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PubMed1998

Substrates of hexokinase, glucose-6-phosphate dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase prevent the inhibitory response induced by ascorbic acid/iron and dehydroascorbic acid in rabbit erythrocytes.

Exposure of intact rabbit erythrocytes or erythrocyte lysates to ascorbic acid/FeCl3 in a glucose-free saline promoted a rapid decline in reduced glutathione and this response was paralleled by inactivation of hexokinase. Under the same conditions, the activity of the enzymes glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase did not show appreciablevariations in intact cells, but was severely inhibited in the cell-free system. Similar results were obtained by replacing ascorbic acid/FeCl3 with dehydroascorbic acid. In addition, both treatments effectively inhibited the activity of purified hexokinase as well as those of glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. Further studies using the cell-free system indicated that the inhibition of enzyme activities elicited by either of the two treatments was effectively counteracted by the specific substrates of these enzymes. The fact that the hexokinase substrate glucose freely permeates the plasma membrane, unlike the substrates of glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphatedehydrogenase, explains the selective inhibition of hexokinase observed in intact cells. The above results also indicate that dehydroascorbic acid is an inhibitor of these enzymes and strongly suggest that it is at least in part responsible for the effects mediated by the cocktail ascorbic acid/FeCl3.

Animals↗
PubMed1976

Effects of tetraacetyl-bis-dehydroascorbic acid, a derivative of ascorbic acid, on Ehrlich cells and HeLa cells (human carcinoma cells).

Derivatives of ascorbic acid were synthesized, and the studies were made on their effects in Ehrlich ascites carcinoma cells, in regard to the inhibition and the prolongation of survival time as well as on the morphological degeneration in HeLa cells. In a model infection study carried out by using tetraacetyl-bis-dehydroascorbic acid in dd mice infected with Ehrlich cells, it was proved that the prolongation of survival time was nearly double in comparison to the control group mice. Also, it was noted that hypertrophy due to abdominal dropsy and body weight were reduced much more than in the control group. From these results, the inhibiting effect of tetraacetyl-bis-dehydroascorbic acid was confirmed. While in the case of DHA and other derivatives, almost no inhibition and prolongation of survival time were observed. As for HeLa cells in a tissue culture, tetraacetyl-bis-DHA, in a dosage of 125-250 mug/ml, demonstrated definitely its morphological degeration. After 125 mug/ml of tetraacetyl-bis-DHA was added to a tissue culture solution of HeLa cells, the cells were washed and recultured. No growth of the cells was observed. Consequently, this substance was confirmed to be anti-HeLa substance with a low toxicity.

Animals↗
PubMedDate not supplied

[Cause of dehydroascorbic acid accumulation in the blood of patients with insulin-dependent diabetes mellitus].

It is known that dehydroascorbic acid (DHAA) produces a diabetogenic effect and its content in the blood increases in diabetes mellitus. It was previously established that the generation of reducing equivalents (RE) in the course of hexosemonophosphate shunt, CO2 production and SH-glutathione regeneration in erythrocytes with and without moderate and maximum oxidation load in vitro were not disturbed in diabetes. The authors have proposed a procedure to study blood and erythrocyte DHAA reductase activity in suspension in health and in insulin-dependent diabetes mellitus by means of redoxstatometry using a device of original design. A significant acceleration of RE transfer through the erythrocyte membrane was detected in diabetes. A lowered participation in this process of the AA in equilibrium DHAA "shuttle" system was recorded in the blood of patients with diabetes mellitus what was mostly expressed under the conditions of acidosis in vitro. Probably "shuttle" function in diabetes was provided by some other redox system which might be located in the plasma. The predominant functioning of this redox system and a decrease of DHAA reductase activity in diabetes resulted in the accumulation of DHAA in the blood of patients with type I diabetes mellitus.

Adult↗
PubMed1985

Mitogenic inhibition and effect on survival of mice bearing L1210 leukemia using a combination of dehydroascorbic acid and hydroxycobalamin.

