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Query: UNIPROT:P06889 (Mol)
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A human volunteer study was conducted to test the effect of vitamin C supplementation on biomarkers of oxygen radical-mediated damage in individuals with a range of serum cholesterol levels. A group of 48 non-smokers, 24 men and 24 women, was selected from a panel of over 100 volunteers to give as wide a range of serum cholesterol levels as possible. None of the volunteers was taking medication to control cholesterol levels and they maintained their normal dietary habits so as not to compromise their cholesterol status. Volunteers were allocated to three groups of 16, each consisting of four males with low cholesterol levels (< 6 mmol/L) matched for age and build with four males with high cholesterol levels (> 6 mmol/L) and eight females matched in the same way. A three-treatment, three-treatment period, cross-over design was adopted to take account of any temporal differences in response. The three treatments given were placebo, 60 mg vitamin C/day (the recommended daily allowance) and 6 g vitamin C/day. Each treatment was given for 14 days with 6 weeks between the treatment periods. All procedures were performed to the standards of Good Clinical Practice. Blood samples were taken at the end of each treatment period. Serum was assayed for cholesterol whilst vitamin C, total antioxidant capacity, lipid peroxidation breakdown products and ras p21 protein levels were measured in plasma. Lymphocytes were examined for DNA damage using the Comet assay and chromosome aberration test. The Comet assay was conducted with and without challenge with hydrogen peroxide and the chromosome aberration test with and without challenge with bleomycin. Vitamin C supplementation caused a statistically significant increase in plasma vitamin C concentrations and total antioxidant capacity but did not affect cholesterol levels or ras p21 protein levels. There was a non-significant dose-related decrease in lipid peroxidation breakdown products with vitamin C supplementation. No effect on DNA damage was observed in the Comet assay, either with or without hydrogen peroxide challenge, or in the chromosome aberration test without bleomycin. However, a statistically significant increase in bleomycin-induced aberrations was found after vitamin C supplementation. This may be due to effects of vitamin C on iron status. Comparison of male and female subjects showed statistically significant differences in plasma vitamin C levels, the antioxidant capacity of the plasma and the number of chromosome aberrations induced by bleomycin challenge of lymphocytes in vitro. The results were the same for both low and high cholesterol subjects. This study provides no evidence of a beneficial effect on any of the biomarkers studied of vitamin C supplementation over a short-term supplementation period of 2 weeks in a population of healthy, non-smoking individuals eating a nutritionally adequate diet.
Environ Mol Mutagen 1997
PMID:The effects of vitamin C supplementation on biomarkers of oxygen radical generated damage in human volunteers with "low" or "high" cholesterol levels. 932 41

Ascorbic acid (AA) has both antioxidant and prooxidant activities. However, there have not been any studies to elucidate the molecular mechanisms that determine whether AA functions as an anti- or a prooxidant during oxidative stress. The results of this study, using the Chinese hamster ovary cell line AS52 as a model system, demonstrate that there is a temporal relationship between the anti- and prooxidant activities of a physiologically relevant concentration of AA (50 microM) and oxidative stress. Treatment of cells with AA (50 microM) 24 hr prior to treatment of the cells with a radical generating system (RGS) results in a statistically significant inhibition of the cytotoxicity and mutagenicity associated with exposure of AS52 cells to oxidative stress. Conversely, cotreatment of cells with AA and the RGS results in a statistically significant increase in both the cytotoxic and mutagenic effects of oxidative stress when compared to cell populations exposed only to the RGS. The results, using a novel histochemical-computer image analysis system to detect hydrogen peroxide (H2O2), also demonstrate that there is a direct correlation between the ability of AA to decrease the levels of H2O2 in cells and the cytotoxic and mutagenic effects of oxidative stress. This study suggests that the time at which AA is administered in relation to exposure to oxidative stress has an impact on AA antimutagenic activity, and this may explain the conflicting results concerning the effectiveness of AA as a cancer chemopreventive agent.
Environ Mol Mutagen 1997
PMID:Antimutagenic and promutagenic activity of ascorbic acid during oxidative stress. 936 13

