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PubMed1998

Hexose transporter expression and function in mammalian spermatozoa: cellular localization and transport of hexoses and vitamin C.

We analyzed the expression of hexose transporters in human testis and in human, rat, and bull spermatozoa and studied the uptake of hexoses and vitamin C in bull spermatozoa. Immunocytochemical and reverse transcription-polymerase chain reaction analyses demonstrated that adult human testis expressed the hexose transporters GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5. Immunoblotting experiments demonstrated the presence of proteins of about 50-70 kD reactive with anti-GLUT1, GLUT2, GLUT3, and GLUT5 in membranes prepared from human spermatozoa, but no proteins reactive with GLUT4 antibodies were detected. Immunolocalization experiments confirmed the presence of GLUT1, GLUT2, GLUT3, GLUT5, and low levels of GLUT4 in human, rat, and bull spermatozoa. Each transporter isoform showed a typical subcellular localization in the head and the sperm tail. In the tail, GLUT3 and GLUT5 were present at the level of the middle piece in the three species examined, GLUT1 was present in the principal piece, and the localization of GLUT2 differed according of the species examined. Bull spermatozoa transported deoxyglucose, fructose, and the oxidized form of vitamin C, dehydroascorbic acid. Transport of deoxyglucose and dehydroascorbic acid was inhibited by cytochalasin B, indicating the direct participation of facilitative hexose transporters in the transport of both substrates by bull spermatozoa. Transport of fructose was not affected by cytochalasin B, which is consistent for an important role for GLUT5 in the transport of fructose in these cells. The data show that human, rat, and bull spermatozoa express several hexose transporter isoforms that allow for the efficient uptake of glucose, fructose, and dehydroascorbic acid by these cells.

Animals↗
PubMed1999

Specificity of ascorbate analogs for ascorbate transport. Synthesis and detection of [(125)I]6-deoxy-6-iodo-L-ascorbic acid and characterization of its ascorbate-specific transport properties.

Cellular ascorbic acid accumulation occurs in vitro by two distinct mechanisms: transport of ascorbate itself or transport and subsequent intracellular reduction of its oxidized product, dehydroascorbic acid. It is unclear which mechanism predominates in vivo. An easily detectable compound resembling ascorbate but not dehydroascorbic acid could be a powerful tool to distinguish the two transport activities. To identify compounds, 21 ascorbate analogs were tested for inhibition of ascorbate or dehydroascorbic acid transport in human fibroblasts. The most effective analogs, competitive inhibitors of ascorbate transport with K(i) values of 3 microM, were 6-deoxy-6-bromo-, 6-deoxy-6-chloro-, and 6-deoxy-6-iodo-L-ascorbate. No analog inhibited dehydroascorbic acid transport. Using substitution chemistry, [(125)I]6-deoxy-6-iodo-L-ascorbate (1.4 x 10(4) mCi/mmol) was synthesized. HPLC detection methods were developed for radiolabeled and nonradiolabeled compounds, and transport kinetics of both compounds were characterized. Transport was sodium-dependent, inhibited by excess ascorbate, and similar to that of ascorbate. Transport of oxidized ascorbate and oxidized 6-deoxy-6-iodo-L-ascorbate was investigated using Xenopus laevis oocytes expressing glucose transporter isoform GLUT1 or GLUT3. Oxidation of ascorbate or its analog in media increased uptake of ascorbate in oocytes by 6-13-fold compared with control but not that of 6-deoxy-6-iodo-L-ascorbate. Therefore, 6-deoxy-6-iodo-L-ascorbate, although an effective inhibitor of ascorbate transport, either in its reduced or oxidized form was not a substrate for dehydroascorbic acid transport. Thus, radiolabeled and nonradiolabeled 6-deoxy-6-iodo-L-ascorbate provide a new means for discriminating dehydroascorbic acid and ascorbate transport in ascorbate recycling.

Animals↗
PubMed1998

13C NMR studies of vitamin C transport and its redox cycling in human erythrocytes.

