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)

Vitamin C is a reducing substance, an electron donor. When vitamin C donates its two high-energy electrons to scavenge free radicals, much of the resulting dehydroascorbate is re-reduced to vitamin C and therefore used repeatedly. Conventional wisdom is correct in that only small amounts of vitamin C are necessary for this function because of its repeated use. The point missed is that the limiting part in nonenzymatic free radical scavenging is the rate at which extra high-energy electrons are provided through NADH to re-reduce the vitamin C and other free radical scavengers. When ill, free radicals are formed at a rate faster than the high-energy electrons are made available. Doses of vitamin C as large as 1-10 g per 24 h do only limited good. However, when ascorbate is used in massive amounts, such as 30-200+ g per 24 h, these amounts directly provide the electrons necessary to quench the free radicals of almost any inflammation. Additionally, in high concentrations ascorbate reduces NAD(P)H and therefore can provide the high-energy electrons necessary to reduce the molecular oxygen used in the respiratory burst of phagocytes. In these functions, the ascorbate part is mostly wasted but the necessary high-energy electrons are provided in large amounts.
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PMID:A unique function for ascorbate. 192 74

Enzymatic systems able to reduce either dehydroascorbate or ascorbyl radical back to ascorbate by "recycling" vitamin C may contribute to lowering the nutritional requirement of it and to increase tissue antioxidant capacity. The activities of two enzymatic activities, GSH-dehydroascorbate reductase (two-electron reduction pathway) and NADH-semidehydroascorbate reductase (one-electron reduction pathway) in pig tissues, have been investigated. The activity of glutathione-dependent reduction of dehydroascorbate, although measurable, appeared negligible taking into consideration the low physiological substrate concentration. On the other hand, the one-electron reduction of ascorbyl radical resulted fast enough to slow down the consumption of the antioxidant vitamin.
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PMID:Enzymatic recycling of oxidized ascorbate in pig heart: one-electron vs two-electron pathway. 192 13

Ascorbate irreversibly inhibited morphological transformation induced by methylcholanthrene in C3H/10T1/2 cells. To determine the mechanisms of this inhibition, we studied ascorbate uptake, redox potential, matrix proteins, and lipid composition of 10T1/2 cells. Ascorbate (16.8 nmol/dish) saturated cells and reduced the NADH-to-NAD+ ratio. Daily treatments with ascorbate, 28 nmol/dish, maintained intracellular ascorbate and reduced NADH by half. Matrix collagen and glycoproteins were stimulated by ascorbate, Iso-ascorbate, and dehydroascorbate in a dose-dependent manner. Both ascorbate and dehydroascorbate reduced total lipids with time; neutral lipids increased but were released into the media, phospholipids were modified, cholesterol-phospholipid ratios declined, and an inverse relationship between unsaturation index and cholesterol-phospholipids was apparent. Lipophilic bodies gradually accumulated. Our data suggest that inhibition of transformation by ascorbate, Iso-ascorbate, or dehydroascorbate may be associated with regulation of the redox potential, glycoproteins, and lipids in 10T1/2 cells.
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PMID:Mechanisms of ascorbic acid-induced inhibition of chemical transformation in C3H/10T1/2 cells. 196 76

Exposure of isolated mouse hepatocytes to a toxic concentration of acetaminophen (5 mM) resulted in damage to the mitochondrial respiratory apparatus. The nature of this damage was investigated by measuring respiration stimulated by site-specific substrates in digitonin-permeabilized hepatocytes after acetaminophen exposure. Respiration stimulated by succinate at energy-coupling site 2 was most sensitive to inhibition and was decreased by 47% after 1 h. Respiration supported by NADH-linked substrates (site 1) was also decreased but to a lesser extent, while there was no decrease in the rate of ascorbate + N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD)-supported respiration (site 3). The loss of mitochondrial respiratory function was accompanied by a decrease in ATP levels and ATP/ADP ratios in the cytosolic compartment and was preceded by a loss of reduced glutathione in both the cytosol and mitochondria. All these effects occurred well before the loss of cell membrane integrity. The putative toxic metabolite of acetaminophen, N-acetyl-p-benzoquinonimine (NAPQI), produced a similar pattern of respiratory dysfunction in isolated hepatic mitochondria. Respiration stimulated by succinate- and NADH-linked substrates was very sensitive to 50 microM NAPQI, while ascorbate + TMPD-supported respiration was unaffected. The interaction between NAPQI and the respiratory chain was further investigated using submitochondrial particles. Succinate dehydrogenase (associated with respiratory complex II) was found to be very sensitive to NAPQI, while NADH dehydrogenase (respiratory complex I) was inhibited to a lesser extent. Our results indicate that a loss of the ability to utilize succinate- and NADH-linked substrates due to attack of the respiratory chain by NAPQI causes a disruption of energy homeostasis in acetaminophen hepatotoxicity.
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PMID:Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. 200 47