The present study was designed to test the effect of a combination of dehydroascorbic acid (DHA) and hydroxycobalamin (vitamin B12) on the survival of mice bearing L1210 leukemia. Results showed a significant increase in survival of treated mice compared with controls (p less than or equal to 0.0001) (Student's t-test). This positive effect was significantly lost when DHA was substituted by ascorbic acid (AA) in the same experimental conditions. In vitro findings also revealed that the DHA-B12 combination specifically inhibited mitoses of L1210 cells while non-neoplastic L929 cells were not affected.

Animals↗
PubMed1997

Determination of ascorbic and dehydroascorbic acids in blood plasma and serum by liquid chromatography.

A liquid-chromatography (LC) method with ultraviolet detection for measuring ascorbic (AA) and dehydroascorbic acid (DHA) in human blood and serum was studied. The method used an ODS reversed-phase column and cetyltrimethyl ammonium bromide as an ion-pairing agent. AA was measured before and after the reduction of DHA with dithiothreitol. The absence of interferences resulting from hemolysis products was verified and also the stability of the ascorbic acid in metaphosphoric acid extracts. The analytical parameters, linearity (1-80 micrograms/ml), accuracy (recovery, 96.7-100.7%) and precision (C.V. = 3.1%), show that the method is reliable and adequate for measuring the total vitamin C content in serum and plasma.

Ascorbic Acid↗
PubMed1994

Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid.

The cellular accumulation of vitamin C, a substance critical to human physiology, is mediated by transporters located at the cell membrane, and is regulated in a cell-specific manner. Neoplastic cells may have special needs for vitamin C. Therefore, we investigated the transport of vitamin C in a human myeloid leukemia cell line (HL-60). The HL-60 cells lacked the capacity to transport the reduced form of vitamin C, ascorbic acid, but they showed a remarkable ability to transport the oxidized form of vitamin C, dehydroascorbic acid (DHA). Uptake-accumulation studies indicated that the HL-60 cells accumulated ascorbic acid when provided with DHA. Kinetic analysis showed the presence of two functional activities involved in the uptake of DHA, one with low affinity and one with high affinity. Cytochalasin B and phloretin, which inhibit the passage of glucose through the facilitative glucose transporters, also inhibited the transport of DHA by HL-60 cells. Transport of DHA was completed by D- but not L-hexoses, and was sensitive to D-hexose-dependent counter transport acceleration. These data support the concept that HL-60 myeloid leukemic cells transport DHA through the facilitative hexose transporters (glucose transporters) and accumulate the reduced form of ascorbic acid.

3-O-Methylglucose↗
PubMed2001

Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke.

Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Animals↗
PubMed1987

Rapid and sensitive determination of dehydroascorbic acid in addition to ascorbic acid by reversed-phase high-performance liquid chromatography using a post-column reduction system.

An improved procedure for the direct determination of l-dehydroascorbic acid (DHAA), in addition to l-ascorbic acid (AA), has been developed. The two biologically active forms of vitamin C were separated using reversed-phase high-performance liquid chromatography. DHAA was reduced to AA with dithiothreitol (DTT) in a post-column reaction system. Complete conversion was achieved at 50 degrees C using a 1-ml reaction coil. Recoveries were in the range of 95-99% and both forms could be detected spectrophotometrically at 267 nm with high sensitivity. Reproducible results [relative standard deviations 2.4% (DHAA) and 1.0% (AA), n = 5] were obtained when the method was applied to the analysis of rose hip samples.

Ascorbic Acid↗
PubMed1999

Hormone-regulated and glucose-sensitive transport of dehydroascorbic acid in immature rat granulosa cells.

