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)

We performed biochemical studies on isolated mitochondria from a muscle biopsy specimen in a patient with Lowe's syndrome. Respiratory controls of mitochondrial preparations with substrates reducing nicotinamide adenine dinucleotide and with a flavoprotein-linked substrate were markedly diminished, but the oxygen consumption was normal with ascorbate and tetramethylphenylenediamine as substrates, which suggested a defect in electron transport prior to the cytochromes. The organelles also showed decreased adenosine diphosphate phosphorylate-oxygen ratio, indicating a partial uncoupling. These findings suggest that Lowe's syndrome could be considered a mitochondrial disease.
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PMID:Mitochondrial defects in Lowe's oculocerebrorenal syndrome. 669 27

Paraquat inhibits the in vitro hepatic microsomal metabolism of both ethylmorphine and aniline. Inclusion of ascorbate with paraquat in the incubations did not alter the paraquat effect on ethylmorphine N-demethylase activity but potentiated the inhibition of aniline p-hydroxylase activity. Ascorbate alone was without effect on the metabolism of either substrate. Paraquat stimulated the hepatic microsomal oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) equally in the absence of mixed-function oxidase (MFO) substrates or in the presence of ethylmorphine; in the presence of aniline the rate of NADPH oxidation was significantly greater. Also, in the presence of aniline, ascorbate potentiated the paraquat-induced NADPH oxidation, while it was ineffective with paraquat on NADPH oxidation in the presence of ethylmorphine or in the absence of substrates for the microsomal MFO system. The potentiated inhibition of aniline metabolism, concomitant with the potentiated stimulation of NADPH oxidation, was consistent whether liver microsomal fractions were prepared from control rats or from animals induced with phenobarbital. Investigation of possible influences on NADPH cytochrome c reductase activity was precluded by the rapid nonenzymatic reduction of cytochrome c by ascorbate. The paraquat-ascorbate redox couple would not reduce cytochrome P-450. These data suggest that a paraquat interaction with the active microsomal MFO enzyme system plays a role in the depletion of cellular NADPH stores that occurs after paraquat administration in vivo. This mechanism may play a significant role in the development of paraquat toxicity and in the potentiated toxicity observed with ascorbate and paraquat.
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PMID:Ascorbic acid potentiates the substrate-specific inhibition of mixed-function oxidation and the stimulation of NADPH oxidation caused by paraquat. 671 12

The respiratory components of the envelope membrane preparation of Neisseria meningitidis were investigated. Oxidase activities were demonstrated in this fraction in the presence of succinic acid, reduced nicotinamide adenine dinucleotide, and ascorbate-N,N,N',N'-tetramethyl-p-phenylene-diamine (TMPD). Differences in the kinetics of inhibition by terminal oxidase inhibitors on the three oxidase activities indicated that ascorbate-TMPD oxidation involved only an azide-sensitive oxidase, whereas oxidation of the physiological substrates involved two oxidases, one of which was relatively azide resistant. Spectrophotometric studies revealed that ascorbate-TMPD donated its electrons exclusively to cytochrome o, whereas the physiological substrates were oxidized via both cytochromes o and a. The effects of class II inhibitors on the oxidases suggest terminal branching of the electron transport chain at the cytochrome b level. A model of the respiratory system in N. meningitidis is proposed.
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PMID:Terminal branching of the respiratory electron transport chain in Neisseria meningitidis. 676 15

