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PubMed1999

Inhibition of aldose reductase in human erythrocytes by vitamin C.

Ascorbic acid, or vitamin C, has been reported to lower erythrocyte sorbitol concentrations, and present studies were performed to determine the mechanism of this effect. Incubation of erythrocytes with increasing concentrations of glucose (5-40 mM) progressively increased erythrocyte sorbitol contents, reflecting increased flux through aldose reductase. At extracellular concentrations of 90 microM, both ascorbic acid and its oxidized form, dehydroascorbate, decreased intracellular sorbitol by 25 and 45%, respectively. This inhibition was not dependent on the extracellular glucose concentration, or on erythrocyte contents of free NADPH or GSH. To test for a direct effect of ascorbate on aldose reductase, erythrocyte hemolysates were prepared and supplemented with 100 microM NADPH. Hemolysates reduced glucose to sorbitol in a dose-dependent manner that was inhibited with a Ki of 120 microM by the aldose reductase inhibitor tetramethylene glutaric acid. Above 100 microM, ascorbic acid also lowered hemolysate sorbitol generation by about 30%. Studies with ascorbic acid derivatives showed that the reducing capacity of ascorbic acid was not required for inhibition of sorbitol production from glucose in erythrocyte hemolysates. These results show that high, but physiologic, concentrations of ascorbic acid can directly inhibit erythrocyte aldose reductase, and provide a rationale for the use of oral vitamin C supplements in diabetes.

Aldehyde Reductase↗
PubMed1979

An ascorbate-mediated transmembrane-reducing system of the human erythrocyte.

Actively metabolizing human erythrocytes catalyze the extracellular reduction of ferricyanide to ferrocyanide. Because neither of these anions can enter the cell, reducing equivalents generated in the course of glycolysis must in some manner be transferred across the cell membrane, thereby resulting in ferricyanide reduction. Work described in this paper suggests that the transmembrane reduction is effected by ascorbic acid. This compound in its oxidized form (dehydroascorbate) rapidly enters the cell. Here it obtains reducing equivalents which appear to come from NADH made available at the level of glyceraldehyde 3-phosphate dehydrogenase. Once reduced, it leaves the cell as ascorbic acid and accomplishes the non-enzymatic reduction of ferricyanide.

Ascorbic Acid↗
PubMed2003

Vitamin C recycling is enhanced in the adaptive response to leptin-induced oxidative stress in keratinocytes.

Leptin acts on energy metabolism and plays a role in skin repair and in the modulation of cellular redox balance as well. Here, we investigated the effects of leptin on the redox homeostasis in keratinocytes, by evaluating reactive oxygen species (ROS) generation, glutathione content, antioxidant enzymes, activating protein 1 (AP-1) activity, and expression of AP-1-dependent, differentiation-specific genes. We also evaluated the systems involved in the maintenance of a positive ascorbate/dehydroascorbate ratio, i.e., transport and recycling. Leptin altered the keratinocyte redox state, as evident by enhanced ROS generation, oxidized/reduced glutathione ratio, and AP-1 activity. Still, this phenomenon was temporary. Indeed, we found an adaptive response, as demonstrated by an early induction of catalase and a late induction of specific dehydroascorbate reductase activities. In particular, leptin-treated cells showed an increased ability to reduce dehydroascorbate, both in a NADH, lipoic acid- and in a NADPH, thioredoxin-dependent manner. Our results show that leptin may induce adaptation to oxidative stress in skin, leading to an improved vitamin C homeostasis.

Adaptation, Physiological↗
PubMed1990

Glycation of lens proteins by the oxidation products of ascorbic acid.

