Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome-deficient cells of a strain of Escherichia coli lacking 5-amino-levulinate synthetase have been used to study proton translocation associated with the reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase region of the electron transport chain. Menadione was used as electron acceptor, and mannitol was used as the substrate for the generation of intracellular NADH. The effects of iron deficiency on NADH- and D-lactate-menadione reductase activities were studied in iron-deficient cells of a mutant strain unable to synthesize the iron chelator enterochelin; both activities were reduced. The NADH- menadione reductase activity in cytochrome-deficient cells was associated with proton translocation and could be coupled to the uptake of proline. However proton translocation associated with the NADH-menadione reductase activity was prevented by a mutation in an unc gene. It was concluded that there is no proton translocation associated with the NADH-dehydrogenase region of the electron transport chain in E. coli and that the proton translocation obtained with mannitol as substrate is due to the activity of membrane-bound adenosine triphosphatase.
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PMID:Proton translocation in cytochrome-deficient mutants of Escherichia coli. 15 8

1. Enzyme systems responsible for formation of cyclopropane ring-cleavage metabolites (M1 and M2) of illudin S in rat liver were characterized. 2. The enzymes were localized in the cytosol fraction and utilized NADPH alone as electron donor; they were not affected by oxygen and had low pH optima. 3. Formation of metabolites M1 and M2 was inhibited completely by dicumarol (10(-4) M), an inhibitor of DT-diaphorase. 4. Menadione (10(-4) M) and quercetin (10(-4) M) both inhibited formation of M1 and M2 by 35% and 15%, respectively, but quinacrine, barbital, pyrazole and p-chloromercuribenzoic acid had no significant effect. 5. Results show that the enzyme systems may differ from DT-diaphorase, aldehyde oxidase, xanthine oxidase, ketone reductase, aldose reductase, aldehyde reductase and alcohol dehydrogenase, known cytosolic enzymes responsible for xenobiotic metabolism.
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PMID:Metabolism by rat liver cytosol of illudin S, a toxic substance of Lampteromyces japonicus. II. Characterization of illudin S-metabolizing enzyme. 137 39

1. In both guinea-pig and rat heart, mitochondrial NADH-ubiquinone-reductase and soluble DT-diaphorase accounted for 49-50% and 48-50% of menadione metabolism, respectively. Microsomal NADPH-cytochrome P450-reductase was responsible for less than 1% of menadione reduction. 2. Menadione was a high-affinity substrate for all reductases (Km values from 1 to 10 microM). 3. Marked amounts of O2-. (superoxide anion) were generated as a consequence of cardiac metabolism of menadione. 4. Menadione-induced O2-. generation was about 3-fold higher in guinea-pig than in rat heart. 5. All results were compared with data obtained on guinea-pig and rat liver.
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PMID:One- and two-electron reduction of menadione in guinea-pig and rat cardiac tissue. 139 83

Menadione is a synthetic derivative of the natural vitamins K with antiinflammatory activity among its potentially significant clinical properties. We have found this agent to stimulate the production of superoxide anion (O2-) in human polymorphonuclear leukocytes (PMN) and dimethylsulfoxide-differentiated HL-60 cells in a time-, cell number-, and drug concentration-dependent manner. Conversely, menadione attenuates both O2- production and lysozyme release in cells stimulated by phorbol myristate acetate (PMA), fMet-Leu-Phe, or Ca2+ ionophore. 4-Acetamido-4'-isothiocyano-2-2'-disulfonic acid stilbene and 4,4'-diisothiocyano-2-2'disulfonic acid stilbene, agents which inhibit transmembrane O2-) flux, do not alter menadione's effects on superoxide dismutase (SOD) inhibitable cytochrome c reduction in resting or PMA-stimulated PMN. Likewise, quinone reductase inhibitors, warfarin and dicumarol, known to attenuate vitamin K-dependent responses and enhance quinone-mediated oxidative stress, have no effect upon menadione-stimulated O2- production. Furthermore, menadione-induced suppression of stimulus-mediated lysozyme release is not reversed by cotreatment with oxygen metabolite scavenging enzymes SOD and catalase. Nevertheless, under conditions of restricted oxygen supply, the suppressive effect of menadione on stimulant-induced lysozyme release is greatly diminished. Thus, although pharmacological manipulation suggests otherwise, there appears to exist at least a component of the inhibitory activity of menadione that is oxygen dependent, and may be oxidative stress-related.
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PMID:Alteration of human granulocyte functional responses by menadione. 170 Jun 67

