reduced growth rate as measured by plant height and leaf number was consistent with the DHAR-mediated reduction of photosynthetic function. Increasing DHAR expression maintained higher levels of chlorophyll, RbcL, light-harvesting complex II, and photosynthetic functioning, resulting in delayed leaf aging. The effect of DHAR expression on leaf aging inversely correlated with the level of lipid peroxidation, indicating that DHAR functions to protect against ROS-mediated damage. These observations support the conclusion that through its Asc recycling function, DHAR affects the level of foliar ROS and photosynthetic activity during leaf development and as a consequence, influences the rate of plant growth and leaf aging.

Ascorbic Acid↗
PubMed1979

Degradation of ascorbic acid (vitamin C) in iron-supplemented cows' milk.

The fate of [6-carbon-14] ascorbic acid in iron-supplemented and unsupplemented raw milk was studied by anion-exchange chromatography, which permitted quantitative analysis of the conversion of ascorbate to dehydroascorbate and diketogulonate as a function of time. Iron catalyzed an increase in the rate of autoxidation of ascorbate to dehydroascorbate but did not alter the equilibrium concentrations of ascorbate, dehydroascorbate, and diketogulonate. The conversion of ascorbate to dehydroascorbate and of dehydroascorbate to diketogulonate occurred rapidly even in unsupplemented milk. Thus, trace metal supplementation may not affect materially the vitamin C content of stored milk.

2,3-Diketogulonic Acid↗
PubMed1994

A novel-dehydroascorbate reductase from spinach chloroplasts homologous to plant trypsin inhibitor.

Dehydroascorbate reductase has been isolated from spinach chloroplasts and purified to apparent homogeneity. The N-terminal amino acid sequence of the enzyme is homologous to the Kunitz-type trypsin inhibitors from plant sources. It is shown that spinach DHA reductase and soybean trypsin inhibitor are both capable of reducing dehydroascorbate when in the reduced (thiol) form but acquire trypsin-inhibiting activity in the oxidized (disulfide) state. Reduced chloroplast thioredoxins also reduce dehydroascorbate.

Amino Acid Sequence↗
PubMed1992

Ascorbate-mediated transmembrane electron transport and ascorbate uptake in leukemic cell lines are two different processes.

Transmembrane reduction of extracellular oxidants by K562 and U937 leukemic cells was stimulated by catalytic amounts of ascorbate or dehydroascorbate. This stimulation was not due to transport of ascorbate in different redox states in and out of the cells. The membrane redox cycle was strictly dependent on the presence of the cells at every stage, and showed high affinity for ascorbate with simple linear kinetics. Metabolic inhibitors and sulfhydryl reagents inhibited this stimulation. Ascorbate uptake was also dependent on oxidation, but in a very different manner and with much lower affinity for ascorbate. The uptake was non-saturable in the concentration range used. There was some release of ascorbate from the cells, which cannot account for an appreciable part of the reduction of extracellular electron acceptors.

Ascorbic Acid↗