Proliferation of smooth muscle cells and deposition of extracellular matrix proteins are important events in the formation of atherosclerotic plaques. We have investigated the direct and matrix-mediated effects of ascorbate on the proliferation rate of vascular smooth muscle cells (VSMC) isolated from the guinea-pig aorta. In the presence of ascorbate, cells showed a bi-phasic growth pattern. At 125 microM ascorbate, -3H--thymidine incorporation was stimulated 25%. However, higher concentrations of ascorbate gradually decreased cell-incorporated radioactivity up to 50% at 2 mM ascorbate. These effects of ascorbate on DNA synthesis in VSMC were paralleled by the changes in cell number and were not due to ascorbate cytotoxicity. Alpha-tocopherol (0.1 mM), individually and in combinations with 1 mm ascorbate, also inhibited DNA synthesis in VSMC. Ascorbate also influenced proliferation of smooth muscle cells through matrix-mediated effect. New VSMC culture plated on extracellular matrices deposited by smooth muscle cells in the presence of 0.1-1 mM ascorbate had up to 50% lower proliferation rate than on matrices from ascorbate-deficient cells, as assessed by [3H]-thymidine incorporation. This effect was independent from alpha-tocopherol and specific inhibitors of collagen synthesis: L-azetidine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid. An ascorbate-dependent matrix effect was specific for smooth muscle cells grown on VSMC and human skin fibroblast-originated matrices, but not for human vascular endothelial cells. The possible involvement of ascorbate in the regulation of smooth muscle cells proliferation by its antioxidant/pro-oxidant effects and regulation of extracellular matrix composition are discussed.
J Mol Cell Cardiol 1997 Dec
PMID:Ascorbate affects proliferation of guinea-pig vascular smooth muscle cells by direct and extracellular matrix-mediated effects. 944 35

Previously it was reported that hyperoxia induced death of the human lung adenocarcinoma cell line (A549 cells) by necrosis, not by apoptosis. This study examined proliferation and death of untransformed human small airway epithelial (SAE) cells in normoxia or hyperoxia in comparison with A549 cells. We tested the hypothesis that SAE cells respond differently to hyperoxic injury than do A549 cells. We measured total cell number and viability, thymidine incorporation (SAE cells only), lactate dehydrogenase (LDH) release, and apoptotic changes as markers for cell proliferation and death. Protective effects of antioxidant vitamins also were examined in SAE cells. In normoxia, subconfluent SAE cells had less apoptosis and fewer detached cells, but higher thymidine incorporation than did near-confluent cells. Hyperoxia suppressed thymidine incorporation and augmented apoptosis in both subconfluent and near-confluent SAE cells. Hyperoxia decreased the total cell number only in subconfluence, whereas SAE cell viability declined with hyperoxia in near confluence, but not in subconfluence. For SAE cells, necrosis assessed by LDH release was minimal in all conditions and was not augmented by hyperoxia in SAE cells. In contrast, normoxic A549 cells proliferated more rapidly than did SAE cells with a large number of cells detached during the culture. A549 cells underwent necrotic cell death under confluent or in hyperoxic conditions, but had much less apoptotic cell death. In SAE cells, vitamin E partially prevented the decline of thymidine incorporation with hyperoxia in subconfluence and protected against apoptotic changes with hyperoxia in both subconfluent and near-confluent conditions. Vitamin C prevented apoptosis with hyperoxia only in near-confluent SAE cells. Thus, SAE cells maintained balanced apoptosis and cell proliferation that were altered by cell density and hyperoxia and demonstrated very little necrosis with hyperoxia. Although A549 cells underwent cell death mainly by necrosis, they also were influenced by cell density and hyperoxia. Cell density also determined specific antioxidant vitamin protection in SAE cells.
Am J Respir Cell Mol Biol 1998 Sep
PMID:The effects of hyperoxic injury and antioxidant vitamins on death and proliferation of human small airway epithelial cells. 973 Aug 70

The effect of estrogens, including estrone (E1), estradiol-17beta (E2), estriol (E3) and 2-hydroxyestradiol (2-OH-E2), on the oxidative damage induced by ferrylmyoglobin (ferrylMb) was investigated. These estrogens inhibited lipid peroxidation induced by ferrylMb. The ability of 2-OH-E2 to inhibit lipid peroxidation was much greater than the other estrogens. Furthermore, 2-OH-E2 trapped 2,2'-azobis-(2-amidinopropane)-dihydrochloride peroxyl radicals more rapidly, and among these estrogens only 2-OH-E2 reacted with 2,2-diphenyl-1-picrylhydrazyl. These results suggest that the ability of 2-OH-E2 to inhibit lipid peroxidation is because it scavenges lipid peroxyl and carbon-centered radicals. Estrogens, except for 2-OH-E2, partially prevented the inactivation of alcohol dehydrogenase (ADH) induced by ferrylMb. Of interest, however, the exposure of sulfhydryl (SH) enzymes to ferrylMb in the presence of 2-OH-E2 dramatically increased the inhibition of the enzyme activity. Ascorbic acid (ASA) and reduced glutathione (GSH) strongly inhibited the inactivation of ADH induced by ferrylMb in the presence of 2-OH-E2. During the reaction of ferrylMb with ASA or GSH in the presence of 2-OH-E2, large amounts of oxymyoglobin were formed, suggesting the involvement of the semiquinone from 2-OH-E2 in the reduction of metmyoglobin. Presumably, the semiquinone formed from 2-OH-E2 oxidizes the SH group of enzymes to facilitate the rapid inactivation of the SH enzymes induced by ferrylMb.
J Steroid Biochem Mol Biol 1998 Oct
PMID:Effect of estrogens on the oxidative damage induced by ferrylmyoglobin. 978 30

