Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative DNA damage, as expressed by 8-hydroxydeoxyguanosine (8-OHdG), was investigated in calf thymus DNA exposed to either ultraviolet radiation or to FeCl2/H2O2 in a Fenton-like reaction. The influence of iron (absent in the UV system and present in the FeCl2/H2O2 system) and pH (7.4 and 4.0) on the effect of glutathione (GSH), ascorbate, and 5-aminosalicylic acid (5-ASA, a drug used in the treatment of chronic inflammatory bowel diseases) was examined in these systems. Without iron, all three compounds considerably reduced 8-OHdG formation (i.e., acted as scavengers), while in the presence of iron salts, 8-OHdG formation was accelerated (except for GSH at pH 7.4), i.e., the compounds acted as prooxidants. This effect was augmented at low pH. The prooxidant property of 5-ASA may have implications for its clinical use. Maximum scavenging effect for all the compounds investigated was obtained at much lower doses than the maximum enhancing effect. This demonstrates that to the end of oxy-radical scavenging, the concentration of the GSH, ascorbate, and 5-ASA, respectively, should be chosen to obtain maximum antioxidant effect and minimum prooxidant effects. The significance of this finding for the selection of antioxidant dose is important but remains to be investigated further.
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PMID:8-Hydroxydeoxyguanosine in vitro: effects of glutathione, ascorbate, and 5-aminosalicylic acid. 151 38

The roles of glutathione (GSH), cysteine, vitamin C, liposome-encapsulated superoxide dismutase (L-SOD) and vitamin E in preventing oxidative DNA damage and cytotoxicity in the rat kidney after administration of potassium bromate (KBrO3) to male F344 rats were investigated by measuring 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative DNA product, lipid peroxidation (LPO) levels and relative kidney weight (RKW). Combined pre- and posttreatment of animals with 2 x 800 mg/kg GSH i.p. inhibited the increase of 8-OH-dG, LPO levels and RKW caused by 80 mg/kg KBrO3 i.p. administration. In contrast, pretreatment with 0.3 ml/kg diethylmaleate (DEM) i.p., a depletor of tissue GSH, was associated with elevation of 8-OH-dG, LPO levels and RKW after a 20 mg/kg KBrO3 i.p. treatment, which itself caused no change. Administration of KBrO3 itself reduced renal non-protein thiol levels, but this was inhibited by the two doses of exogenous GSH. Combined treatment with DEM and KBrO3 lowered the non-protein thiol level in the kidney more than did DEM treatment alone. Protective effects against the oxidative damage caused by KBrO3 were also observed for pre- and posttreatment with 400 mg/kg cysteine i.p., another sulfhydryl compound, and daily i.g. application of 200 mg/kg vitamin C for 5 days. However, no influence was evident after pre- and posttreatment with 18,000 U/kg L-SOD i.p. or daily i.g. 100 mg/kg of vitamin E for 5 days. The results suggest that intracellular GSH plays an essential protective role against renal oxidative DNA damage and nephrotoxicity caused by KBrO3.
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PMID:The protective role of glutathione, cysteine and vitamin C against oxidative DNA damage induced in rat kidney by potassium bromate. 154 73

We have investigated hydroxyl free radical mediated damage to pBR322 DNA produced by ascorbate/iron and oxygen in a phosphate-buffered in vitro system. An observed lag phase in DNA nicking suggests a multi-target model of hydroxyl free radical attack on DNA. In the present report we further examine the model system and show that there is a "heat labile" component of the ascorbate/iron system which can be completely restored by the readdition of ascorbate. These observations have allowed us to rule out the possibility that intermediates build up in the reaction and act independently of ascorbate to increase the reaction rate. We have investigated the initial rate of OH production with two OH trapping agents, salicylate and deoxyguanosine, and find that the lag in DNA nicking is not due to a corresponding lag in the production of OH as assessed by formation of the products, dihydroxybenzoic acids and 8-hydroxydeoxyguanosine, respectively. We have found that the energy of activation for DNA supercoiled nicking is 13.9 kcal/mole and for OH trapping by salicylate is 21.1 kcal/nmole. These two activation energies are sufficiently different to suggest that the rate-limiting steps of these two reactions are different. Investigation of the rate of oxygen consumption during the ascorbate/iron-mediated DNA damage showed that oxygen was not a limiting component at any point in the reaction. The addition of catalase slowed down oxygen consumption by 31% and this data taken together with our previous observations on the model implicate hydrogen peroxide as a key intermediate in DNA damage caused by hydroxyl free radical.
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PMID:Characterization of hydroxyl free radical mediated damage to plasmid pBR322 DNA. 254 8

