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)

Coenzyme Q (CoQ0) and other quinones were shown to be potent insulin secretagogues in the isolated pancreatic islet. The order of potency was CoQ0 congruent to benzoquinone congruent to hydroquinone-menadione. CoQ6 and CoQ10 (ubiquinone), duroquinone and durohydroquinone did not stimulate insulin release. CoQ0's insulinotropism was enhanced in calcium-free medium and CoQ0 appeared to stimulate only the second phase of insulin release. CoQ0 inhibited inositol mono-, bis- and trisphosphate formation. Inhibitors of mitochondrial respiration (rotenone, antimycin A, FCCP and cyanide) and the calcium channel blocker verapamil, did not inhibit CoQ0-induced insulin release. Dicumarol, an inhibitor of quinone reductase, did not inhibit CoQ0-induced insulin release, but it did inhibit glucose-induced insulin release suggesting that the enzyme and quinones play a role in glucose-induced insulin release. Quinones may stimulate insulin release by mimicking physiologically-occurring quinones, such as CoQ10, by acting on the plasma membrane or in the cytosol. Exogenous quinones may bypass the quinone reductase reaction, as well as many reactions important for exocytosis.
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PMID:Stimulation of insulin release from pancreatic islets by quinones. 172 Mar 33

A water-soluble quinone, coenzyme Q0 (CoQ0), was shown to stimulate insulin release, and dicumarol, an inhibitor of quinone reductase, inhibited glucose-induced insulin release in pancreatic islets. Since this suggested that quinone reductase might play some role in physiological insulin release, this enzyme was characterized in islets. More than 90% of the total activity was located in the cytosol, but the specific enzyme activity was highest in the microsomal fraction. The relative rates of activity with various substrates (CoQ0 approximately equal to durohydroquinone greater than menadione greater than duroquinone greater than CoQ6 = CoQ10 greater than ferricyanide) were similar to those described previously for quinone reductase from liver Dicumarol, chlorpromazine, and T3 were much more potent inhibitors of the enzyme when NADPH was the coenzyme than when NADH was the coenzyme. Dicumarol was the most potent inhibitor. The enzyme was not inhibited by rotenone. Islets ranked second to liver in quinone reductase activity, but the activity in islets was much closer to that found in all other tissues examined. Quinone reductase may play a role in insulin secretion.
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PMID:Quinone reductase enzyme activity in pancreatic islets. 187 76

A 40% reduction of the diameter of the ascending aorta maintained for 60 days induced the formation of a compensate cardiac hypertrophy in rabbits without changing the value of the azide insensitive Ca2+-ATPase activity in comparison to control hearts. The cardiac mitochondria isolated from constricted animals assayed in presence of glutamate and succinate did not show a change in the R.C.I. and ADP/O values in comparison to the controls, whilst the QO2 value enhanced or decreased respectively when determined with glutamate or succinate. The intramuscular injections of CoQ10 (12 mg/kg body weight/48 h) enhanced the mitochondrial CoQ10 concentrations both in the control and in the constricted animals and further increased the QO2 value determined in both groups of animals when glutamate was used as the substrate. The production of O2.- radicals by the level of the complexes I and III of the respiratory chain, did not change in the constricted animals, nor in the animals administered with CoQ10 in comparison to the control. CoQ10 augmented the rate of oxygen consumption by the submitochondrial particles only in the constricted animals. Moreover, the treatment with the coenzyme or the constriction of the aorta, did not modify the cardiac superoxide dismutase activity, but increased the glutathione peroxidase activity only in the banded animals. In addition, in the CoQ10 treated animals there was a reduction of NADH-diaphorase activity both in the control and constricted animals, while the malondialdehyde, generated during the thiobarbituric acid test, and the cardiac content of lipofuscin were decreased.
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PMID:The effect of treatment with coenzyme Q10 on the mitochondrial function and superoxide radical formation in cardiac muscle hypertrophied by mild aortic stenosis. 303 17

The blood level of [14C]coenzyme Q10 and the redox levels of [14C]coenzyme Q10 in the liver and heart were measured after intravenous injection of [14C]coenzyme Q10 solubilized in multilamellar liposomes into guinea pigs. The blood level of radioactivity declined biexponentially with half-lives of 11.5 min and 15.6 h in the first and second phases, respectively. The levels of reduced [14C]coenzyme Q10 in the liver and heart reached 55.8 and 46.4%, respectively, of the labeled compound in the tissues at 30 min after the injection. Coenzyme Q10-reducing activity in cytosol, microsomes and mitochondria was also investigated. This activity was found in all the fractions. The total activity was the highest in the liver cytosol. Moreover, the results of experiments using a purified enzyme suggested that one of the coenzyme Q10-reducing enzymes was NAD(P)H: quinone oxidoreductase [EC 1.6.99.2, DT-diaphorase]. These results are discussed in relation to the protective effect of reduced coenzyme Q10 against lipid peroxidation in membranes.
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PMID:Redox levels of intravenously administered [14C]coenzyme Q10 and coenzyme Q10-reducing activity in subcellular fractions of guinea pig liver. 392 43