Antioxidants are known to play an important role in mitigating oxidative stress injury. Regional concentrations of non-enzymatic antioxidants, redox ratio and lipid peroxides were studied in normal, ischemic and ischemic-reperfused rat hearts. Isolated perfused rat hearts were made globally ischemic for 45 min and reperfused for 15 min. Right ventricular wall (RVW), septum (S) and left ventricular wall (LVW) from control, ischemic (I) and reperfused (I-R) hearts were analysed. Tocopherol, retinol and ascorbic acid concentrations in different regions of perfused control hearts were not different. Reduced glutathione (GSH) was significantly lower in the RVW, while S and LVW had about three-fold higher levels. Oxidized glutathione (GSSG) was lower in the RVW and most concentrated in the LVW. The GSH:GSSG ratio was highest in the septum while RVW and LVW had similar values. Lipid hydroperoxide (LPx) concentrations in the three regions of control hearts were not different from each other. In I and I-R hearts, vitamin E declined in all three regions but the loss was significant only in the septum in the I group and in the septum and LVW of the I-R group. Vitamin A showed significant loss in all three regions of the I-R group. Vitamin C declined significantly only in the RVW of the I-R group. GSH increased in the RVW of the I and I-R groups compared to controls. GSSG was increased in the RVW and septum of the I group and in all regions of the I-R group. The redox ratio, GSH:GSSG, decreased in all regions of both I and I-R groups. LPx were increased in the septum of the I group and in all regions of the I-R group. Despite unique regional differences in non-enzymatic antioxidants, a comparable increase in LPx in the I-R group and similar extent of reduction in the redox ratio in different regions of the I and I-R groups, suggest that each myocardial region may use different antioxidant mechanisms to withstand oxidative stress.
J Mol Cell Cardiol 1999 Jan
PMID:Regional differences in non-enzymatic antioxidants in the heart under control and oxidative stress conditions. 1007 27

Delphinidine-3-(p-coumaroylrutinoside)-5-glucoside (nasunin), an anthocyanin was isolated as purple colored crystals from eggplant peels, Solanum melongena L. 'Chouja'. Using an electron spin resonance spectrometer and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), spin trapping, hydroxyl (.OH) or superoxide anion radicals (02*-) generated by the Fenton reaction or the hypoxanthine-xanthine oxidase system were measured as DMPO-OH or DMPO-OOH spin adducts. L-Ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetra-methyl-2-(4,8,12-trimethyltridecyl)-2 H-1-benzopyran-6yl-hydrogen phosphate] potassium salt (EPC-K1) and bovine erythrocyte superoxide dismutase (SOD) were used as standards for .OH and O2*-, respectively. Nasunin directly scavenged O2*- with a potency of 143+/-8 SOD-equivalent units/mg), and inhibited formation of DMPO-OH (0.65+/-0.07 EPC-K1 micromol/mg). A spectrophotometric study showed that nasunin formed an iron complex with a molar ratio of nasunin : Fe3+ of 2 : 1. Therefore, hydroxyl radical scavenging by nasunin is not due to direct radical scavenging but inhibition of .OH generation by chelating iron. Nasunin (1 microM) significantly protected against lipid peroxidation of brain homogenates (p<0.001) as measured by malonaldehyde and 4-hydroxyalkenals. These findings demonstrate that nasunin is a potent O2*- scavenger and iron chelator which can protect against lipid peroxidation.
Res Commun Mol Pathol Pharmacol 1998 Nov
PMID:Antioxidant activity of nasunin, an anthocyanin in eggplant. 1010 May 9

Ascorbic acid serves a vital role as a pre-eminent antioxidant. In animals, it has been shown to be concentrated in granulosa and theca cells of the follicle, in luteal cells of the corpus luteum, and in the peripheral cytoplasm of the oocyte. We have previously identified hormonally-regulated ascorbic acid transporters in rat granulosa and luteal cells, and herein present preliminary evidence for the presence of a transporter for ascorbic acid in human granulosa-lutein cells. Granulosa-lutein cells were obtained from the follicular fluid of patients undergoing in-vitro fertilization. Following an overnight incubation, the cells were incubated with [14C]-ascorbic acid (0.15 microCi; 150 microM) and ascorbic acid uptake was determined. The uptake of ascorbic acid was saturable with a Michaeli's constant (Km) and maximum velocity (Vmax) of 21 microM and 3 pmol/10(6) cells/min respectively. Ouabain, low Na+ medium, and dinitrophenol significantly inhibited ascorbic acid uptake (P<0.05). Neither the presence of insulin, human chorionic gonadotrophin (HCG), insulin-like growth factor (IGF)-I, nor IGF-II affected the uptake of ascorbic acid in a statistically significant fashion. Following saturation of cellular uptake, the ascorbic acid level was estimated to be 1.04 pmoles/10(6) cells or approximately 1 mM, a high concentration similar to that seen in rat luteal cells. Active ascorbic acid transport in human granulosa-lutein cells appears to occur via a Na+ - and energy-dependent transporter, with high levels of ascorbic acid being accumulated in these cells.
Mol Hum Reprod 1999 Apr
PMID:Identification and characterization of an ascorbic acid transporter in human granulosa-lutein cells. 1032