Bovine lens water-soluble proteins were incubated with [I-14C]ascorbic acid (ASA) for 6 days, and the incorporation into protein was measured at daily intervals. Aliquots were also withdrawn to determine the distribution of label among the various ASA oxidation products. A linear incorporation into protein was observed in the presence of NaCNBH3, however, little or no incorporation was seen in its absence. TLC analysis showed a complete loss of ASA by day 3, whereas both dehydroascorbate (DHA) and diketogulonic acid (DKG) remained constant for 6 days, consistent with the linear incorporation into protein. The amino acid composition of the proteins glycated in the presence of NaCNBH3 was identical to controls except for a 70% reduction in lysine residues and a corresponding increase in an unknown product which eluted slightly earlier than methionine. In the absence of NaCNBH3 lysine decreased linearly to 20% with an additional decrease in arginine and histidine at later times concurrent with protein crosslinking. DHA and DKG were prepared and incubated directly with lens proteins for an 8 day period. Both compounds glycated lens protein as evidenced by an increased binding to a boronate affinity column. SDS-PAGE showed that both compounds were also capable of causing protein crosslinking. DHA is apparently capable of reacting directly with protein since glycation was observed with the ASA analog, reductic acid, which can be oxidized to dehydroreductic acid, but which cannot be hydrolyzed to an open chain structure. DHA also produced a lysine adduct which was not obtained with DKG, supporting the idea that both species have glycating ability.

2,3-Diketogulonic Acid↗
PubMed2000

Ascorbate regeneration by the reduced form of 2-amino-3-carboxy-1, 4-naphthoquinone, a strong growth stimulator for bifidobacteria.

Nonenzymatic reduction of dehydroascorbate into ascorbate by the reduced form (quinol form) of 2-amino-3-carboxy-1,4-naphthoquinone, a strong growth stimulator for bifidobacteria, has been found. The bimolecular reaction rate constant was evaluated as 9 M(-)(1) s(-)(1) at pH 7.0. This reaction has been successfully coupled with enzymatic regeneration of the naphthoquinol by NAD(P)H in cell-free extracts of Bifidobacterium longum 6001. The overall reaction is a regeneration of NAD(P)(+) by dehydroascorbate [or a regeneration of ascorbate by NAD(P)H], in which the naphthoquinone/quinol redox couple functions as an electron transfer mediator. Kinetic study of the reduction of dehydroascorbate with related quinol compounds suggested the significance of the amino substituent of the naphthoquinol. A mechanism of the electron transfer from the quinol to dehydroascorbate is proposed, where the first step of the reaction is a nucleophilic addition of the C(2)-amino substituent of the naphthoquinol to the C(2)-position of dehydroascorbate to form a Schiff base intermediate.

Ascorbic Acid↗
PubMed1994

Ascorbate is the primary reductant of the phenoxyl radical of etoposide in the presence of thiols both in cell homogenates and in model systems.