2-Methyl-1,4-naphthoquinone (menadione) inhibits Ca2+-ATPase activity of cardiac sarcoplasmic reticulum membrane vesicles in a time- and concentration-dependent way; after 60 min of preincubation an apparent Ki value of 33.5 microM was calculated. Inhibition is not reversible in that it persists even after the drug is removed and Ca2+-ATPase activity is assayed in a menadione-free medium. GSH (2 mM), but not DTT, is able to prevent and reverse the inhibition of Ca2+-ATPase by menadione. The relative importance of menadione metabolism in the inhibition of Ca2+-ATPase was studied in cell-free systems composed of vesicles and subcellular fractions containing metabolizing enzymes. Under these experimental conditions, 105,000g supernatants isolated from heart or liver that biotransform menadione through DT-diaphorase reduce the inhibition of Ca2+-ATPase activity determined by menadione. Also liver microsomes that biotransform menadione through NADPH-cytochrome P450 reductase decrease the inhibition by menadione. By contrast, cardiac microsomes that do not biotransform the drug do not influence the effect of menadione. These results indicate that, under the experimental conditions used for this study, menadione does not require metabolism to inhibit cardiac sarcoplasmic reticulum Ca2+-ATPase activity.
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PMID:Inhibition of cardiac sarcoplasmic reticulum Ca2+-ATPase activity by menadione. 252 55

Hepatocytes isolated from phenobarbital (PB)-pretreated and naive male Sprague-Dawley rats were incubated with menadione under one of three oxygen conditions (0, 21, or 95% oxygen) for 3 hr. During this time, samples were drawn and assayed for lactate dehydrogenase release and trypan blue exclusion as indices of cytotoxicity. Neither parameter indicated any significant difference in menadione-induced cytotoxicity between naive and PB-pretreated hepatocytes. Likewise, no difference was observed between hepatocytes incubated in 21% versus 95% O2. Consistent with the oxyradical hypothesis of menadione-induced cytotoxicity, hepatocytes incubated under 0% O2 (95:5; N2:CO2) did not exhibit any menadione cytotoxicity. Hepatic microsomes prepared from PB-pretreated rats exhibited a threefold increase in NADPH cytochrome P450 reductase activity over those of controls. Menadione-stimulated superoxide (O2-) production was twofold higher in PB pretreated versus naive liver microsomes. However, PB pretreatment failed to produce an increase in O2- production in intact hepatocytes or in hepatocytes disrupted by sonication. The failure of PB pretreatment to increase menadione-induced cytotoxicity and superoxide production in either intact or sonicated hepatocytes suggests that a concomitant cytoprotective mechanism is induced as well. The data further indicate that the cytoprotective elements are located in a nonmicrosomal fraction of the cell. In support of this, we observed PB-induced increases in glutathione levels, glutathione reductase, and DT-diaphorase activities. These findings indicate that PB-induced enhancements of the hepatocellular cytoprotective mechanisms collectively compensate for the increased redox cycling mechanism, resulting in a mitigation of the anticipated increased hepatocellular cytotoxicity of menadione.
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PMID:Phenobarbital-induced cytosolic cytoprotective mechanisms that offset increases in NADPH cytochrome P450 reductase activity in menadione-mediated cytotoxicity. 254 42

The cytotoxic properties of quinones, such as menadione, are mediated through one electron reduction to yield semi-quinone radicals which can subsequently enter redox cycles with molecular oxygen leading to the formation of reactive oxygen radicals. In this study the role of reduction and oxidation in the toxicity of mitoxantrone was studied and its toxicity compared with that of adriamycin and menadione. The acute toxicity of mitoxantrone was not mediated through one-electron reduction, since inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells against oxidative damage, did not affect its toxicity. Adriamycin was the most potent inhibitor of protein and RNA synthesis of the three quinones. Menadione, at concentrations up to 25 microM, did not inhibit either protein or RNA synthesis unless dicoumarol, an inhibitor of DT-diaphorase, was also present. The two-electron reduction of menadione by DT-diaphorase is therefore a protective mechanism in the cell. This enzyme also protected against the toxicity of high concentrations (100 microM) of mitoxantrone. The inhibitory effect of mitoxantrone, but not of menadione or adriamycin, on cell growth was prevented by inhibiting the activity of cytochrome P450-dependent mixed function oxidase (MFO) system using metyrapone. This suggests that mitoxantrone is oxidised to a toxic intermediate by the MFO system.
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PMID:The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells. 255 92

