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)

The results of this study show the quinone-dependent reduction of tertiary amine N-oxides to the corresponding tertiary amines by rat liver preparations. The reduction of imipramine N-oxide to imipramine mediated by liver mitochondria, microsomes, and cytosol proceeded in the presence of both NAD(P)H and menadione under anaerobic conditions. When menadione was replaced with 1, 4-naphthoquinone or 9,10-anthraquinone, similar results were obtained in the cytosolic reduction. The quinone-dependent reducing activity in liver cytosol was inhibited by dicumarol and carbon monoxide. This result suggested that the activity is caused by DT-diaphorase, a cytosolic quinone reductase, and hemoproteins in liver cytosol. In fact, catalase and hemoglobin showed the ability to reduce imipramine N-oxide when supplemented with DT-diaphorase. The hemoproteins also exhibited the N-oxide reductase activity with reduced menadione, menadiol. The N-oxide reductase activity of the hemoproteins was also exhibited with 1,4-dihydroxynaphthalene, 1,4,9, 10-tetrahydroxyanthracene, or 1,4-dihydroxy-9,10-anthraquinone. Furthermore, hematin revealed a significant N-oxide-reducing activity in the presence of menadiol. The reduction appears to proceed in two steps. The first step is reduction of menadione to menadiol by a quinone reductase with NADPH or NADH. The second step is nonenzymatic reduction of tertiary amine N-oxides to tertiary amines by menadiol, catalyzed by the heme group of hemoproteins. Cyclobenzaprine N-oxide and brucine N-oxide were also transformed similarly to the corresponding amine by the quinone-dependent reducing system.
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PMID:A unique tertiary amine N-oxide reduction system composed of quinone reductase and heme in rat liver preparations. 988 15

Dihydrolipoamide dehydrogenase (LADH) lipoamide reductase activity decreased whereas enzyme diaphorase activity increased after LADH treatment with myeloperoxidase (MPO) dependent systems (MPO/H2O2/halide, MPO/NADH/halide and MPO/H2O2/nitrite systems. LADH inactivation was a function of the composition of the inactivating system and the incubation time. Chloride, iodide, bromide, and the thiocyanate anions were effective complements of the MPO/H2O2 system. NaOCl inactivated LADH, thus supporting hypochlorous acid (HOCl) as putative agent of the MPO/H2O2/NaCl system. NaOCl and the MPO/H2O2/NaCl system oxidized LADH thiols and NaOCl also oxidized LADH methionine and tyrosine residues. LADH inactivation by the MPO/NADH/halide systems was prevented by catalase and enhanced by superoxide dismutase, in close agreement with H2O2 production by the LADH/NADH system. Similar effects were obtained with lactoperoxidase and horse-radish peroxidase supplemented systems. L-cysteine, N-acetylcysteine, penicillamine, N-(2-mercaptopropionylglycine), Captopril and taurine protected LADH against MPO systems and NaOCl. The effect of the MPO/H2O2/NaNO2 system was prevented by MPO inhibitors (sodium azide, isoniazid, salicylhydroxamic acid) and also by L-cysteine, L-methionine, L-tryptophan, L-tyrosine, L-histidine and reduced glutathione. The summarized observations support the hypothesis that peroxidase-generated "reactive species" oxidize essential thiol groups at LADH catalytic site.
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PMID:Inactivation of myocardial dihydrolipoamide dehydrogenase by myeloperoxidase systems: effect of halides, nitrite and thiol compounds. 1019 78