Phenoxyl radicals are intermediates in the oxidation of phenolic compounds to quinoid derivatives (quinones, quinone methides), which are known to act as ultimate mutagenic, carcinogenic, and cytotoxic agents by directly interacting with macromolecular targets or by generating toxic reactive oxygen species. One-electron reduction of phenoxyl radicals may reverse oxidative activation of phenolic compounds to quinoids, thus preventing their cytotoxic effects. In the present work, we studied interactions of ascorbate, thiols (glutathione, dihydrolipoic acid, and metallothioneins), and combinations thereof with the phenoxyl radical generated by tyrosinase-catalyzed oxidation of VP-16 [etoposide, 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucop yra noside)], a hindered phenol widely used as an antitumor drug. We found by liquid chromatography-ionspray mass spectrometry and electron spin resonance (ESR) that tyrosinase caused oxidation of VP-16 to its o-quinone and aromatized derivative via intermediate formation of the phenoxyl radical. Both ascorbate and thiols (GSH, dihydrolipoic acid, and metallothioneins) were able to directly reduce the VP-16 phenoxyl radical and prevent its oxidation. The characteristic ESR signal of the VP-16 phenoxyl radical was quenched by the reductants. The semidehydroascorbyl radical ESR signal was detected in the presence of ascorbate; thiols did not produce signals in the ESR spectra. In combinations, ascorbate plus GSH and ascorbate plus metallothionein acted independently and additively in reducing the VP-16 phenoxyl radical. Ascorbate was more reactive: the VP-16-dependent oxidation of GSH or metallothionein commenced only after complete oxidation of ascorbate. The semidehydroascorbyl radical ESR signal preceded the quenching of the VP-16 phenoxyl radical by GSH and metallothionein. In the presence of ascorbate plus dihydrolipoic acid, ascorbate was also more reactive toward the VP-16 phenoxyl radical than dihydrolipoic acid, but the ascorbate concentration was maintained at the expense of its regeneration from dehydroascorbate by dihydrolipoic acid. In ESR spectra, the semidehydroascorbyl radical ESR signal was continuously detected and then was abruptly substituted by the VP-16 phenoxyl radical signal. When VP-16 and tyrosinase were incubated in the presence of retina or hepatocyte homogenates, a two-phase lag period was observed by ESR for the appearance of the VP-16 radical signal: an ascorbate-dependent part (semidehydroascorbyl radical observable, sensitive to ascorbate oxidase) and thiol-dependent part (no radical signals in the spectra, sensitive to mersalyl acid). About 50% of the thiol-dependent part of the lag period could be accounted for by endogenous GSH (as revealed by treatment with GSH peroxidase+cumene hydroperoxide).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Inhibition of human leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by ascorbic acid. An effect mediated by the free radical monodehydroascorbate.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity in microsomes isolated from cultured lymphoid (IM-9) cells or freshly isolated human leukocytes was markedly decreased by either ascorbic acid or its oxidized derivative, dehydroascorbate. Inhibition of IM-9 leukocyte HMG-CoA reductase activity was log linear between 0.01 and 10 mM ascorbic acid (25 and 81% inhibition, respectively) and 0.1 and 10 mM dehydroascorbate (5 and 75% inhibition, respectively). Inhibition was noncompetitive with respect to HMG-CoA (Km = 10.2 microM (RS); ascorbic acid, Ki = 6.4 mM; dehydroascorbate, Ki = 15 mM) and competitive with respect to NADPH (Km = 16.3 microM; acetic acid, Ki = 6.3 mM; dehydroascorbate, Ki = 3.1 mM). Ascorbic acid and dehydroascorbate are interconverted through the free radical intermediate monodehydroascorbate. Reducing agents are required to convert dehydroascorbate to monodehydroascorbate, but prevent formation of the free radical from ascorbate. In microsomes from IM-9 cells, the reducing agent, dithiothreitol, abolished HMG-CoA reductase inhibition by ascorbate but enhanced inhibition by dehydroascorbate. In addition, the concentration of monodehydroascorbate present in ascorbate solutions was directly proportional to the degree of HMG-CoA reductase inhibition by 1.0 mM ascorbate. Fifty per cent inhibition of enzyme activity occurred at a monodehydroascorbate concentration of 14 microM. These data indicate that monodehydroascorbate mediates inhibition of HMG-CoA reductase by both ascorbate and dehydroascorbate. This effect does not appear to be due to free radical-induced membrane lipid modification, however, since both ascorbate and dehydroascorbate inhibited the protease-solubilized, partially purified human liver enzyme. Since inhibition of HMG-CoA reductase occurs at physiological concentrations of ascorbic acid in the human leukocyte (0.2-1.72 mM), this vitamin may be important in the regulation of endogenous cholesterol synthesis in man.

Ascorbic Acid↗
PubMed1980

Rapid mobilization of ferritin iron by ascorbate in the presence of oxygen.

L-(-)-ascorbate mobilizes iron from horse-spleen ferritin in the presence of oxygen at pH 8.0. The reaction is strongly stimulated by Cu2+. Dehydroascorbate and other stable oxidation products of ascorbate are ineffective. We present evidence that monodehydroascorbate mobilizes ferritin iron by reduction.