Ascorbic acid is concentrated in granulosa cells of the follicle, and ascorbate deficiency causes follicular atresia. Dehydroascorbic acid (DHAA), the oxidized form of ascorbic acid, serves as an important source for the recycling of ascorbate. As we previously demonstrated endocrine up-regulation of ascorbic acid transport by granulosa cells, we investigated DHAA as an alternate source of ascorbate in the follicle. Granulosa cells were cultured for 24 h, and DHAA uptake was initiated by the addition of 14C-labeled ascorbic acid (300 microM) in the presence of ascorbic acid oxidase (2 U/ml), which catalyzes DHAA production. Almost 90% of accumulated DHAA was present as ascorbic acid within 2 h. Preculture of cells for 24 h with FSH (50 ng/ml) and IGF-I (30 ng/ml) significantly stimulated DHAA uptake compared with the control (158 +/- 16 vs. 43 +/- 8 pmol/10(6) cells, respectively). DHAA uptake by granulosa cells was inhibited by D-glucose (ID50, approximately 2.5 mM) and by the glucose transport inhibitors phloretin (200 microM) and cytochalasin B (10 microM), which reduced uptake to 13 +/- 2% and 8 +/- 3% of the control, respectively. Northern and Western analysis of GLUT1 in granulosa cells following 24 h coincubation with FSH and IGF-I revealed up-regulation of GLUT1 at both the messenger RNA and protein levels (1.6- and 1.3-fold of control, respectively), suggesting that the stimulatory effects of FSH and IGF-I on DHAA transport are mediated by the induction of GLUT1. GLUT4 protein was not detectable by Western analysis. Endocrine-regulated DHAA transport may represent an important mechanism for maintaining adequate antioxidant tone within the developing follicle.

Animals↗
PubMed1997

Inactivation of intracellular proteolysis and cathepsin B enzyme activity by dehydroascorbic acid and reactivation by dithiothreitol in perfused rat heart.

The selective inhibition of some subcomponents of intracellular protein degradation was characterized under exposure to the cyclic multiketone thiol oxidizing agents dehydroascorbic acid (DHA) and alloxan. Proteins of the isolated perfused rat heart were labeled in vitro with a 10-min infusion of [3H] leucine, and subsequent release of radiolabeled amino acid from cell proteins was measured. As determined previously, four subcomponents of total proteolysis can be distinguished; the first three subcomponents are reversibly inhibited by the thiol-reactive agent diamide: (a) The rapid turnover proteins comprise most of the [3H] leucine release from 20 min to 3 hr after labeling. (b) Following 3 hr of degradation, the lysosomal (insulin-responsive) subcomponent comprises 35-40% of [3H] leucine release. (c) A third nonlysosomal (adrenergic-responsive) subcomponent comprises 35%. (d) A fourth nonlysosomal subcomponent consisting of 25% of [3H] leucine release is uninhibited by diamide. Infusion of supraphysiologic DHA (1 mM) or alloxan (1.5 mM) promptly mimicked the proteolytic inhibitory action of diamide on the first three subcomponents, but did not inhibit the diamide-resistant subcomponent. Infusion of a physiologic extracellular DHA concentration of 5 microM caused little or no change in proteolysis. The proteolytic inhibitory action of DHA (1 mM) could be reversed by concurrent infusion of dithiothreitol (DTT, 1.5 mM) simultaneously with continued DHA. DHA (1 mM) caused direct inhibition of the purified sulfhydryl proteinase cathepsin B (EC 3.4.22.1), which was reversible by subsequent excess DTT (5 mM). Results indicate that a nontoxic endogenous multiketone thiol oxidant can reversibly inhibit some proteolytic processes in viable tissue; however, approximately 25% of the observed proteolysis is uninhibited. Reversible inactivation of sulfhydryl proteinases, including cathepsin B, is among the possible multiple mechanisms of this DHA action.

Alloxan↗
PubMed1994

A note on distribution of human plasma levels of ascorbic and dehydroascorbic acid.

Ascorbic acid concentrations in 102 human plasma samples ranged from 1 to 15 micrograms ml-1 with a mean concentration at about 8 micrograms ml-1, corresponding to the results of other authors. Dehydroascorbic acid was found only in traces, independent of ascorbic acid concentrations. The ascorbic acid concentrations in plasma of four persons, examined twice with a four-years interim period revealed no obvious differences over time. It is suggested that the variability of plasma ascorbic acid concentrations is mainly determined by long-term dietary habits.