The levels and subcellular distribution of enzymes involved in defenses against reactive oxygen superoxide dismutase (SOD; E.C.1.15.1.1), glutathione peroxidase (GPX; E.C.1.11.1.9), catalase (CAT; E.C.1.11.1.6), and DT-diaphorase (DT; E.C.1.6.99.2) and of the conjugating enzymes glutathione transferase (GST; E.C.2.5.1.18) and p-sulphotransferase (p-ST; E.C.2.8.2.1) in the corpus luteum of ovaries from pregnant and non-pregnant pigs were investigated. In addition, non-protein thiols and glutathione reductase (GRD; E.C.1.6.4.2) were examined in the same manner. The total cytosolic activities of CAT, DT, GRD, and p-ST were significantly increased, whereas total GST activity was decreased in the pregnant corpus luteum compared to the corresponding activities in non-pregnant corpus luteum. In the case of the mitochondrial fraction from pregnant corpus luteum, GPX and GRD displayed significant increases in specific activity. Upon subfractionation of the mitochondrial fraction (i.e. mitoplast preparation), SOD activity was distributed equally between the mitoplasts and the supernatant. CAT and GPX activities were mainly recovered in the supernatant, while the major GRD activity pelleted with the mitoplasts. Microsomes from pregnant corpus luteum demonstrated increased specific GPX activity and decreased SOD activity compared to the non-pregnant corpus luteum. No differences in the non-protein thiol levels in the cytosolic, mitochondrial, or microsomal fractions from the corpus luteum were observed between non-pregnant and pregnant sows.
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PMID:Levels and subcellular distributions of detoxifying enzymes in the ovarian corpus luteum of the pregnant and non-pregnant pig. 1048 30

A series of indolequinones including derivatives of EO9 bearing various functional groups and related indole-2-carboxamides have been studied with a view to identifying molecular features which confer substrate specificity for purified human NAD(P)H:quinone oxidoreductase (DT-diaphorase), bioreductive activation to DNA-damaging species, and selectivity for DT-diaphorase-rich cells in vitro. A broad spectrum of substrate specificity exists, but minor changes to the indolequinone nucleus have a significant effect upon substrate specificity. Modifications at the 2-position are favorable in terms of substrate specificity as these positions are located at the binding site entrance as determined by molecular modeling studies. In contrast, substitutions at the (indol-3-yl)methyl position with bulky leaving groups or a group containing a chlorine atom result in compounds which are poor substrates, some of which inactivate DT-diaphorase. Modeling studies demonstrate that these groups sit close to the mechanistically important amino acids Tyr 156 and His 162 possibly resulting in either alkylation within the active site or disruption of charge-relay mechanisms. An aziridinyl group at the 5-position is essential for potency and selectivity to DT-diaphorase-rich cells under aerobic conditions. The most efficient substrates induced qualitatively greater single-strand DNA breaks in cell-free assays via a redox mechanism involving the production of hydrogen peroxide (catalase inhibitable). This damage is unlikely to form a major part of their mechanism of action in cells since potency does not correlate with extent of DNA damage. In terms of hypoxia selectivity, modifications at the 3-position generate compounds which are poor substrates for DT-diaphorase but have high hypoxic cytotoxicity ratios.
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PMID:Bioreductive activation of a series of indolequinones by human DT-diaphorase: structure-activity relationships. 1051 77

Protective effect of the cellular ubiquinone (UQ) reducing system linked to cytosolic NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) against hydrogen peroxide (H2O2)-induced lipid peroxidation was investigated using UQ and control hepatocytes freshly isolated from rats injected with UQ-10 and the vehicles 14 d in advance, respectively. The UQ hepatocytes had higher levels of ubiquinol (UQH2)-10 content and NADPH-UQ reductase activity than the control hepatocytes but did not differ in other antioxidant factors from the latter cells. The UQ hepatocytes exhibited higher cell viability and lower release of lactate dehydrogenase than the control hepatocytes when they were exposed to H2O2 of up to 100 mM for 1 h at 37 degrees C. Furthermore, the formation of thiobarbituric acid reactive substances (TBARS) by H2O2 was almost completely inhibited in the UQ hepatocytes. Decreases in UQH2 and alpha-tocopherol contents and NADPH-UQ reductase activity by H2O2 exposure were observed in both types of the hepatocytes, but those levels in the UQ hepatocytes after the exposure were still higher than in the control hepatocytes. The decreases in ascorbic acid, reduced glutathione and protein thiol contents and DT-diaphorase activity by H2O2 were not different between in the two types of hepatocytes. Antioxidant enzyme activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione S-transferase and glutathione reductase in the hepatocytes were not inhibited by H2O2. From these results, it was concluded that the cellular UQ reducing system linked to cytosolic NADPH-UQ reductase functions mainly as an antioxidant defense for cellular membranes.
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PMID:Antioxidant roles of cellular ubiquinone and related redox cycles: potentiated resistance of rat hepatocytes having stimulated NADPH-dependent ubiquinone reductase against hydrogen peroxide toxicity. 1059 33