Ascorbate was maintained in the media during a long-term culture by HL-60 cells. The chemical oxidation of ascorbate was reversed in vitro by living HL-60 cells and was related to the amount of cells added. The increase of NADH concentration by lactate addition to cells was accompanied by an increase of both ascorbate regeneration and ferricyanide reduction. Further, plasma membrane enriched fractions from HL-60 cells revealed enhancement of both ascorbate regeneration and ferricyanide reduction in the presence of NADH when previously treated with detergent. The blockage of cell surface carbohydrates by wheat germ agglutinin (WGA) and Concanavalina ensiformis (Con A) lectins significantly inhibited the regeneration of ascorbate caused by the cells. These results support the idea that ascorbate is externally regenerated by the NADH-ascorbate free radical reductase as a part of the transplasma membrane redox system.
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PMID:Ascorbate is regenerated by HL-60 cells through the transplasmalemma redox system. 200 84

Adrenochrome is reduced by ascorbate in a reaction accompanied by a large and rapid oxygen uptake. The rates of adrenochrome reduction and the concomitant oxygen uptake are decreased in the presence of superoxide dismutase or catalase. The species formed on the one-electron reduction of adrenochrome (i.e., the semiquinone) was shown by pulse radiolysis to rapidly react with oxygen (9.10(8) M-1.s-1), indicating the occurrence of a redox cycling in a system formed by adrenochrome, a reducing agent, and oxygen. Adrenochrome is also reduced to the corresponding semiquinone by complex I of beef heart submitochondrial particles supplemented with NADH, while succinate is unable to support this reduction. The o-semiquinone is the intermediate species in the superoxide-generating cycle resulting from both non-enzymatic and enzymatic reduction. The toxic effects of adrenochrome and its pathophysiological role can be explained, at least in part, on the basis of the demonstrated cycle.
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PMID:Direct and respiratory chain-mediated redox cycling of adrenochrome. 215 18

Hindered phenols are widely used food preservatives. Their pharmacological properties are usually attributed to high antioxidant activity due to efficient scavenging of free radicals. Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) also cause tissue damage. Their toxic effects could be due to the production of phenoxyl radicals. If phenoxyl radicals can be recycled by reductants or electron transport, their potentially harmful side reactions would be minimized. A simple and convenient method to follow phenoxyl radical reactions in liposomes and rat liver microsomes based on an enzymatic (lipoxygenase + linolenic acid) oxidation system was used to generate phenoxyl radicals from BHT and its homologues with substitutents in m- and p-positions. Different BHT-homologues display characteristic ESR signals of their radical species. In a few instances the absence of phenoxyl radical ESR signals was found to be due to inhibition of lipoxygenase by BHT-homologues. In liposome or microsome suspensions addition of ascorbyl palmitate resulted in disappearance of the ESR signal of phenoxyl radicals with concomittant appearance of the ascorbyl radical signal. After exhaustion of ascorbate, the phenoxyl radical signal reappears. Comparison of the rates of ascorbyl radical decay in the presence or absence of BHT-homologues showed that temporary elimination of the phenoxyl radical ESR signal was due to their reduction by ascorbate. Similarly, NADPH or NADH caused temporary elimination of ESR signals as a result of reduction of phenoxyl radicals in microsomes. Since ascorbate and NADPH might generate superoxide in the incubation system used, SOD was tested. SOD shortened the period, during which the phenoxyl radicals ESR signal could not be observed. Both ascorbyl palmitate and NADPH exerted sparing effects on the loss of BHT-homologues during oxidation. These effects were partly diminished by SOD. These data indicate that reduction of phenoxyl radicals was partly superoxide-dependent. It is concluded that redox recycling of phenoxyl radicals can occur by intracellular reductants like ascorbate and microsomal electron transport.
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PMID:Generation and recycling of radicals from phenolic antioxidants. 216 53