Ascorbic Acid↗
PubMed1998

Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome.

The glucose transporter protein syndrome (GTPS) is caused by defective transport of glucose across the blood-brain barrier via the glucose transporter GLUT1, resulting in hypoglycorrhachia, infantile seizures, and developmental delay. Recent reports indicated that GLUT1 is a multifunctional transporter. We investigated the transport of vitamin C in its oxidized form (dehydroascorbic acid) via GLUT1 into erythrocytes of 2 patients with GTPS. In both patients, uptake of oxidized vitamin C was 61% of the mothers' values. Our findings are consistent with recent observations that vitamin C is transported in its oxidized form via GLUT1. We speculate that impaired transport of this substrate and perhaps other substrates in GTPS might contribute to the pathophysiology of this condition.

Adult↗
PubMed2000

Interaction of respiratory burst and uptake of dehydroascorbic acid in differentiated HL-60 cells.

HL-60 cells differentiated with DMSO increased their rates of uptake of ascorbate when they were activated with PMA. The rates observed after this activation were essentially the same as those with dehydroascorbic acid as the original transport substrate. The effect of activation was sensitive to the antioxidant enzymes superoxide dismutase and catalase. When ascorbate was oxidized in situ by chemical or enzymic oxidation, the rates of uptake were similar to those after activation of the cells by phorbol ester; however, in the latter case the extracellular vitamin remained largely in the reduced form and there was very little loss by degradation, whereas after immediate oxidation no more reduced ascorbate could be found outside the cells after a few minutes and a significant part of the total vitamin was lost. The generation of superoxide by xanthine/xanthine oxidase stimulated the uptake of ascorbate much less than the activation by phorbol ester; H(2)O(2) was even less effective. Stimulation of the uptake by phorbol ester was also insensitive to GSH, in contrast with stimulation by the chemical oxidation of ascorbate. Stimulation of ascorbate uptake by phorbol ester was sensitive to the respiratory-burst inhibitor diphenyliodonium as well as the protein kinase C inhibitor staurosporine, indicating the respiratory burst as the cause of stimulation. Activation of the cells by the phorbol ester also stimulated the uptake of dehydroascorbate as the original substrate, in a manner insensitive to antioxidants or inhibitors of the respiratory burst. In all cases the intracellular vitamin was completely in the reduced form. Kinetic characterization by the calculation of maximal velocities and apparent K(m) values and assaying for the dependence of uptake rates on the ionic milieu and for inhibition by glucose analogues and inhibitors of glucose transport revealed that after treatment with phorbol ester the uptake of total vitamin C in differentiated HL-60 cells was largely due to the low-affinity high-capacity glucose transporter. In contrast, in non-stimulated cells reduced ascorbate was taken up by the Na(+)-dependent high-affinity low-capacity ascorbate transporter. This change was probably due to the oxidation of ascorbate and, simultaneously, the recruitment of additional transporter molecules to the cell surface.