Male and female C57B1/6 mice were rendered vitamin A-deficient, and the effects of this deficiency on certain xenobiotic-metabolizing enzymes and defenses against oxidative stress were examined. Vitamin A deficiency significantly increased the levels of DT-diaphorase, glutathione transferase, and catalase in the hepatic cytosolic fraction from male mice (5.2-, 1.6-, and 3.5-fold, respectively), as well as from female mice (4.8-, 3.3-, and 2.4-fold, respectively). In the hepatic mitochondrial fraction (containing peroxisomes) from male animals, the activities of urate oxidase and catalase were increased 3.4- and 1.7-fold, respectively. The activity of catalase in the mitochondrial fraction from female mice was not affected by vitamin A deficiency, whereas the activity of peroxisomal urate oxidase was increased 2.9-fold. The hepatic level of ubiquinone was increased somewhat. The significance of the increases observed here is presently unclear, but it may be speculated that vitamin A and/or its metabolites are somehow involved in the down-regulation of these proteins. Another possibility is that these enzymes are increased as a result of hepatic oxidative stress caused by vitamin A deficiency. However, vitamin A deficiency had no effect on the activity of superoxide dismutase in this study, whereas the activity of glutathione peroxidase was slightly decreased (27%) in the hepatic cytosolic fraction from male mice. In addition, the hepatic level of alpha-tocopherol was decreased dramatically in the vitamin A-deficient animals.
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PMID:Effects of vitamin A deficiency on selected xenobiotic-metabolizing enzymes and defenses against oxidative stress in mouse liver. 1064 45

The paper presents results showing differential response to paraquat toxicity in Wistar rats and Swiss strain of mice. Paraquat-induced pulmonary biochemical responses in the two animal species were studied at different time point after giving a single intraperitoneal injection of the respective LD(10) doses of the herbicide paraquat to rats and mice. Paraquat induced different biochemical responses including different protective responses in the two animal species. As a protective response, NADPH-specific quinone reductase is induced in rats, while catalase is induced in mice. It is implied that an early induction of catalase in mice as opposed to rats may account for the resistance of Swiss mice to paraquat toxicity. Xanthine oxidase, which was induced in rats, remains unaffected in mice indicating that the enzyme contributes to paraquat toxicity only in Wistar rats. Time-course studies were also conducted to compare the differential responses of antioxidant enzymes and lipid peroxidation between the two species. The results of the study led us to suggest that the manifestation of paraquat toxicity involve distinct differences in early pulmonary biochemical responses in Wistar rats and Swiss mice.
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PMID:Paraquat induces different pulmonary biochemical responses in Wistar rats and Swiss mice. 1069 69