13C NMR spectra of labeled [1-13C]- and [2-13C]ascorbic acid were seen to contain resonances arising from the intra- and extracellular populations in suspensions of human erythrocytes; i.e., they displayed the "split-peak" phenomenon. This new observation enabled the ready determination of the location, whether inside or outside cells, of the redox reactions in which the vitamin C was involved and to monitor the transport of the compounds into and out of the cells. Thus, the membrane permeability of ascorbic acid and the apparent Vmax and KM for the reduction of dehydroascorbic acid were determined in a noninvasive manner. In contrast to other work, evidence was found of a transporter of dehydroascorbic acid which is different from the glucose transporter. This transport system also appeared to be involved in the simultaneous reduction of dehydroascorbic acid on its passage into the cells. A second reduction process appeared to occur extracellularly, by the passage of reducing equivalents through the plasma membrane, as occurs with the reduction of ferricyanide. Evidence is presented that the processes of vitamin C recycling rely on different cellular sources of reducing equivalents. Whereas the transport and reduction via the membrane appeared to be dependent on glycolysis (NADH), the reduction of intracellular dehydroascorbic acid, formed in the process of transmembrane electron transfer or by transport from the outside of the cell, is currently thought to depend on NADPH.

4-Chloromercuribenzenesulfonate↗
PubMed1998

Colony-stimulating factors signal for increased transport of vitamin C in human host defense cells.

Although serum concentrations of ascorbic acid seldom exceed 150 micromol/L, mature neutrophils and mononuclear phagocytes accumulate millimolar concentrations of vitamin C. Relatively little is known about the mechanisms regulating this process. The colony-stimulating factors (CSFs), which are central modulators of the production, maturation, and function of human granulocytes and mononuclear phagocytes, are known to stimulate increased glucose uptake in target cells. We show here that vitamin C uptake in neutrophils, monocytes, and a neutrophilic HL-60 cell line is enhanced by the CSFs. Hexose uptake studies and competition analyses showed that dehydroascorbic acid is taken up by these cells through facilitative glucose transporters. Human monocytes were found to have a greater capacity to take up dehydroascorbic acid than neutrophils, related to more facilitative glucose transporters on the monocyte cell membrane. Ascorbic acid was not transported by these myeloid cells, indicating that they do not express a sodium-ascorbate cotransporter. Granulocyte (G)- and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated increased uptake of vitamin C in human neutrophils, monocytes, and HL-60 neutrophils. In HL-60 neutrophils, GM-CSF increased both the transport of dehydroascorbic acid and the intracellular accumulation of ascorbic acid. The increase in transport was related to a decrease in Km for transport of dehydroascorbic acid without a change in Vmax. Increased ascorbic acid accumulation was a secondary effect of increased transport. Triggering the neutrophils with the peptide fMetLeuPhe led to enhanced vitamin C uptake by increasing the oxidation of ascorbic acid to the transportable moiety dehydroascorbic acid, and this effect was increased by priming the cells with GM-CSF. Thus, the CSFs act at least at two distinct functional loci to increase cellular vitamin C uptake: conversion of ascorbic acid to dehydroascorbic acid by enhanced oxidation in the pericellular milieu and increased transport of DHA through the facilitative glucose transporters at the cell membrane. These results link the regulated uptake of vitamin C in human host defense cells to the action of CSFs.

Ascorbic Acid↗
PubMedDate not supplied

Vitamin C uptake and recycling among normal and tumor cells from the central nervous system.

Specialized cells transport vitamin C in its reduced form using sodium-dependent cotransporters (SVCT1 and SVCT2). Additionally, different cells transport the oxidized form of vitamin C, dehydroascorbic acid, through glucose transporters (GLUTs). We have proposed recently a model for vitamin C uptake that resolves the apparent contradiction that although only ascorbic acid is detectable in vivo, there are cells that transport only dehydroascorbic acid. We carried out a detailed kinetic analysis to compare the mechanisms of vitamin C uptake in normal human melanocytes, neurons isolated from brain cortex, hypothalamic ependymal-glial cells, and astrocytes. Uptake of ascorbic acid was also analyzed in the human oligodendroglioma cell line TC620, in human choroid plexus papilloma cells (HCPPC-1), and in the neuroblastoma cell line Neuro-2a. Melanocytes were used to carry out a detailed analysis of vitamin C uptake. Analysis of the transport data by the Lineweaver-Burk plot revealed the presence of one functional component (K(m) 20 microM) involved in ascorbic acid transport by melanocytes. Vitamin C sodium-dependent saturable uptake was also observed in neurons and hypothalamic tanycytes. We confirmed SVCT2 expression in neurons by in situ hybridization; however, SVCT2 expression was not detected in astrocytes in situ. Functional data indicate that astrocytes transport mainly dehydroascorbic acid, using the glucose transporter GLUT1. Our functional uptake analyses support the hypothesis that astrocytes are involved in vitamin C recycling in the nervous system. This recycling model may work as an efficient system for the salvage of vitamin C by avoiding the hydrolysis of dehydroascorbic acid produced by antioxidative protection.