Animals↗
PubMed2005

Dehydroascorbate transport in human chondrocytes is regulated by hypoxia and is a physiologically relevant source of ascorbic acid in the joint.

OBJECTIVE: To evaluate the dehydroascorbate (DHA) transport mechanisms in human chondrocytes. METHODS: The transport of L-(14)C-DHA in human chondrocytes was analyzed under various conditions, including the use of RNA interference (RNAi), to determine the role of glucose transporter 1 (GLUT-1) and GLUT-3 in L-14C-DHA transport and to evaluate the effects of physiologically relevant oxygen tensions on L-14C-DHA transport. In order to estimate the contributions of reduced ascorbic acid (AA) and DHA to intracellular ascorbic acid (Asc), the quantities of AA and DHA were measured in synovial fluid samples from osteoarthritis (OA) patients and compared with the reported levels in rheumatoid arthritis (RA) patients. RESULTS: DHA transport in human chondrocytes was glucose-sensitive, temperature-dependent, cytochalasin B-inhibitable, modestly stereoselective for L-DHA, and up-regulated by low oxygen tension. Based on the RNAi results, GLUT-1 mediated, at least in part, the uptake of DHA, whereas GLUT-3 had a minimal effect on DHA transport. DHA constituted a mean 8% of the total Asc in the synovial fluid of OA joints, in contrast to 80% of the reported total Asc in RA joints. CONCLUSION: We provide the first evidence that chondrocytes transport DHA via the GLUTs and that this transport mechanism is modestly selective for L-DHA. In the setting of up-regulated DHA transport at low oxygen tensions, DHA would contribute 26% of the total intracellular Asc in OA chondrocytes and 94% of that in RA chondrocytes. These results demonstrate that DHA is a physiologically relevant source of Asc for chondrocytes, particularly in the setting of an inflammatory arthritis, such as RA.

Arthritis, Rheumatoid↗
PubMed1987

[Features of vitamin C metabolism and the functional status of the liver in alcoholism and alcoholic delirium in the stage of detoxification therapy].

The metabolism of vitamin C and the function of the liver were investigated in 106 patients suffering from alcoholism (34 with clinical stage 1, 53 with clinical stage 2, and 19 with alcoholic delirium). The levels of ascorbic acid (AA) were reduced while those of dehydroascorbic (DAA) and diketogulonic acids (DKGA) were elevated. Red blood cells presented an increase in both AA and DAA and a decrease in DKGA concentrations. AA excretion with the urine was diminished. Considerable liver dysfunction was ascertained. Intensity of the normalization of AA metabolism coincided in time with the normalization of liver enzyme levels (ALT, AsT, CE). Degree of changes in AA metabolism in alcoholism may to a certain degree depend on the severity of liver dysfunction.

Adult↗
PubMed1997

Cyanate causes depletion of ascorbate in organisms.

Ascorbate-dehydroascorbate redox cycle plays a key role in protecting organisms from an excess of oxidants. Recently, we found a novel reaction of dehydroascorbate with cyanate under the conditions of neutral pH and ordinary temperature. In this report, we demonstrated that through this irreversible reaction, cyanate causes the depletion of ascorbate in the matrix, where the ascorbate-dehydroascorbate redox cycle revolves. When the leaves of weed (Erigeron canadensis) were soaked in sodium cyanate solution generally used as a herbicide, the depletion of ascorbate as well as dehydroascorbate in them was observed, followed by the change in color from green to brown. These results suggest that a possible way of cyanate toxicity is to inflict oxidative stress on organisms.

Animals↗
PubMed1995

Dehydroascorbate reductase activity in bovine lens.

The bovine lens was studied for the presence of dehydroascorbate reductase activity. The activity was found to be restricted primarily to the mitochondrial fraction isolated from the cortex-epithelial fraction of the tissue. It was not detectable in the cytosolic fraction. The Km of reaction with dehydroascorbate was approximately 0.45 mM. These studies suggest that the reduction of dehydroascorbate to ascorbate in the mitochondria takes place enzymatically as well as nonenzymatically, GSH being the source of reducing electrons in both the cases. The enzymatic mechanism may assume a greater role in situations of oxidative stress which lead to GSH depletion. The presence of this enzyme in the mitochondria is considered with a normally more severe oxidative condition therein.