The experiments reported here were designed to test the hypothesis that the two-electron quinone reductase DT-diaphorase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] functions to maintain membrane-bound coenzyme Q (CoQ) in its reduced antioxidant state, thereby providing protection from free radical damage. DT-diaphorase was isolated and purified from rat liver cytosol, and its ability to reduce several CoQ homologs incorporated into large unilamellar vesicles was demonstrated. Addition of NADH and DT-diaphorase to either large unilamellar or multilamellar vesicles containing homologs of CoQ, including CoQ9 and CoQ10, resulted in the essentially complete reduction of the CoQ. The ability of DT-diaphorase to maintain the reduced state of CoQ and protect membrane components from free radical damage as lipid peroxidation was tested by incorporating either reduced CoQ9 or CoQ10 and the lipophylic azoinitiator 2,2'-azobis(2,4-dimethylvaleronitrile) into multilamellar vesicles in the presence of NADH and DT-diaphorase. The presence of DT-diaphorase prevented the oxidation of reduced CoQ and inhibited lipid peroxidation. The interaction between DT-diaphorase and CoQ was also demonstrated in an isolated rat liver hepatocyte system. Incubation with adriamycin resulted in mitochondrial membrane damage as measured by membrane potential and the release of hydrogen peroxide. Incorporation of CoQ10 provided protection from adriamycin-induced mitochondrial membrane damage. The incorporation of dicoumarol, a potent inhibitor of DT-diaphorase, interfered with the protection provided by CoQ. The results of these experiments provide support for the hypothesis that DT-diaphorase functions as an antioxidant in both artificial membrane and natural membrane systems by acting as a two-electron CoQ reductase that forms and maintains the antioxidant form of CoQ. The suggestion is offered that DT-diaphorase was selected during evolution to perform this role and that its conversion of xenobiotics and other synthetic molecules is secondary and coincidental.
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PMID:The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. 863 8

The experiments reported here were undertaken to test the hypothesis that the antioxidative, reduced form of hydrophobic phase coenzyme Q (CoQ) may be generated and maintained by the two-electron quinone reductase, DT-diaphorase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] by catalyzing formation of the hydroquinone form of CoQ. This enzyme was isolated and purified from rat liver cytosol and its reduction of several CoQ homologs incorporated into large unilamellar vesicles (LUVETs) was demonstrated. The addition of NADH and DT-diaphorase to LUVETs and to multilamellar vesicles (MLVs) containing CoQ homologs, including CoQ9 and CoQ10, resulted in essentially complete reduction of the CoQ. Incorporation of either CoQ9H2 or CoQ10H2 and the lipophylic radical generator 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN) into MLVs in the presence of DT-diaphorase and NADH maintained the reduced state of CoQ and inhibited lipid peroxidation. The reaction between DT-diaphorase and CoQ was also demonstrated in isolated rat liver hepatocytes in which incorporation of CoQ10 provided protection from adriamycin (adr)-induced mitochondrial membrane damage. The role of DT-diaphorase in the antioxidant activity of CoQ was demonstrated by the co-incorporation of dicoumarol (dic), a potent inhibitor of DT-diaphorase, resulting in a loss of protection by incorporated CoQ10. These results support the antioxidant function of DT-diaphorase in both artificial and natural membrane systems by acting as a two-electron CoQ reductase which forms and maintains CoQ in the reduced state.
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PMID:The two-electron quinone reductase DT-diaphorase generates and maintains the antioxidant (reduced) form of coenzyme Q in membranes. 926 2

The conditions under which Coenzyme Q (CoQ) may protect platelet mitochondrial function of transfusional buffy coats from aging and from induced oxidative stress were investigated. The Pasteur effect, i.e. the enhancement of lactate production after inhibition of mitochondrial respiratory chain, was exploited as a marker of mitochondrial function as it allows to calculate the ratio of mitochondrial ATP to glycolytic ATP. Reduced CoQ10 improves platelet mitochondrial function of transfusional buffy coats and protects the cells from induced oxidative stress. Oxidized CoQ is usually less effective, despite the presence, shown for the first time in this study, of quinone reductase activities in the platelet plasma membranes. The addition of a CoQ reducing system to platelets is effective in enhancing the protection of platelet mitochondrial function from the oxidative stress. The results support on one hand a possibility of protection of mitochondrial function in aging by exogenous CoQ intake, on the other a possible application in protection of transfusional buffy coats from storage conditions and oxidative deterioration.
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PMID:Ubiquinol and a coenzyme Q reducing system protect platelet mitochondrial function of transfusional buffy coats from oxidative stress. 1206 7