Animals↗
PubMed2004

Ebselen is a dehydroascorbate reductase mimic, facilitating the recycling of ascorbate via mammalian thioredoxin systems.

Ebselen is a selanazal drug recently revealed as a highly efficient peroxiredoxin mimic catalyzing the hydroperoxide reduction by the mammalian thioredoxin system [thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH]. The mammalian Trx system is a dehydroascorbic acid reductase recycling ascorbic acid essential for cell functions. Here we report that ebselen strongly facilitated the recycling of ascorbic acid by the TrxR both with and without Trx present. Reduction of dehydroascorbic acid by TrxR has a pH optimum of 6.4, and only approximately 55% of this activity at a physiological pH of 7.4. Ebselen at 6 microM enhances this reaction three-fold and with the same pH optimum of 6.4. The mechanism of the ebselen effect is suggested to involve reduction of dehydroascorbic acid by the ebselen selenol, a highly efficient two-electron reductant. Thus, ebselen acts as an antioxidant to lower the peroxide tone inside cells and to facilitate the recycling of dehydroascorbic acid to ascorbic acid, so as to increase the radical scavenging capacity of ascorbic acid directly or indirectly via vitamin E. The high ascorbic acid recycling efficiency of ebselen at pH 6.4 may play a major role in oxidatively stressed cells, where cytosol acidosis may trigger various responses, including apoptosis.

Animals↗
PubMed1989

Ascorbate and dehydroascorbate: distribution in mononuclear cells of healthy elderly people.

Concentrations of ascorbic acid and total ascorbate (ascorbic acid + dehydroascorbic acid) were determined in mononuclear cells from eight elderly men and nine elderly women (aged greater than 65 y) on controlled intakes of vitamin C. No increase in mononuclear cell ascorbic acid concentration was observed for intakes between 30 and 280 mg/d. A significant increase in total ascorbate concentrations was observed for the same range of intakes (p less than 0.01), primarily because of an increase in dehydroascorbic acid. Women were found to have significantly higher ascorbic acid concentrations in mononuclear cells than men (p less than 0.02) for similar intakes of vitamin C. No difference was observed for total ascorbate concentrations. The ratio of dehydroascorbate to ascorbate increased with increasing intake of vitamin C for both men and women.

Aged↗
PubMed1998

Transport mechanisms for vitamin C in the JAR human placental choriocarcinoma cell line.

We investigated the transport pathways available for the uptake of vitamin C in the human placental choriocarcinoma cell line, JAR. These cells were found to possess the capacity to accumulate the vitamin when presented either in the oxidized form (dehydroascorbic acid) or in the reduced form (ascorbate). Dithiothreitol and 5,5'-dithiobis(2-nitrobenzoic acid) were used to maintain vitamin C as ascorbate and dehydroascorbic acid, respectively. The uptake of these two forms of vitamin C in JAR cells was found to occur by different mechanisms. The uptake of the dehydroascorbic acid was Na(+)-independent and was mediated by facilitative glucose transporters as evidenced from the inhibition of the uptake process by glucose. On the other hand, the uptake of ascorbate was Na(+)-dependent and was not sensitive to inhibition by glucose. Substitution of Na+ with other monovalent cations abolished the uptake of ascorbate completely. The uptake process was, however, not influenced by anions. Kinetic analysis indicated the presence of a single saturable transport system for ascorbate with a Michaelis-Menten constant of 22 +/- 1 microM. The dependence of the uptake rare of ascorbate on Na+ concentration exhibited sigmoidal kinetics, suggesting interaction of more than one Na+ ion with the transporter. The Hill coefficient for the Na+ interaction was 2, indicating that the Na(+)-dependent ascorbate transport is electrogenic. The Na(+)-dependent stimulation of ascorbate uptake was primarily due to an increase in the affinity of the transporter for ascorbate in the presence of Na+. It is concluded that the JAR placental trophoblast cell line expresses two different transport systems for vitamin C: one for the reduced form of the vitamin ascorbate; and the other for the oxidized form of the vitamin dehydroascorbic acid.