A method for the detection of rare adducts in DNA has been developed by combining the resolution of high-performance liquid chromatography with the specificity and sensitivity of electrochemical detection. Many adducts are electrochemically active, while the normal bases, except for guanine, are not. Enzymatic hydrolysis of DNA is used to obtain the deoxynucleosides for analysis, or where appropriate, acid hydrolysis or thermal depurination of DNA is used to free the adduct base for analysis. Various types of DNA damage have been induced by in vitro exposure of DNA to acrolein, dimethyl sulfate, sodium nitrite, ascorbate/Cu2+ and gamma-irradiation. Several adducts are detected at a level of one adduct in 10(5)-10(6) normal bases in micrograms of DNA. The method is also useful for measuring O6-methylguanine (O6MeGua) in DNA from rats treated with N-nitrosodimethylamine and 8-hydroxydeoxyguanosine (oh8dG), and O6-MeGua in DNA from bacteria treated with hydrogen peroxide and dimethyl sulfate. oh8dG, which appears to be the most suitable marker for measuring the steady-state level of oxidative DNA damage, can be measured at fmol levels in DNA from normal rat tissues. The method is applicable to the analysis of DNA base damage caused by major endogenous processes relevant to aging, such as deamination, methylation and oxidation. The analysis of DNA adducts with this simple assay also may be potentially useful for studies on carcinogenesis and as a tool in studies on the epidemiology of cancer.
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PMID:Detection of DNA adducts by high-performance liquid chromatography with electrochemical detection. 265 Sep 7

Restriction of energy intake (ER), without malnutrition of essential nutrients, has repeatedly been demonstrated to increase longevity in rodents. In the antioxidant theory of aging the lack of balance between the generation of free radicals and free radical scavenging was thought to be a main causal agent, in the aging process. From this point of view the antiaging effect induced by ER might be due to the lower rate of free-radical production and related damage induced by a lower metabolic rate. The antiaging effects of ER might also occur in humans. This study explored the effects of a 10-week moderately energy-restricted diet (80% of habitual) in 24 non-obese middle-aged men (16 ER subjects, 8 controls) on resting metabolic rate (RMR) and indicators of the primary antioxidant defense system, oxidative stress and genotoxicity. RMR decreased significantly in both groups, even when adjustments were made for the change in body composition. The increase in blood vitamin C concentration correlated with the increase in urinary 8-hydroxydeoxyguanosine (80HdG) excretion. The change in urinary 80HdG excretion also correlated with the change in RMR per kg fat-free mass. No differences between groups were found for changes in indicators of genotoxicity, erythrocyte catalase, glutathione peroxidase and superoxide dismutase activity and in plasma vitamin E, A or beta-carotene concentrations. We conclude that 10 weeks of moderate ER did not affect indicators of antioxidative capacity, oxidative stress and genotoxicity of humans. Since subjects were not in energy balance at the end of the study, no conclusions can be made with respect to long-term effects.
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PMID:Short-term moderate energy restriction does not affect indicators of oxidative stress and genotoxicity in humans. 756

We have established an experimental model of oral contraceptive-induced hepatocellular carcinomas (HCCs) in female Wistar rats, revealing that ethynylestradiol (EE) and norethindrone acetate have actions as both initiators and promoters. The present time-sequence study was undertaken to clarify the role of free radicals in estrogen induction of HCC by measuring detoxifying enzyme activities and levels of 8-hydroxydeoxyguanosine (8-OH-dG) and by assessing the effects of concomitant vitamin C, vitamin E or beta-carotene administration on hepatocarcinogenesis. During 12 months oral administration of EE (0.075 or 0.75 mg/day), the 8-OH-dG levels reached peak values after 1 month, when they were significantly elevated as compared with the controls. Glutathione peroxidase demonstrated a tendency to decrease. Histologically, pre-neoplastic lesions assessed by immunohistochemical staining for placental glutathione S-transferase (GST-P) were first observed at 2 months in the groups given 0.075 and 0.75 mg/day of EE alone, with incidences of HCC at 12 months being 8.7% and 38.5% respectively. Combined administration of vitamins with 0.075 mg EE/day reduced the elevation of the 8-OH-dG levels. GST-P-positive lesions were first observed at 4 months in the vitamin E group and at 6 months in the vitamin C and beta-carotene groups. As compared with the value in the 0.075 mg EE alone group, vitamin administration significantly reduced the numbers of GST-P-positive foci after 12 months of treatment. The incidences of HCC at 12 months were 0% in the vitamin C group, 4.5% in the vitamin E group and 4.8% in the beta-carotene group, i.e. administration of the vitamins inhibited the development of GST-P-positive foci, with suppression of HCC. The results thus suggest that free radicals play an important role in the induction of HCC by estrogen.
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PMID:Role of reactive oxygen in synthetic estrogen induction of hepatocellular carcinomas in rats and preventive effect of vitamins. 772 63