Coenzyme Q10 supplementation increases life-span of rats fed on a diet enriched with polyunsaturated fatty acids (Quiles, J.L., Ochoa, J.J., Huertas, J.R., Mataix, J., 2004b. Coenzyme Q supplementation protects from age-related DNA double-strand breaks and increased lifespan in rats fed on a PUFA-rich diet. Exp. Gerontol. 39, 189-194). Our study was set as a first attempt to establish a mechanistic link between life span extension and CoQ10 supplementation. When rats were fed on a PUFAn-6 plus CoQ10 diet, levels of CoQ10 were increased in plasma membrane at every time point compared to control rats fed on a PUFAn-6-alone diet. Ratios of CoQ9 to CoQ10 were significantly lower at every time point in both liver plasma membranes and homogenates of CoQ10-supplemented animals. CoQ10 supplementation did not affect cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1), which increased significantly with aging, but plasma membrane-bound NQO1 decreased significantly in the CoQ10-supplemented group at 12 months, when maximal incorporation of exogenous CoQ10 was observed. Neither aging nor the diet affected NADH-cytochrome b5 reductase levels. Glutathione-dependent anti-oxidant activities such as cytosolic glutathione-S-transferase (GST) and microsomal Se-independent glutathione peroxidase decreased with aging and supplementation with CoQ10 attenuated this decay. 2,2' Azobis amidinopropane (AAPH)-induced oxidation of membranes was significantly higher in aged rats, and supplementation with CoQ10 also inhibited this increase. Consistent with higher CoQ10 levels and enhanced anti-oxidant protection, plasma membrane Mg2+-dependent neutral sphingomyelinase was inhibited by dietary CoQ10 in aged rats. Our results support the involvement of thiol-dependent mechanisms in the potentiation of the anti-oxidant capacity of membranes in CoQ10-supplemented rats, further supporting the potentially beneficial anti-oxidative role of dietary CoQ10 during aging. The possibility that a decreased CoQ9/CoQ10 ratio in animals fed on the PUFAn-6-rich plus CoQ10 diet could also influence longevity is also discussed.
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PMID:Enhanced anti-oxidant protection of liver membranes in long-lived rats fed on a coenzyme Q10-supplemented diet. 1612 50

Two-electron reduction of quinones catalyzed by NAD(P)H:quinone oxidoreductase (NQO1) protects cells against oxidative stress and toxic quinones. In fact, low level of NQO1 activity is often associated with increased risk of developing different types of tumours and with toxic effects linked to environmental quinones. In a previous report we analyzed the relationship between the oxidative stress induced by UV radiation and CoQ10 content in Burkitt's lymphoma cell lines compared to HL-60. The basal content of CoQ10 in Raji cells was slightly higher compared to HL-60. Moreover, after irradiation or ubiquinone supplementation in the medium, reduced CoQ10 levels were higher in Raji and Daudi cells compared to HL-60. In the present work, in order to inquire if NQO1 plays a role in the CoQ reducing capacity observed in the lymphoblastoid cell lines, we analyzed the transcription and translation products of this gene in Raji and Daudi cells, compared to cell lines possessing low and high NQO1 activity. The amount of transcripts of this gene in lymphoblastoid cells was comparable to that observed in HL-60 cells (low activity), as well as the level of two alternatively spliced mRNAs; one of which is described for the first time in this work. From the genotype analysis of polymorphisms C609T and C465T we observed that HL-60, Raji and Daudi cells were all heterozygous. Furthermore, NQO1 enzyme activity and protein synthesis in the cytosol of Raji and Daudi cells were undetectable. Therefore in Burkitt's lymphoma cell lines the NQO1 gene is not efficiently translated and this effect is not related to (C609T) polymorphism. Further studies will be necessary to find the enzyme responsible for CoQ10 reducing activity observed in lymphoma cell lines. On the other hand, this result suggests a careful re-evaluation of data concerning loss of NQO1 activity and polymorphisms in tumour cells.
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PMID:NAD(P)H:quinone oxidoreductase (NQO1) loss of function in Burkitt's lymphoma cell lines. 1909 2

Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.
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PMID:Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content. 2601 31


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