Ascorbic Acid↗
PubMed2002

Up-regulation and polarized expression of the sodium-ascorbic acid transporter SVCT1 in post-confluent differentiated CaCo-2 cells.

Human cells acquire vitamin C using two different transporter systems, the sodium-ascorbic acid co-transporters with specificity for ascorbic acid, and the facilitative glucose transporters with specificity for dehydroascorbic acid. There is no information on the mechanism of vitamin C transport across the intestinal barrier, a step that determines the bioavailability of vitamin C in humans. We used the colon carcinoma cell line CaCo-2 as an in vitro model for vitamin C transport in enterocyte-like cells. The results of transport kinetics, sodium dependence, inhibition studies, and reverse transcriptase-PCR analysis indicated that CaCo-2 cells express the sodium-ascorbate co-transporters SVCT1 and SVCT2, the dehydroascorbic acid transporters GLUT1 and GLUT3, and a third dehydroascorbic acid transporter with properties expected for GLUT2. Analysis by real time quantitative PCR revealed that the post-confluent differentiation of CaCo-2 cells was accompanied by a marked increase (4-fold) in the steady-state level of SVCT1 mRNA, without changes in SVCT2 mRNA levels. Functional studies revealed that the differentiated cells expressed only one functional ascorbic acid transporter having properties expected for SVCT1, and transported ascorbic acid with a V(max) that was increased at least 2-fold compared with pre-confluent cells. Moreover, post-confluent Caco-2 cells growing as monolayers in permeable filter inserts showed selective sorting of SVCT1 to the apical membrane compartment, without functional evidence for the expression of SVCT2. The identification of SVCT1 as the transporter that allows vectorial uptake of ascorbic acid in differentiated CaCo-2 cells has a direct impact on our understanding of the mechanism for vitamin C transport across the intestinal barrier.

Ascorbic Acid↗
PubMed1998

Determination of the ascorbate free radical concentration in mixtures of ascorbate and dehydroascorbate.

Ascorbate free radical is considered to be a substrate for a plasma membrane redox system of eukaryotic cells, and might be involved in stimulation of cell proliferation. It can be generated by transition metal-dependent oxidation of ascorbate or by an equilibrium reaction of ascorbate with dehydroascorbic acid. Using ESR spectroscopic measurements at pH 7.4, we show that when ascorbate and dehydroascorbic acid are mixed at concentrations lower than 2.5 mM, the ascorbate free radical concentration was determined by metal-dependent reactions and not by the equilibrium reaction. We conclude that, for studies under physiological conditions, the ascorbate free radical concentration cannot simply be calculated from the equilibrium constant and the ascorbate and dehydroascorbic acid concentration, but has to be determined experimentally.

Ascorbic Acid↗
PubMed1998

Loss of glutathione, ascorbate recycling, and free radical scavenging in human erythrocytes exposed to filtered cigarette smoke.

Exposure of human erythrocytes to filtered cigarette smoke in vitro inhibited their capacity to reduce dehydroascorbic acid (ascorbate recycling activity). Glucose uptake was not affected, implying that dehydroascorbic acid transport was not inhibited by the smoke treatment. The intracellular reduction of cationic nitroxide free radicals, which provides a measure of ascorbate recycling, was also inhibited by cigarette smoke. A major factor in the inhibition of free radical reduction was glutathione depletion. However, glutathione depletion alone could not account for the inhibition of free radical reduction because a restoration of the glutathione pool in hemolyzed cells only partially restored free radical reduction activity. Another factor inhibiting free radical reduction was a lowering of pH, which was attributed mainly to the uptake of CO2 and was reversible by restoring the physiological pH. Exogenous glutathione spared both intracellular glutathione and free radical reduction activity. The rate of depletion of intracellular glutathione was similar to that of extracellular glutathione, indicating that the erythrocyte membrane did not significantly attenuate thiol-reactive species in smoke. Protein thiols were also depleted by cigarette smoke, but to a much lesser extent than was glutathione. Ascorbate was relatively unaffected by cigarette smoke; significant intracellular ascorbate levels remained after glutathione was barely detectable. Autooxidizable reducing agents, capable of reducing both reduced piperidinyl (Tempo) and pyrrolidinyl (Proxyl) nitroxides partitioned from filtered cigarette smoke into aqueous solutions. Attempts to detect cigarette smoke-derived oxidants in buffer solutions or in cell suspensions with a prereduced Tempo nitroxide, whose oxidation properties resemble those of ascorbate, were unsuccessful. The results of this study suggest that chemical modification of glutathione is a major damage mechanism of filtered cigarette smoke, whereas free radical oxidations are relatively insignificant.