Radical scavenging by reconstituted lyophilized powders of water extracts from 16 common vegetables was measured using electron spin resonance (ESR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), hydroxyl radicals, (.OH) or superoxide anion radicals (O2.-), as DMPO-OH or DMPO-OOH spin adducts. On a dry weight basis, eggplant, and red, yellow and green bell pepper extracts showed potent superoxide anion radical scavenging activities (SOD-like activities). Ascorbate oxidase- or heat-treatments, decreased SOD-like activities in bell pepper extracts suggesting that ascorbate accounts for much of their free radical scavenging activity. Eggplant epidermis extract exhibited the most potent hydroxyl radical scavenging and SOD-like activities. Eggplant SOD-like activity did not decrease after ascorbate oxidase treatment, but decreased following ultrafiltration demonstrating that SOD-like activity is partially due to high molecular weight substances. Nasunin, an anthocyanin in eggplant epidermis, showed markedly potent superoxide anion radical scavenging activity, while it inhibited hydroxyl radical generation probably by chelating ferrous ion.
Biochem Mol Biol Int 1999 Jun
PMID:Superoxide anion and hydroxyl radical scavenging activities of vegetable extracts measured using electron spin resonance. 1041 Feb 44

Etoposide (VP-16) is extensively used to treat cancer, yet its efficacy is calamitously associated with an increased risk of secondary acute myelogenous leukemia. The mechanisms for the extremely high susceptibility of myeloid stem cells to the leukemogenic effects of etoposide have not been elucidated. We propose a mechanism to account for the etoposide-induced secondary acute myelogenous leukemia and nutritional strategies to prevent this complication of etoposide therapy. We hypothesize that etoposide phenoxyl radicals (etoposide-O(.)) formed from etoposide by myeloperoxidase are responsible for its genotoxic effects in bone marrow progenitor cells, which contain constitutively high myeloperoxidase activity. Here, we used purified human myeloperoxidase, as well as human leukemia HL60 cells with high myeloperoxidase activity and provide evidence of the following. 1) Etoposide undergoes one-electron oxidation to etoposide-O(.) catalyzed by both purified myeloperoxidase and myeloperoxidase activity in HL60 cells; formation of etoposide-O(.)radicals is completely blocked by myeloperoxidase inhibitors, cyanide and azide. 2) Intracellular reductants, GSH and protein sulfhydryls (but not phospholipids), are involved in myeloperoxidase-catalyzed etoposide redox-cycling that oxidizes endogenous thiols; pretreatment of HL60 cells with a maleimide thiol reagent, ThioGlo1, prevents redox-cycling of etoposide-O(.) radicals and permits their direct electron paramagnetic resonance detection in cell homogenates. VP-16 redox-cycling by purified myeloperoxidase (in the presence of GSH) or by myeloperoxidase activity in HL60 cells is accompanied by generation of thiyl radicals, GS(.), determined by HPLC assay of 5, 5-dimethyl-1-pyrroline glytathionyl N-oxide glytathionyl nitrone adducts. 3) Ascorbate directly reduces etoposide-O(.), thus competitively inhibiting etoposide-O(.)-induced thiol oxidation. Ascorbate also diminishes etoposide-induced topo II-DNA complex formation in myeloperoxidase-rich HL60 cells (but not in HL60 cells with myeloperoxidase activity depleted by pretreatment with succinyl acetone). 4) A vitamin E homolog, 2,2,5,7, 8-pentamethyl-6-hydroxychromane, a hindered phenolic compound whose phenoxyl radicals do not oxidize endogenous thiols, effectively competes with etoposide as a substrate for myeloperoxidase, thus preventing etoposide-O(.)-induced redox-cycling. We conclude that nutritional antioxidant strategies can be targeted at minimizing etoposide conversion to etoposide-O(.), thus minimizing the genotoxic effects of the radicals in bone marrow myelogenous progenitor cells, i.e., chemoprevention of etoposide-induced acute myelogenous leukemia.
Mol Pharmacol 1999 Sep
PMID:Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. 1046 37


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