Trimetazidine (TMZ) is an anti-ischemic compound whose precise mode of action is unknown, although several studies have suggested a metabolic effect, and there have been reports of protection of mitochondria against oxidative stress damage. Using a Langendorff rat heart model, we examined the effects of TMZ on the mitochondrial damage following 30 minutes of ischemia and 5 minutes of reperfusion. Mitochondrial respiration with succinate, glutamate-malate and ascorbate-N,N,N',N'-tetramethylphenylenediamine (TMPD) as substrates was significantly decreased following ischemia-reperfusion. Preperfusion with 10(-5) M TMZ had no effect on these rates in normoxic or ischemic hearts. However, 10(-3) M TMZ significantly decreased the glutamate-malate rate in mitochondria from normoxic hearts, and this rate was not further decreased following ischemia-reperfusion, and 10(-3) M TMZ also partially protected ascorbate-TMPD activity. The effect on glutamate-malate was probably due to an inhibition of complex I by TMZ, which specifically inhibited reduced nicotinamide-adenine-dinucleotide-cytochrome c reductase and complex I in lysed mitochondria. We also studied the effects of TMZ on the activity of pyruvate dehydrogenase (PDH) in normoxic and ischemic hearts perfused with 0.5 mM palmitate, which caused the enzyme to be almost completely inactivated. After short periods of ischemia (10-20 minutes) the PDH inactivation by palmitate was progressively lost. Preperfusion with 10(-5) M TMZ had a tendency to decrease lactate dehydrogenase release, accompanied by a maintenance of the inhibition of PDH by palmitate. This may allow the heart to oxidize fatty acids preferentially during reperfusion, hence removing possible toxic acyl esters.
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PMID:Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion. 764 24

The ability of O2 metabolites derived from the xanthine-xanthine oxidase system to inhibit mitochondrial function was examined using freshly isolated rat liver mitochondria. Under 2,4-dinitrophenol-uncoupled conditions, mitochondria exposed to free radicals exhibited a significant decrease in O2 consumption supported by NAD(+)-linked substrates, but showed almost no change in O2 consumption in the presence of succinate and ascorbate. Oxidative stress caused the loss of intramitochondrial nicotinamide nucleotides, and addition of NAD+ fully prevented any fall in O2 consumption with NAD(+)-linked substrates. The activity of electron-transfer complex I (NADH oxidase and NADH-cytochrome c oxidoreductase) and the energy-dependent reduction of NAD+ by succinate were unaltered by oxidative stress. Exposure to free radicals also had an uncoupling effect at all three coupling sites. The degree of mitochondrial swelling was closely correlated with the inhibition of State-3 oxidation of site-I substrates and with the increase in State-4 oxidation of succinate. The immunosuppressive agent cyclosporin A completely prevented the mitochondrial damage induced by oxygen free radicals (swelling, Ca2+ release, sucrose trapping, uncoupling and selective inhibition of the mitochondrial respiration of site-I substrates). The same protective effect was found when Ca2+ cycling was prevented, either by chelating Ca2+ with EGTA or by inhibiting Ca2+ reuptake with Ruthenium Red. These findings suggest that the deleterious effect of free radicals on mitochondria in the present experimental system was triggered by the cyclosporin A-sensitive and Ca(2+)-dependent membrane transition, and not by direct impairment of the mitochondrial inner-membrane enzymes.
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PMID:Oxidative damage to mitochondria is mediated by the Ca(2+)-dependent inner-membrane permeability transition. 769 Oct 56

Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO, molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.
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PMID:The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. 795 18

Excess free radicals are linked to many diseases, including aging, atherosclerosis, and cancer. Previously, we have shown that MA-631 (a complex herbal mixture) inhibits human low-density lipoprotein (LDL) oxidation and may play a role in prevention of atherosclerosis. In this study we further evaluated the in vivo and in vitro antioxidant activity of MA-631. Both the alcoholic and aqueous extracts of MA-631 inhibited enzymatic- and nonenzymatic-induced rat liver microsomal lipid peroxidation in a concentration-dependent manner. The thiobarbituric acid-reactive substances (TBARS) values (nmol malondialdehyde (MDA)/mg microsomal protein) were 1.43 +/- 0.18 for microsomes alone (baseline for enzymatic system), 19.63 +/- 2.50 for microsomes + reduced nicotinamide adenine dinucleotide phosphate (NADPH) (oxidation without inhibitor), 9.89 +/- 1.41 for heated microsomes (baseline for nonenzymatic system), and 27.15 +/- 0.08 for microsomes + ascorbate (oxidation without inhibitor). The concentrations (micrograms/2 ml) of MA-631 which produced 50% inhibition (IC50) of enzymatic- and non-enzymatic-induced lipid peroxidation were 15.2 +/- 2.0 and 17.0 +/- 2.6, respectively, for the aqueous extract, and 4.3 +/- 0.8 and 6.4 +/- 1.2, respectively, for the alcoholic extract. A 2% MA-631 (w:w) supplemented diet fed to rats for three weeks inhibited in vivo, toluene-induced microsomal lipid peroxidation in the brain, kidney, liver, and heart. These results imply that MA-631 may be useful in the prevention of free radical-linked diseases.
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PMID:In vitro and in vivo inhibition of microsomal lipid peroxidation by MA-631. 809 Aug 22