Biological Transport↗
PubMed1996

Protective action of dehydroascorbic acid on the Ah receptor-dependent and receptor-independent induction of lipid peroxidation in adipose tissue of male guinea pig caused by TCDD administration.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on lipid peroxidation, 3H-Me-glucose (3H-Me-glu), and 14C-dehydroascorbic acid (14C-DHA) uptakes were studied in adipose tissue of male guinea pig. Under in vitro test conditions, using isolated adipose tissue in a culture medium (explant culture), TCDD reduced the uptake of 3H-Me-glu and 14C-DHA in a dose- and time-dependent fashion. The IC50 values of TCDD's action were 0.04 and 2 nM on 14C-DHA and 3H-Me-glu uptakes, respectively. TCDD (10 nM) also suppressed glucose transporting activity within 15 minutes in explant-cultured adipocytes. Cytochalasin B (CB) and nonlabeled D-glucose inhibited 14C-DHA uptake also in a dose-dependent manner. In addition, TCDD was found to induce lipid peroxidation in explant-cultured adipose tissue. This effect of TCDD was similar to that of a typical lipid peroxidation inducer, CCl4, and it was dose and time dependent. TCDD caused a statistically significant rise in lipid peroxidation at a concentration as low as 0.1 nM after 60 minutes of treatment in explant culture. Unexpectedly, the Ah receptor partial antagonists, 4,7-phenanthroline and alpha-naphthoflavone, did not fully antagonize TCDD-induced lipid peroxidation in explant-cultured adipocytes. In vivo treatment of TCDD also induced lipid peroxidation. Among seven organs of male guinea pig tested, the levels of lipid peroxidation in adipose tissue and in liver increased at 1 and 40 days following a single i.p. dose of TCDD (1 microgram/kg). The results of an in vivo time-course study indicated that such an effect of TCDD was most pronounced after 40 days of treatment. Finally, we have tested the protective role of some antioxidants on TCDD-induced lipid peroxidation under explant-culture conditions. The results indicated that DHA, but not ascorbic acid, could completely abolish TCDD-induced lipid peroxidation. The protective effect of DHA on TCDD-induced lipid peroxidation was stronger than that of alpha-tocopherol and uric acid, and this effect was blocked by CB. We conclude from these studies that TCDD acts in this guinea pig tissue through two different routes: one is the Ah receptor-dependent route causing the reduction of the level of glucose transporters and subsequent decrease of cellular uptake of DHA and the other, the Ah receptor-independent route causing the overall lipid peroxidation. Nevertheless, it appears likely that both events are antagonized by DHA.

Adipose Tissue↗
PubMed2001

Degradation of dehydroascorbic acid in parenteral nutrition mixtures.

The degradation of ascorbic acid (AA) stored in parenteral nutrition (PN) regimens is initially by oxidation, catalysed by trace elements, in particular copper. After prolonged storage the concentration of AA remains relatively constant, with little variation, due to the lack of available oxygen. The initial degradation product is dehydroascorbic acid (DHAA). This is generated in an anaerobic environment, and is hypothesised to degrade by hydrolysis. It is the purpose of this investigation to ascertain the effect of temperature and trace elements on the anaerobic degradation of DHAA, and to identify the kinetics of the reaction. A stability-indicating reversed-phase HPLC assay was used. The column contained C(18) reverse-phase packing (Luna), mean diameter 5 microm. The column dimensions were 15 cm long with an internal diameter of 0.4 cm. The mobile phase consisted of methanol: phosphate buffer (pH 7.8: 0.067 mol dm(-3)) at a ratio of 40: 60 (v/v) and also included Cetrimide (mixed alkyltrimethylammonium bromide) (0.05 mol dm(-3)) as an ion pair reagent. The flow rate was 0.7 ml min(-1) and detection was by ultra-violet light absorption at 278 nm. This assay was used to monitor the degradation rate of DHAA in PN mixtures with and without trace elements over a range of temperatures (5-35 degrees C). Results indicated a first order reaction that was temperature-dependent but trace elements independent.

Dehydroascorbic Acid↗
PubMed1984

Effects of ascorbic and dehydroascorbic acid on the multiplication of tumor ascites cells in vitro.

The effects of AA and DHA on ATP C+ cell multiplication in vitro were studied by measuring incorporation of 3H thymidine into DNA. The results obtained demonstrate that both AA and DHA have the same effects: they favor cell multiplication at low doses and inhibit it at high doses. Experiments carried out with serial doses of both these substances revealed that AA is more efficient in determining both stimulating and inhibiting effects. The lesser efficiency of DHA may be attributed to its limited stability in culture medium. Studies on the effect of high doses of AA and DHA added to the culture medium in single or fractionated doses revealed that fractionated administration is more efficient in inhibiting cell multiplication than single administration.

Animals↗