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)

The microsomal fraction of human platelets catalyzed the conversion of arachidonic acid to an unstable platelet-aggregating factor and a hydrolyzed product on the thin-layer chromatography (TLC). This product was isolated on TLC, purified by silica gel column chromatography and identified by combined gas chromatography-mass spectrometry as the hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9, 12L-dihydroxy-5, 10-heptadecatrienoic acid (thromboxane B2). The enzymatic activity was dependent upon methemoglobin and tryptophan as cofactors. Reduced glutathione had no effect either alone or in combination with other cofactors. Methemoglobin could be replaced by hematin or hemin; and tryptophan by 3-indolacetic acid or catecholamines. The apparent requirement for methemoglobin is due to the reductive activity of ferriprotoporphyrin IX. The reaction, however, catalyzed by the ferriprotoporphyrin IX in the thromboxane synthesizing system is different from that described for the decomposition of lipid peroxides. Certain transition metals and hydrogen donors, such as hydroquinone and ascorbate, which have been shown to stimulate the catalytic activity of ferriproroporphyrin IX in the decomposition of 15-hydroperoxy-prostaglandin E1 are inhibitors of thromboxane B2 formation. This enzyme preparation also transformed eicosa-8. 11, 14-trienoic acid to an unknown product on TLC. The enzyme system was rapidly inactivated upon incubation in the reaction mixture.
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PMID:Biosynthesis of thromboxane B2: assay, isolation, and properties of the enzyme system in human platelets. 1 39

Purification of soluble guanylate cyclase activity from rat liver resulted in loss of enzyme responsiveness to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), nitroprusside, nitrite, and NO. Responses were restored by addition of heat-treated hepatic supernatant fraction, implying a requirement for heat-stable soluble factor(s) in the optimal expression of the actions of the activators. Addition of free hematin, hemoglobin, methemoglobin, active or heat-inactivated catalase partially restores responsiveness of purified guanylate cyclase to MNNG, NO, nitrite, and nitroprusside. These responses were markedly potentiated by the presence of an appropriate concentration of reducing agent (dithiothreitol, ascorbate, cysteine, or glutathione), which maintains heme iron in the ferro form and favors formation of paramagnetic nitrosyl . heme complexes from the activators. High concentrations of heme or reducing agents were inhibitory, and heme was not required for the expression of the stimulatory effects of Mn2+ or Mg2+ on purified guanylate cyclase. Preformed nitrosyl hemoglobin (10 micron) increased activity of the purified enzyme 10- to 20-fold over basal with Mn2+ as the metal cofactor and 90- to 100-fold with Mg2+. Purified guanylate cyclase was more sensitive to preformed NO-hemoglobin (minimally effective concentration, 0.1 micron) than to MNNG (1 micron), nitroprusside (50 micron), or nitrite (1 mM). A reducing agent was not required for optimal stimulation of guanylate cyclase by NO-hemoglobin. Maximal NO-hemoglobin-responsive guanylate cyclase was not further increased by subsequent addition of NO, MNNG, nitrite, or nitroprusside. Activation by each agent resulted in analogous alterations in the Mn2+ and Mg2+ requirements of enzyme activity, and responses were inhibited by the thiol-blocking agents N-ethylmaleimide, arsenite, or iodoacetamide. The results suggest that NO-hemoglobin, MNNG, NO, nitrite, and nitroprusside activate guanylate cyclase through similar mechanisms. The stimulatory effects of preformed NO-hemoglobin combined with the clear requirements for heme plus a reducing agent in the optimal expression of the actions of MNNG, NO, and related agents are consistent with a role for the paramagnetic nitrosyl . heme complex in the activation of guanylate cyclase.
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PMID:Restoration of the responsiveness of purified guanylate cyclase to nitrosoguanidine, nitric oxide, and related activators by heme and hemeproteins. Evidence for involvement of the paramagnetic nitrosyl-heme complex in enzyme activation. 3 Jul 78