The possible mutagenicity of the water-soluble contents of cigarette smoke (WSCS) was evaluated by using the Vicia faba root tip micronucleus test. The results showed significant changes in micronucleus frequency which were caused by each different concentration of WSCS. This indicates that the Vicia faba root tip micronucleus test might be used as one kind of mutagenic detection method for cigarette smoke. A comparative evaluation on the mutagenicity of 10 brands of cigarettes was carried out. Results confirmed that various degrees of mutagenicity were found for all of the brand cigarettes, among them, Huaihai was the highest, while Camellia was the lowest. The micronucleus frequencies were reduced by adding tea polyphenol, nicotinamide adenine, vitamin C and sodium selenite to the WSCS. The results suggest that these added substances might reduce the genetic injury induced by cigarette smoke.
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PMID:Vicia faba root tip micronucleus test on the mutagenicity of water-soluble contents of cigarette smoke. 856 97

Detection of Cr(V) in the reduction of Cr(VI) by whole live mice and its characterization were carried out by low frequency electron paramagnetic resonance (EPR). Intravenous injection of Cr(VI) to mice generated Cr(V). The Cr(V) was found predominantly in the liver with a small amount in the blood. Liver homogenates from Cr(VI) treated mice generated essentially the same Cr(V) spectrum as that obtained from the whole live mice. This Cr(V) species was identified to be a Cr(V)-nicotinamide adenine dinucleotide (NAD) (P)H complex with an oxygen bond to Cr(V). Pretreatment of the mice with ascorbic acid and glutathione reduced the Cr(V) formation, while pretreatment with reduced nicotinamide adenine dinucleotide (NADH) enhanced it. Metal chelators, ethylenediaminetetraacetic acid (EDTA), 1,10-phenanthroline, and diethylenetriaminepentaacetic acid (DTPA) inhibited the intensity of the Cr(V) signal. The results suggest that Cr(V) generated in the whole body of a live animal is a Cr(V)-NAD(P)H complex and NAD(P)H/flavoenzymes and not glutathione or ascorbate as the major one-electron Cr(VI) reductant responsible for observed formation of Cr(V)-NAD(P)H complex in vivo.
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PMID:Low frequency electron paramagnetic resonance investigation on metabolism of chromium (VI) by whole live mice. 885 27

Cytosolic NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) accounted for about 68% of the total ubiquinone (UQ) reductase activity in rat liver homogenate [Takahashi, T. et al. (1995) Biochem. J. 309, 883-890]. We investigated the effects of various factors on this enzyme activity in rat liver cytosol with the aim of elucidating its physiological roles. The NADPH-UQ reductase in rat liver cytosol catalyzed the reduction of UQ to UQH2 with concomitant oxidation of equimolar NADPH. The optimal pH was around 7.4, and the optimal temperatures were about 28 degrees C for NADH and about 37 degrees C for NADPH. NADH, deamino NADH, and deamino NADPH were much less active hydrogen donors than NADPH, whereas reduced nicotinamide mononucleotide, ascorbate, erythorbate, reduced glutathione, and cysteine were inactive. As the hydrogen acceptor, UQ-9 had the highest Vmax/Km among the long-chain UQ homologues tested. FAD and FMN stimulated the activity. Anionic detergents, Mg2+ and Sr2+ also enhanced the activity. Rotenone, malonic acid, antimycin A, and KCN, which inhibit mitochondrial and microsomal electron transfer enzymes, superoxide dismutase, and acetylated cytochrome c had no effect on the NADPH-UQ reductase activity. These results indicated that the NADPH-UQ reductase in rat liver cytosol is a flavoprotein that reduces UQ-10 by a two-electron reduction mechanism and is distinguishable from known microsomal and mitochondrial enzymes, as well as DT-diaphorase [EC 1.6.99.2].
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PMID:Characterization of NADPH-dependent ubiquinone reductase activity in rat liver cytosol: effect of various factors on ubiquinone-reducing activity and discrimination from other quinone reductases. 888 15


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