This study was designed to (1) evaluate retinal lipid peroxidation in early diabetes by the method specific for free malondialdehyde and 4-hydroxyalkenals, (2) identify impaired antioxidative defense mechanisms and (3) assess if enhanced retinal oxidative stress in diabetes is prevented by the potent antioxidant, DL-alpha-lipoic acid. The groups included control and streptozotocin-diabetic rats treated with or without DL-alpha-lipoic acid (100 mg kg(-1) day(-1), i.p., for 6 weeks). All parameters were measured in individual retinae. 4-Hydroxyalkenal concentration was increased in diabetic rats (2.63+/-0.60 vs. 1.44+/-0.30 nmol/mg soluble protein in controls, P<0.01), and this increase was prevented by DL-alpha-lipoic acid (1.20+/-0.88, P<0.01 vs. untreated diabetic group). Malondialdehyde, reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations were similar among the groups. Superoxide dismutase, glutathione peroxidase (GSHPx), glutathione reductase (GSSGRed) and glutathione transferase (GSHTrans) activities were decreased in diabetic rats vs. controls. Quinone reductase was upregulated in diabetic rats, whereas catalase and cytoplasmic NADH oxidase activities were unchanged. DL-alpha-Lipoic acid prevented changes in superoxide dismutase and quinone reductase activities induced by diabetes without affecting the enzymes of glutathione metabolism. In conclusion, accumulation of 4-hydroxyalkenals is an early marker of oxidative stress in the diabetic retina. Increased lipid peroxidation occurs in the absence of GSH depletion, and is prevented by DL-alpha-lipoic acid.
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PMID:Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL-alpha-lipoic acid. 1085 58

In recent years, considerable efforts have been made to identify new chemopreventive agents which could be useful for man. Myrica nagi, a subtropical shrub, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. We have shown a chemopreventive effect of Myrica nagi on cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in mice. Cumene hydroperoxide treatment at a dose level of 30 mg/animal/0.2 ml acetone enhances susceptibility of cutaneous microsomal membrane for iron-ascorbate-induced lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes such as catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and depletion in the level of cutaneous glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes such as glutathione S-transferase and quinone reductase has been observed. Application of Myrica nagi at doses of 2.0 mg and 4.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide (30 mg/animal/0.2 ml acetone) treatment resulted in significant inhibition of cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in a dose-dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation induced by iron ascorbate and xanthine oxidase activities were significantly reduced (P<0.05). In addition the depleted level of glutathione, the inhibited activities of antioxidants, and phase II metabolizing enzymes were recovered to a significant level (P<0.05). The protective effect of Myrica nagi was dose-dependent. In summary our data suggest that Myrica nagi is an effective chemopreventive agent in skin and capable of ameliorating cumene hydroperoxide-induced cutaneous oxidative stress and toxicity.
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PMID:Myrica nagi attenuates cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in Swiss albino mice. 1086 2

Evidence from a number of studies suggests that the mechanism by which tumor necrosis factor (TNF) kills transformed cells involves oxidative stress. NAD(P)H:(quinone acceptor) oxidoreductase (NQO1) is an antioxidant enzyme with particular relevance to cancer. The MCF-7 breast cancer cell line was stably transfected with rat NQO1 cDNA to determine whether increased NQO1 activity alters sensitivity to TNF-induced apoptosis. Five clones, with a range of NQO1 enzyme activities from 5- to 50-fold greater than the MCF-7 line, and two control transfectants were examined. Northern blot hybridization analyses and reverse transcription-PCR demonstrated that the increase in NQO1 activity in the transfectants was attributable to expression from the transfected rat sequence. Based on sulforhodamine B assays for the number of viable cells, the NQO1 clones showed increased sensitivity to EO9, an indoloquinone that undergoes bioactive reduction by NQO1. Viability studies also demonstrated that the NQO1 transfectants were significantly more sensitive to TNF than the control transfectants or MCF-7 parent. This increased sensitivity could not be explained by changes in superoxide dismutase or catalase activity or to increased sensitivity to oxidative stress in general, as assessed by response to hydrogen peroxide and paraquat treatment. Using dichlorodihydrofluorescein diacetate as a probe, we found that the NQO1 transfectants had no difference in baseline level of oxidative stress compared to the control cells but did exhibit greater intracellular oxidative stress after TNF treatment. We conclude that NQO1 can affect the TNF-mediated pathway to apoptosis.
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PMID:Increased tumor necrosis factor-alpha sensitivity of MCF-7 cells transfected with NAD(P)H:quinone reductase. 1091 79


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