Ascorbic Acid↗
PubMed1992

Ascorbic acid status in uremics.

Plasma levels of ascorbic acid (AA) and dehydroascorbic acid (DHA) were estimated in 27 patients of end stage renal failure (ESRF) on standard conservative therapy (group A) and 9 patients of ESRF on maintenance haemodialysis (MHD; group B). Fourteen healthy subjects matched for age and sex served as control (group C). The dietary intake of vitamin C was significantly decreased in group A than in group B compared to control. Similarly, plasma AA was significantly lowered to 0.801 +/- 0.283 mg per cent in group A compared to 1.421 +/- 0.47 mg per cent in control. While it was just lowered to 1.058 +/- 0.272 mg per cent in group B. Although plasma level of DHA was raised to 0.243 +/- 0.486 mg per cent and 0.166 +/- 0.54 mg per cent in groups A and B respectively, the increase was not statistically significant. In our present study, the DHA/AA ratio was found to be inversely proportional to the plasma AA. Further, this ratio has been claimed to be a better indicator of overall reducing atmosphere (i.e., profile of vitamin C) of the body.

Ascorbic Acid↗
PubMed1972

Stimulation of the hexose monophosphate shunt in human neutrophils by ascorbic acid: mechanism of action.

The addition of either ascorbic acid or dehydroascorbic acid to a suspension of polymorphonuclear leukocytes caused a dramatic increase in the resting hexose monophosphate shunt activity. A sequence of reactions involving dehydroascorbate, reduced glutathione, and reduced nicotinamide adenine dinucleotide phosphate is described to explain this stimulation. This sequence could provide an alternate method of producing H(2)O(2) and a bactericidal mechanism which is independent of myeloperoxidase.

Ascorbic Acid↗
PubMedDate not supplied

Ascorbic acid and diabetes mellitus.

Dehydroascorbic acid, the oxidized form of vitamin C, causes diabetes when injected into animals and has been reported to be present in increased amounts in the blood of patients with diabetes mellitus and even in prediabetics. One of the earliest changes in diabetes mellitus is electron-microscopic evidence of damage to the inner endothelial lining of the blood vessels. Certain bioflavonoids, which are natural non-toxic food substances from plants, like rutin from buckwheat, prevent the oxidation of ascorbic acid and seem to protect the endothelium when given with vitamin C; it is therefore suggested that all vitamin C tablets should be combined with these flavonoids.

Animals↗
PubMed1990

Reduction of extracellular methemoglobin by erythrocytes.

Erythrocytes, suspended in a glucose-containing buffer, catalyzed the partial reduction of extracellular methemoglobin. Physiological concentrations of ascorbic acid or dehydroascorbic acid greatly enhanced the rate of reaction and the ultimate extent of reduction. The relationship between erythrocyte concentration and initial reaction rate was nonlinear, which suggested that the rate limiting factor was not an erythrocyte membrane enzyme. Also, significant dehydroascorbate-stimulated reduction occurred even when the erythrocytes and methemoglobin were separated by a dialysis membrane. The above observations indicate that the transfer of reducing equivalents across the erythrocyte membrane and reduction of extracellular methemoglobin can be accomplished by release and recycling of ascorbic acid.

Ascorbic Acid↗
PubMed1998

Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase.