As described previously, the microsomes and cytosol from bovine ciliary body exhibited a significant reductase activity toward tertiary amine N-oxide such as imipramine N-oxide when supplemented with menadione. In the present study, the menadione-dependent N-oxide reduction was further examined with preparations of bovine ocular tissues. The reduction of imipramine N-oxide occurred much more significantly when the microsomes and cytosols from bovine ciliary body were supplemented with both menadione and NAD(P)H, compared with menadione alone. The cytosolic menadione-dependent reduction, but not the microsomal one, was markedly inhibited by dicumarol, suggesting the involvement of DT-diaphorase in the reaction. Localization of the menadione-dependent N-oxide reductase activity in bovine ocular tissues indicated that the highest activity resided in the ciliary body, followed by retinal pigment epithelium-choroid, iris, retina and cornea. When the cytosol from bovine ciliary body was fractionated with ammonium sulfate, the distribution of the menadione-dependent N-oxide reductase activity in the resultant fractions was parallel, but roughly, to that of DT-diaphorase activity, supporting the assumption that the flavoenzyme was involved in the cytosolic menadione-dependent N-oxide reduction. We proposed a new mechanism for the metabolic reduction of tertiary amine N-oxide in the eye: Menadione is reduced to the corresponding diol by quinone-reducing enzymes and then tertiary amine N-oxide is reduced by the diol to the corresponding amine nonenzymatically.
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PMID:Metabolism of drugs in the eye. Menadione-dependent reduction of tertiary amine N-oxide by preparations from bovine ocular tissues. 262 98

1. Relationship between quinone recycling, glucuronidation and benzo(a)pyrene (BaP) oxygenation was investigated in uninduced mouse liver microsomes--native and modified by Fe3+.FeEDTA and/or superoxide (O2-.)-initiated lipid peroxidation. 2. A functional coupling between glucuronidation of reduced quinones and BaP metabolism, not discernible during BaP metabolism by native uninduced microsomes, was demonstrable in the presence of a model quinone, vitamin K3 (menadione). 3. Menadione inhibited BaP oxygenation in microsomal preparations, by siphoning off electrons from cytochrome P-450, while addition of UDPGA reversed this effect by glucuronidation of menadiol. 4. Fe3+.FeEDTA and/or O2-.-initiated lipid peroxidation decreased, to different extent, the microsomal enzymatic activities involved in quinone metabolism. The most sensitive was quinone reductase activity, which was reduced by 77%. Under peroxidative conditions menadione was a less effective inhibitor of BaP metabolism. 5. The important role of the balance between quinone reductase and UDP-glucuronyltransferase activities in the coupling with BaP oxygenation is discussed. A mechanism by which vitamin K3 could exert a regulatory effect on BaP metabolism is proposed.
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PMID:Interaction between vitamin K3 and benzo(a)pyrene metabolism in uninduced microsomes. 283 Jan 52

The cytotoxicity of menadione (2-methyl-1,4-naphthoquinone) and benzo(a)pyrene-3,6-quinone (BP-3,6-Q) was tested in cultures of adult rat hepatocytes and human fibroblasts. Menadione induced DNA strand breaks, cell membrane damage and depletion of reduced glutathione (GSH) in both hepatocytes and fibroblasts. In fibroblasts, effects on both DNA and membrane integrity were potentiated by the presence of dicoumarol, a specific inhibitor of the 2-electron reduction of quinones by DT-diaphorase, whereas in hepatocytes only the cell membrane damage was sensitive to dicoumarol. Results indicate that menadione toxicity is mediated via 1-electron reduction, although in hepatocytes different reactive species may be responsible for damage to DNA and to the membrane. BP-3,6-Q induced DNA strand breaks in fibroblasts at concentrations as low as 1 microM. The extent of DNA damage was insensitive to dicoumarol. Even after GSH depletion and inhibition of glucuronidation and sulphate conjugation, BP-3,6-Q caused no DNA damage in hepatocytes. In contrast to menadione, BP-3,6-Q did not induce cell membrane leakage or decrease in GSH levels in either hepatocytes or fibroblasts. These studies show the complexity of the metabolic pathways involved, in terms of activation and detoxification processes, in the toxicity of quinones.
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PMID:Induction of cell damage by menadione and benzo(a)pyrene-3,6-quinone in cultures of adult rat hepatocytes and human fibroblasts. 406 Jan 94


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