Animals↗
PubMed2002

Effect of zinc on antioxidant response in maize (Zea mays L.) leaves.

Maize (Zea mays L. cv kanaujia) plants grown with Zn [10 (control), 0.1 (low) and 20 microM (high)], were investigated for concentration of antioxidants and activities of antioxidative enzymes in leaves. Young leaves of low Zn plants developed whitish-necrotic spots. Leaves of both low and high Zn plants showed decrease in chlorophyll concentration and accumulation of lipid peroxides, ascorbate and dehydroascorbate, associated with a decrease in the activity of ascorbate peroxidase and superoxide dismutase. Low and high Zn, however, showed diverse effect on glutathione reductase. While low Zn increased the activity of glutathione reductase, high Zn decreased its activity. Zinc effect on antioxidative constituents suggested Zn involvement in sustaining the antioxidative defense system in maize leaves.

Antioxidants↗
PubMed1986

Ascorbate transport by AtT20 mouse pituitary corticotropic tumor cells: uptake and secretion studies.

Ascorbate is an important cofactor in the biosynthesis of alpha-amidated endocrine and neural peptides. Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme responsible for the generation of mature COOH-terminal alpha-amidated peptides from COOH-terminal glycine-extended peptides, and this enzyme requires ascorbate for full activity in vitro. Also, cultured intermediate pituitary lobe cells contain PAM and require ascorbate for the COOH-terminal alpha-amidation of alpha MSH. Since pituitary cells are not capable of synthesizing ascorbate, the ability of the cells to accumulate the cofactor must play an important role in the biosynthesis of alpha-amidated peptides. The AtT20 corticotropic pituitary tumor cell line also contains PAM and a potential site for COOH-terminal alpha-amidation of the pro-ACTH/endorphin-derived hinge peptide and was, thus, used for the study of cellular ascorbate transport. Radiolabeled L-[1-14C]ascorbate ([1-14C]ascorbate) was incubated with the cells under various conditions, and the accumulation of radioactivity by the cells was followed. Reverse phase HPLC was used to identify the integrity of the labeled ascorbate, both intra- and extracellular, during the course of the experiments. The uptake of [1-14C]ascorbate was saturable (Km = 31.5 microM), sodium and temperature dependent, and stereoselective. The products of ascorbate autooxidation, dehydroascorbate and 2,3-diketogulonic acid, did not inhibit [1-14C]ascorbate uptake. To study the presence of ascorbate in the secretory granules, cells were incubated with [1-14C]ascorbate and then induced to secrete with isoproterenol or 8-bromo-cAMP. A 2- to 6-fold stimulation of ACTH secretion over the basal secretion rate was observed; however, the secretion of intracellular [1-14C]ascorbate did not change significantly with stimulation, suggesting that very little of the cellular ascorbate was contained within secretory granules.

2,3-Diketogulonic Acid↗
PubMed2004

The effect of Botrytis cinerea infection on the antioxidant profile of mitochondria from tomato leaves.

Infection of tomato leaves with the necrotrophic fungus Botrytis cinerea resulted in substantial changes in enzymatic and non-enzymatic components of the ascorbate-glutathione cycle as well as in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione transferase (GST), and l-galactono-gamma-lactone dehydrogenase (GLDH) activities. In the initial phase of the 5 d experiment CuZn SOD was the most rapidly induced isoform (up to 209% of control), whereas later on its activity increase was not concomitant with the constant total SOD enhancement. Starting from the second day B. cinerea infection diminished the mitochondrial antioxidant capacity by decreasing activities of ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) as well as declining ascorbate and glutathione contents. This was accompanied by dehydroascorbate (DHA) and oxidized glutathione (GSSG) accumulation that resulted in ascorbate and glutathione redox ratios decreases. The strongest redox ratio decline of 29% for ascorbate and of 34% for glutathione was found on the 3rd and 2nd days, respectively. Glutathione reductase (GR) induction (185% of control 2 d after inoculation) was insufficient to overcome the decreased antioxidant potential of glutathione. Changes in the ascorbate pool size were closely related to the activity of l-galactono-gamma-lactone dehydrogenase (GLDH). The activities of two glutathione-dependent enzymes: GSH-Px and GST were increased from day 1 to day 4. These results demonstrated that in B. cinerea-tomato interaction mitochondria could be one of the main targets for infection-induced oxidative stress.