The effects of five naturally occurring antioxidants, beta-carotene (BC), vitamin C (VC), vitamin E (VE), ellagic acid (EA) and epigallocatechin gallate (EGCG) on 8-hydroxydeoxyguanosine (8-OH-dG) formation by 2-nitropropane (2-NP), a hepatocarcinogen in rats, were studied. Four days oral administration of VE (100 mg/kg BW/day) or EA (100 mg/kg BW/day) significantly inhibited 8-OH-dG formation in the liver nuclear DNA of male F-344 rats injected with 2-NP (100 mg/kg BW, i.p., killed 6 h later). The same treatment with EGCG (100 mg/kg BW/day) showed slight, but not significant, inhibition. In contrast, 4 days' oral administration of BC (100 mg/kg BW/day) or VC (300 mg/kg BW/day) and 3 weeks' feeding of the two (either at 0.5% in the diet) did not produce any inhibitory effects on 8-OH-dG formation. Thus, it is expected that VE and EA may have anticarcinogenic effects towards 2-NP.
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PMID:Inhibitory effects of vitamin E and ellagic acid on 8-hydroxydeoxyguanosine formation in liver nuclear DNA of rats treated with 2-nitropropane. 775 89

A protector protein from Saccharomyces cerevisiae prevented the inactivation of enzyme and oxidative damage to protein and DNA caused by a thiol/Fe3+/O2 metal-catalyzed oxidation (MCO) system but not when thiol was replaced by ascorbate. In the presence of a reduced thiol such as dithiothreitol and reduced glutathione, however, the protector protein prevented inactivation of E. coli glutamine synthetase against a MCO system comprised of ascorbate and Fe3+. The protector protein also inhibited the fragmentation of protein, incorporation of carbonyl groups into protein, strand breaks in pBluescript plasmid DNA, and the formation of 8-hydroxydeoxyguanosine in calf thymus DNA when induced by either the thiol/Fe3+ system or the ascorbate/Fe3+ system supplemented with dithiothreitol. These results suggest that antioxidant activity of protector protein against a MCO system requires thiol as a reducing equivalent to restore its catalytic activity.
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PMID:Inhibition of metal-catalyzed oxidation systems by a yeast protector protein in the presence of thiol. 791 63

Reactive oxygen species (ROS) induce 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation, which has been proposed as a key biomarker relevant to carcinogenesis. 8-OHdG has been induced in a number of different ways, most often without knowledge of the specific type and amount of ROS generated. We have measured 8-OHdG formation in calf thymus DNA exposed to ionizing radiation under conditions generating either hydroxyl radicals (OH.), superoxide anions (O2-) or both. Additionally, we investigated the relationship between the scavenger effect of the drug 5-aminosalicylic acid (5-ASA) and increasing OH. exposure toward 8-OHdG formation. The effect of this drug was compared to those of the physiological scavengers ascorbate and reduced glutathione (GSH). We found that OH. generated 8-OHdG in a dose-dependent manner, whereas O2- did not cause 8-OHdG formation. 5-ASA, ascorbate and GSH all acted as hydroxyl radical scavengers, although with different concentration-effect curves, emphasizing the importance of using relevant pharmaco-/physiological concentrations in studies focusing on therapeutic applications of scavengers. The scavenger effect of 5-ASA at concentrations > or = 0.1 mM was similar at 30 and 100 Gy radiation, i.e. within a wide range of OH. exposure, which is useful information considering clinical applications where the exact amount of ROS formed is unknown. Both 5-ASA and ascorbate at low concentrations (< or = 0.1 mM) were less efficient in preventing 8-OHdG formation from X-ray generated OH. than was shown in a previous comparable study using light as the source of ROS. This differentiation probably reflects variations in both number and type of ROS formed in the two systems.
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PMID:Radiation-induced formation of 8-hydroxy-2'-deoxyguanosine and its prevention by scavengers. 805 39

Recently we showed that ascorbate and 5-aminosalicylic acid (5-ASA) prevented 8-hydroxydeoxyguanosine (8-OHdG) formation in calf thymus DNA exposed to UV-visible light. However, the ultimate defense against oxidative DNA damage depends on an intracellular/intranuclear effect of the compounds. In the present study we investigated the effect of ascorbate and 5-ASA on 8-OHdG formation in V79 Chinese hamster cells exposed to light from a sun-lamp. Exposure for 1 min (4560 mJ/cm2) increased 8-OHdG formation in cellular DNA to 30-40 times background level. Preincubation of the cells with ascorbate or 5-ASA at concentrations of 0.1, 1 and 10 mM diminished the 8-OHdG formation to 0.67, 0.74 and 0.49 times controls (P < 0.05) for ascorbate respectively, and to 0.82, 0.66 and 0.33 times controls (P < 0.05), for 5-ASA. These findings demonstrate that both ascorbate and 5-ASA prevent oxidative DNA damage in cells by acting as intracellular/intranuclear antioxidants.
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PMID:Effect of ascorbate and 5-aminosalicylic acid on light-induced 8-hydroxydeoxyguanosine formation in V79 Chinese hamster cells. 824 77


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