It has been analised cases of toxic methemoglobinemia in newborns and sucklings on patients of children department city hospital Sombor in period from 1968 to 1979. In all patients methemoglobinemia was caused with wellwater containing nitrates. Originate of this state depends on: growth of child because in first few month of life they have immature methemoglobin reductase in erythrocyte, hypovitaminosis C and gastrointestinal disfunction. Diagnosis was based on anamnestical data that was used water from unhygenic well, on cyanosis of various intensity and that have disappeared during the treatment with vitamin C and not give any recurrence later. In last years number of such cases is decreasing because of better suply with proper drinking water. Further decrease can be achieved with health education and prophylactic peroral consumption of vitamin C in predisposing regions.
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PMID:[Toxic methemoglobinemia in newborns and infants]. 55 47

Chloramines, compounds made up of chlorine and ammonia, when present in tap water used for dialysis cause methemoglobinemia and hemolysis. Ascorbic acid addition has been reported to effectively neutralize chloramines in vitro and in patients dialyzed with the single batch dialysis delivery system. We extended these observations to patients dialyzed with the proportioning dialysis delivery system where exposure time of ascorbic acid to chloramines is shorter. This may be important since we found that the half time of the reaction between ascorbic acid and chloramines is 4 minutes. Red cell oxidant sensitivity in 15 patients was assessed by incubating red cells with ascorbate-cyanide and measuring methemoglobin which averaged 2.17 +/- 0.42 g/100 ml (SEM) before dialysis and 2.87 +/- 0.52 g/100 ml after dialysis (NS). Reduced glutathione (GSH) levels were also measured as an index of red cell oxidant damage. GSH decreased from a mean of 7.40 +/- 0.59 micromoles/g Hb before dialysis to 6.98 +/- 0.52 micronmoles/g Hb after dialysis (P less than 0.01). In 2 patients there was no change in 51Cr red cell survival when dialyzed on either the proportioning system or other chloramine free systems. We conclude that addition of ascorbic acid to neutralize chloramines in tap water is also effective when using the proportioning dialysis delivery system.
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PMID:Prevention of chloramine-induced hemolysis in dialyzed patients. 69 6

The data presented here demonstrate that linoleic acid hydroperoxide in the presence of methemoglobin or hematin activated the carcinogen N-hydroxy-N-acetyl-2-amino-fluorene via the nitroxyl free radical intermediate into 2-nitrosofluorene and N-acetoxy-N-acetyl-2-aminofluorene. Ascorbate inhibited the activation, in which case the free radical intermediate was replaced by the ascorbate free radical. On the basis of optical kinetics, we have established that the rate of linoleic acid hydroperoxide decrease paraleled the rate of N-hydroxy-N-acetyl-2-aminofluorene decrease and also the rate of 2-nitrosofluorene increase. The stoichiometry of the reaction was such that, for every 2 linoleic acid hydroperoxide molecules consumed, 2 N-hydroxy-N-acetyl-2-aminofluorene molecules were oxidized and 1 2-nitrosofluorene and 1 N-acetoxy-N-acetyl-2 aminofluorene molecule was formed.
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PMID:Lipid hydroperoxide activation of N-hydroxy-N-acetylaminofluorene via a free radical route. 127 86

Ascorbic acid has been shown to cause stage-dependent effects on the in vitro development of Plasmodium falciparum. While vitamin C marginally enhanced the development of young parasites, it proved highly destructive to the advanced forms. The present study evaluates the mechanisms by which vitamin C affects the parasite. The treatment of parasitized erythrocytes with ascorbate resulted in the conversion of added salicylate to dihydroxybenzoate products, indicating the involvement of hydroxyl radicals. There was a stage specific sensitivity, increasing conversion with progressing parasite development. This specificity could not be attributed to the altered uptake of salicylate by the parasitized erythrocyte, since salicylate uptake was similar in either parasitized or non-parasitized erythrocytes. In distinction, increased uptake of ascorbate by parasitized erythrocytes could account for an elevated oxidant stress. The treatment with ascorbate also caused the oxidation of hemoglobin to methemoglobin and the peroxidation of membrane lipids. Added catalase markedly inhibited the ascorbate-induced effects on parasite development. "Free" plasmodia were also vulnerable to treatment with ascorbate like the parasites within their host cells. These results are in accord with a free radical mechanism of damage to the infected erythrocytes. During the growth of P. falciparum the infected erythrocytes release increasing levels of iron-containing structures that are redox-active and can catalyze the formation of highly reactive oxygen derived species. The findings also indicate the multiplicity of the mode of action of ascorbate on the host-parasite system.
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PMID:The effects of ascorbate-induced free radicals on Plasmodium falciparum. 159 3