Antioxidants↗
PubMed2005

Modulation of cadmium-induced oxidative stress in Ceratophyllum demersum by zinc involves ascorbate-glutathione cycle and glutathione metabolism.

To understand the interaction between Zn, an essential micronutrient and Cd, a non-essential element, Cd-10 microM and Zn supplemented (10, 50, 100, and 200 microM) Cd 10 microM treated Ceratophyllum demersum L. (Coontail), a free floating freshwater macrophyte was chosen for the study. Cadmium at 10 microM concentration decreased thiol content, enhanced oxidation of ascorbate (AsA) and glutathione (GSH) to dehydroascorbate (DHA) and glutathione disulfide (GSSG), respectively, a clear indication of oxidative stress. Zinc supplementation to Cd (10 microM) treated plants effectively restored thiols, inhibited oxidation of AsA and GSH maintaining the redox molecules in reduced form. Cd-10 microM slightly induced ascorbate peroxidase (APX, E.C. 1.11.1.11) but inhibited monodehydroascorbate reductase (MDHAR, E.C. 1.6.5.4), dehydroascorbate reductase (DHAR, E.C. 1.8.5.1) and glutathione reductase (GR, E.C. 1.6.4.2), enzymes of ascorbate-glutathione cycle (AGC). Zn supplementation restored and enhanced the functional activity of all the AGC enzymes (APX, MDHAR, DHAR and GR). Gamma-glutamylcysteine synthetase (gamma-GCS, E.C. 6.3.2.2) was not affected by Cd as well as Zn, but Zn supplements increased glutathione-S-transferase (GST, E.C. 2.5.1.18) activity to a greater extent than Cd and simultaneously restored glutathione peroxidase (GSH-PX, E.C. 1.11.1.9) activity impaired by Cd toxicity. Zn-alone treatments did not change above investigated parameters. These results clearly indicate the protective role of Zn in modulating the redox status of the plant system through the antioxidant pathway AGC and GSH metabolic enzymes for combating Cd induced oxidative stress.

Ascorbic Acid↗
PubMed2003

Zonal changes in ascorbate and hydrogen peroxide contents, peroxidase, and ascorbate-related enzyme activities in onion roots.

Onion (Allium cepa) roots growing hydroponically show differential zonal values for intra- (symplastic) and extra- (apoplastic) cellular ascorbate (ASC) and dehydroascorbate (DHA) contents and for related enzyme activities. In whole roots, ASC and DHA concentrations were higher in root apex and meristem and gradually decreased toward the root base. Guaiacol peroxidase, ASC peroxidase, monodehydroascorbate oxidoreductase, DHA reductase, catalase, and glutathione reductase activities showed differential activity patterns depending on the zone of the root and their apoplastic or symplastic origin. An in vivo staining of peroxidase activity also revealed a specific distribution pattern along the root axis. Using electron microscopy, hydrogen peroxide was found at different locations depending on the root zone but was mainly located in cell walls from epidermal and meristematic cells and in cells undergoing lignification. A balanced control of all of these molecules seems to exist along the root axis and may be directly related to the mechanisms in which the ASC system is involved, as cell division and elongation. The role of ASC on growth and development in relation to its presence at the different zones of the root is discussed.

Ascorbate Peroxidases↗