Bovine heart submitochondrial particles (SMP) were exposed to continuous fluxes of hydroxyl radical (.OH) alone, superoxide anion radical (O2-) alone, or mixtures of .OH and O2-, by gamma radiolysis in the presence of 100% N2O (.OH exposure), 100% O2 + formate (O2- exposure), or 100% O2 alone (.OH + O2- exposure). Hydrogen peroxide effects were studied by addition of pure H2O2. NADH dehydrogenase, NADH oxidase, succinate dehydrogenase, succinate oxidase, and ATPase activities (Vmax) were rapidly inactivated by .OH (10% inactivation at 15-40 nmol of .OH/mg of SMP protein, 50-90% inactivation at 600 nmol of .OH/mg of SMP protein) and by .OH + O2- (10% inactivation at 20-80 nmol of .OH + O2-/mg of SMP protein, 45-75% inactivation at 600 nmol of .OH + O2-/mg of SMP protein). Importantly, O2- was a highly efficient inactivator of NADH dehydrogenase, NADH oxidase, and ATPase (10% inactivation at 20-50 nmol of O2-/mg of SMP protein, 40% inactivation at 600 nmol of O2-/mg of SMP protein), a mildly efficient inactivator of succinate dehydrogenase (10% inactivation at 150 nmol of O2-/mg of SMP protein, 30% inactivation at 600 nmol of O2-/mg of SMP protein), and a poor inactivator of succinate oxidase (less than 10% inactivation at 600 nmol of O2-/mg of SMP protein). H2O2 partially inactivated NADH dehydrogenase, NADH oxidase, and cytochrome oxidase, but even 10% loss of these activities required at least 500-600 nmol of H2O2/mg of SMP protein. Cytochrome oxidase activity (oxygen consumption supported by ascorbate + N,N,N',N'-tetramethyl-p-phenylenediamine) was remarkably resistant to oxidative inactivation, with less than 20% loss of activity evident even at .OH, O2-, OH + O2-, or H2O2 concentrations of 600 nmol/mg of SMP protein. Cytochrome c oxidase activity, however (oxidation of, added, ferrocytochrome c), exhibited more than a 40% inactivation at 600 nmol of .OH/mg of SMP protein. The .OH-dependent inactivations reported above were largely inhibitable by the .OH scavenger mannitol. In contrast, the O2(-)-dependent inactivations were inhibited by active superoxide dismutase, but not by denatured superoxide dismutase or catalase. Membrane lipid peroxidation was evident with .OH exposure but could be prevented by various lipid-soluble antioxidants which did not protect enzymatic activities at all.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The oxidative inactivation of mitochondrial electron transport chain components and ATPase. 216 88

When 5-methylphenazinium methylsulfate and a reductant (ascorbate or NADH) are added together to a suspension of resealed chromaffin-vesicle membranes, the pH gradient (inside acidic) and the membrane potential (inside positive) established by the H(+)-translocating adenosine triphosphatase (ATPase) are rapidly dissipated. Dissipation of the pH gradient may be observed using either the optical probe acridine orange or the weak base methylamine. Dissipation of the membrane potential may be observed using the potential-dependent dye oxonol VI. A reductant and 5-methylphenazinium methylsulfate added in combination will also abolish a K+ diffusion potential across chromaffin-vesicle membranes but not across liposome membranes. 5-Methylphenazinium methylsulfate oxidizes cytochrome b561 in chromaffin-vesicle ghosts. Ascorbate readily reduces cytochrome b561, but reduction of cytochrome b561 by NADH is greatly enhanced in the presence of 5-methylphenazinium methylsulfate. These results are consistent with a mechanism in which proton gradient dissipation (a net efflux of H+) is caused by an influx of electrons through the membrane-protein cytochrome b561 coupled with an efflux of H carried by the reduced species 5-methyl-10-hydrophenazine. Although 5-methylphenazinium has been thought to accumulate within acidic vesicles as a weak base, this accounts for neither proton gradient dissipation nor for intravesicular accumulation of the compound.
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PMID:5-Methylphenazinium methylsulfate mediates cyclic electron flow and proton gradient dissipation in chromaffin-vesicle membranes. 221 89

Previous studies have shown that the bacterium, Vitreoscilla, generates a respiratory-driven delta psi Na+. Two major respiratory electron transport proteins, NADH dehydrogenase (NADH:Quinone oxidoreductase), and cytochrome o terminal oxidase are candidates for the electrogenic Na+ pumping that mediates the delta psi Na+ formation. The NADH oxidase activity of the membranes was enhanced more by Na+ than by Li+. The NADH:Quinone oxidoreductase activity in the respiratory chain was enhanced by Na+ and Li+, whereas the quinol oxidase activity of cytochrome o was enhanced specifically by Na+, and not by Li+, K+, or choline. Purified cytochrome o, reconstituted into Na(+)-loaded liposomes in the right-side-out orientation, catalyzed a net Na+ extrusion when energized with Q1H2(1). In nonloaded inside-out proteoliposomes, this cytochrome catalyzed a net uptake of 22Na+ when energized with ascorbate/TMPD. Both Na(+)-pumping activities were inhibited by CN-. These results are consistent with the Vitreoscilla cytochrome o being a redox-driven Na+ pump.
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PMID:A cytochrome that can pump sodium ion. 225 29


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