The reactions of the monodehydroascorbate radical (As.-) with various biological molecules were investigated by pulse radiolysis. As.- reacted with both fully reduced and semiquinone forms of hepatic NADH-cytochrome b5 reductase with second-order rate constants of 4.3 x 10(6) and 3.7 x 10(5) M-1 s-1, respectively, at pH 7.0. In contrast, no reaction of As.- with ferrous cytochrome b5 could be detected by pulse radiolysis, whereas the oxidation of cytochrome b5 by As.- was observed by ascorbate-ascorbate oxidase method. This suggests that the rate constant of As.- with the ferrous cytochrome b5 must be several orders in magnitude smaller than that of the disproportionation of As.-. On the other hand, As.- reduced Fe3+EDTA with a second-order rate constant of 4.0 x 10(6) M-1 s-1 but did not reduce ferric hemoproteins such as metmyoglobin, methemoglobin, and cytochrome b5 by either the pulse radiolysis or the ascorbate-ascorbate oxidase method.
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PMID:Kinetic behavior of the monodehydroascorbate radical studied by pulse radiolysis. 188 18

The role of trace metals in the generation of free radical mediated oxidative stress in normal human red cells was studied. Ascorbate and either soluble complexes of Cu(II) or Fe(III) provoked changes in red cell morphology, alteration in the polypeptide pattern of membrane proteins, and significant increases in methemoglobin. Neither ascorbate nor the metal complexes alone caused significant changes to the cells. The rate of methemoglobin formation was a function of ascorbate and metal concentrations, and the chemical nature of the chelate. Cu(II) was about 10-times more effective than Fe(III) in the formation of methemoglobin. Several metals were tested for their ability to compete with Cu(II) and Fe(III). Only zinc caused a significant inhibition of methemoglobin formation by Fe(III)-fructose. These observations suggest that site-specific as well as general free radical damage is induced by redox metals when the metals are either bound to membrane proteins or to macromolecules in the cytoplasm. The Cu(II) and Fe(III) function in two catalytic capacities: (1) oxidation of ascorbate by O2 to yield H2O2, and (2) generation of hydroxyl radicals from H2O2 in a Fenton reaction. These mechanisms are different from the known damage to red cells caused by the binding of Fe(III) or Cu(II) to the thiol groups of glucose-6-phosphate dehydrogenase. Our system may be a useful model for understanding the mechanisms for oxidative damage associated with thalassemia and other congenital hemolytic anemias.
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PMID:Oxidative damage to human red cells induced by copper and iron complexes in the presence of ascorbate. 280 91

Two cases of the congenital methemoglobinemia in children due to the deficiency of NADH-dependent methemoglobin reductase in erythrocytes. These children were referred to the Cardiological Ward at the Child Health Centre with suspected cyanotic heart defect. Cardiological examinations excluded heart defect but an increased blood methemoglobin level and decreased activity of NADH-dependent methemoglobin reductase were found, that caused methemoglobinemia. Methylene blue and vitamin C diminished cyanosis. These cases advocate inclusion of methemoglobinemia into differential diagnosis of cyanotic disorders especially if there is no evident pathology in cardio-vascular system.
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PMID:[Cyanosis in children caused by inherited methemoglobinemia due to deficiency of NADH-dependent methemoglobin reductase in erythrocytes]. 281 7

The purpose of this study was to examine the quantitative relationship between the redox potential of a redox couplet and the alterations it induces in coupling of receptor occupation with enzyme activation. Normal neutrophil membrane preparations containing beta 2-adrenergic receptors were exposed to equimolar mixtures of the following redox couplets: ferrocyanide-ferricyanide, hemoglobin-methemoglobin, ascorbate-dehydroascorbate, lactate-pyruvate, glutathione ox-red, beta-hydroxybutyrate-acetoacetate, and NAD-NADH. There was a linear relationship between the redox potential of the couplets and the degree of change in coupling (p less than 0.001). The apparent redox potential of the high affinity complex was +0.30 +/- 0.093 V. The effect of lactate to uncouple beta-adrenergic receptors was partially blocked by preexposure to isoproterenol. Thus, high affinity state formation is regulated by redox couplets in a manner dependent on their redox potential.
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PMID:Coupling of human beta 2-adrenergic receptors: relationship to redox potential. 284 87


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