Recycling of ascorbic acid from its oxidized forms is required to maintain intracellular stores of the vitamin in most cells. Since the ubiquitous selenoenzyme thioredoxin reductase can recycle dehydroascorbic acid to ascorbate, we investigated the possibility that the enzyme can also reduce the one-electron-oxidized ascorbyl free radical to ascorbate. Purified rat liver thioredoxin reductase catalyzed the disappearance of NADPH in the presence of low micromolar concentrations of the ascorbyl free radical that were generated from ascorbate by ascorbate oxidase, and this effect was markedly stimulated by selenocystine. Dehydroascorbic acid is generated by dismutation of the ascorbyl free radical, and thioredoxin reductase can reduce dehydroascorbic acid to ascorbate. However, control studies showed that the amounts of dehydroascorbic acid generated under the assay conditions used were too low to account for the observed loss of NADPH. Electron paramagnetic resonance spectroscopy directly confirmed that the reductase decreased steady-state ascorbyl free radical concentrations, as expected if thioredoxin reductase reduces the ascorbyl free radical. Dialyzed cytosol from rat liver homogenates also catalyzed NADPH-dependent reduction of the ascorbyl free radical. Specificity for thioredoxin reductase was indicated by loss of activity in dialyzed cytosol prepared from livers of selenium-deficient rats, by inhibition with aurothioglucose at concentrations selective for thioredoxin reductase, and by stimulation with selenocystine. Microsomal fractions prepared from rat liver showed substantial NADH-dependent ascorbyl free radical reduction that was not sensitive to selenium depletion. These results suggest that thioredoxin reductase can function as a cytosolic ascorbyl free radical reductase that may complement cellular ascorbate recycling by membrane-bound NADH-dependent reductases.

Animals↗
PubMed2000

Human vitamin C (L-ascorbic acid) transporter SVCT1.

In human, vitamin C (l-ascorbic acid) is an essential micronutrient required for an array of biological functions including enzymatic reactions and antioxidation. We describe here the molecular cloning of a novel human cDNA encoding a vitamin C transporter SVCT1. SVCT1 is largely confined to bulk-transporting epithelia (e.g., kidney and small intestine) with a putative alternative-splice product present in thymus. Applying radiotracer and voltage-clamp approaches in cRNA-injected Xenopus oocytes, we found that SVCT1 mediates saturable, concentrative, high-affinity l-ascorbic acid transport (K(0.5) = 50-100 microM) that is electrogenic and can be inhibited by phloretin. SVCT1 displays exquisite substrate selectivity, greatly favoring l-ascorbic acid over its isomers d-isoascorbic acid and dehydroascorbic acid and 2- or 6-substituted analogues, whereas glucose and nucleobases are excluded. We have mapped the SLC23A2 gene (coding for SVCT1) to human chromosome 5 in band 5q31.2-31.3, within a region commonly deleted in malignant myeloid (leukemia) diseases. In addition, we have demonstrated that the human SLC23A1 gene product is a related high-affinity l-ascorbic acid transporter (SVCT2) that is widely distributed in brain, retina, and a host of endocrine and neuroendocrine tissues. The molecular identification of the human l-ascorbic acid transporters now provides the tools with which to investigate their roles in vitamin C metabolism in health and disease.

Amino Acid Sequence↗
PubMed1997

Glutathione deficiency potentiates manganese toxicity in rat striatum and brainstem and in PC12 cells.

Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), glutathione (GSH), ascorbic acid (AA), dehydroascorbic acid (DHAA) and uric acid (UA) were determined in the striatum and/or in the brainstem of 3-month-old male Wistar rats after subchronic oral exposure to MnCl2 (20 mg kg-1 daily) alone or associated to buthionine (S,R)sulphoximine-ethyl ester (BSO-E), an inhibitor of GSH synthesis. The NA, DA, DOPAC, GSH and glutathione disulphide (GSSG) concentrations were also determined in PC12 cells incubated with Mn alone or associated with either BSO-E or AA. When PC12 cells were incubated with AA, cellular AA and DHAA concentrations were also determined. It was found that BSO-E: (a) decreased GSH levels in the striatum and in the brainstem; (b) potentiated the Mn-induced increase in AA oxidation and uric acid formation in both brain regions; and (c) potentiated the Mn-induced DA and NA depletion in the brainstem. Moreover, the changes in striatal DA metabolism induced by the BSO-E association with Mn (decrease in DA, DOPAC and HVA levels and in the DOPAC + HVA/DA ratio) are consistent with the hypothesis of a loss of dopaminergic neurons. In PC12 cells, BSO-E decreased GSH and GSSG levels and potentiated the Mn-induced decrease-in DA and NA concentrations. On the contrary, AA antagonised the Mn-induced DA and NA depletion. AA antagonised also the Mn- and MN+ BSO-induced decrease in PC12 cells viability. In conclusion, the impairment of neuronal antioxidant system activity plays a permissive role in the oxidative stress-mediated Mn neurotoxicity.

Animals↗