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

---

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

Superoxide (.O2-) production by the NADPH oxidase of a membrane fraction derived from rabbit peritoneal neutrophils activated by 4 beta-phorbol 12-myristate 13-acetate (PMA) was studied at 25 degrees C under different conditions, and measured by the superoxide dismutase inhibitable reduction of cytochrome c. Whereas PMA-activated rabbit neutrophils incubated in a glucose-supplemented medium exhibited a substantial rate of production of .O2-, the membranes prepared by sonication of the activated neutrophils were virtually unable to generate .O2- in the presence of NADPH. Instead, they exhibited an NADPH-dependent diaphorase activity, measured by the superoxide-dismutase-insensitive reduction of cytochrome c. Upon addition of arachidonic acid, which is known to elicit oxidase activation, the NADPH diaphorase activity of the rabbit neutrophil membranes vanished and was stoichiometrically replaced by an NADPH oxidase activity. The emerging oxidase activity was fully sensitive to iodonium biphenyl, a potent inhibitor of the respiratory burst, whereas the diaphorase activity was not affected. Addition of 0.1% Triton X-100 or an excess of arachidonic acid, acting as detergent, resulted in the reappearance of the diaphorase activity at the expense of the oxidase activity. These results indicate that the diaphorase-oxidase transition is reversible. When the rabbit neutrophil membranes were supplemented with rabbit neutrophil cytosol, guanosine 5'-[gamma-thio]triphosphate and Mg2+, in addition to arachidonic acid, not only the NADPH diaphorase activity disappeared, but the emerging NADPH oxidase activity was markedly enhanced (about 10 times compared to that of membranes treated with arachidonic acid alone). The diaphorase-oxidase transition was accompanied by a 10-fold increase in the Km for NADPH, suggesting a change of conformation propagated to the NADPH-binding site during the transition. The treatment of PMA-activated rabbit neutrophils with cross-linking reagents, like glutaraldehyde or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, prevented the loss of the PMA-elicited oxidase activity upon disruption of the cells by sonication, suggesting that the interactions between the components of the oxidase complex are stabilized by cross-linking.
...
PMID:Respiratory burst of rabbit peritoneal neutrophils. Transition from an NADPH diaphorase activity to an .O2(-)-generating oxidase activity. 217 79

Lactoquinomycin A (LQM-A), an antibiotic containing a quinone moiety in the molecule, inhibited biosyntheses of DNA, RNA and protein to a similar extent in doxorubicin-resistant mouse leukemia L5178Y cells at concentrations higher than 0.08 micrograms/ml. The antibiotic caused cell death in a short period of incubation and the degree of cell death correlated with that of the inhibition of macromolecular syntheses, suggesting that the inhibition of macromolecular syntheses was not a primary effect of LQM-A. LQM-A served as a good electron acceptor, when cytochrome c reductase was used as a quinone reductase. The treatment of the cells with LQM-A significantly reduced cellular NADH and ATP levels. The generation of superoxide radical by LQM-A in cell lysate was observed by reduction of nitro blue tetrazolium, and the production of hydroxyl radical was confirmed by electron spin resonance. The importance of radical formation for the cytotoxicity of LQM-A is discussed.
...
PMID:Mechanism of action of lactoquinomycin A with special reference to the radical formation. 284 12

Incubation of rat-liver mitochondria with menadione in the presence of succinate and rotenone resulted in rapid glutathione and NAD(P)H oxidation followed by Ca2+ release and mitochondrial swelling. Ca2+ release, NAD(P)H oxidation and mitochondrial swelling, were also observed in mitochondria from selenium-deficient rats. Glutathione was only slowly oxidized, suggesting that glutathione oxidation, and subsequent NAD(P)H oxidation via the glutathione peroxidase-glutathione reductase system were not required for Ca2+ release by menadione. Isocitrate prevented and reversed Ca2+ release dose-dependently but dicoumarol had no effect indicating that NADH-ubiquinone oxidoreductase and not DT-diaphorase was responsible for NAD(P)H oxidation. Superoxide anion radical was formed by cyanide-resistant respiration, suggesting that menadione undergoes a one-electron reduction to an autoxidizable semiquinone radical by NADH-ubiquinone oxidoreductase. The inability of menadione to oxidize glutathione in selenium-deficient mitochondria indicates that the metabolism of the superoxide dismutation product, H2O2, by glutathione peroxidase was probably responsible for the glutathione oxidation in selenium-replete mitochondria.
...
PMID:Menadione (2-methyl-1,4-naphthoquinone)-induced Ca2+ release from rat-liver mitochondria is caused by NAD(P)H oxidation. 302 Aug 12

DT diaphorase catalyzes the transfer of two electrons to quinones to form relatively stable hydroquinones, thus protecting cells from damage by semiquinone production and subsequent superoxide radical formation. A rapid and substantial increase in the activity of DT diaphorase occurs in the cytosolic and microsomal fractions of livers of rats with Zajdela ascites hepatoma under conditions which generally depress the activity of other xenobiotic-metabolizing enzymes. The increase is time-dependent, parallels the increase in the specific activity of DT diaphorase of the growing hepatoma cells, and is limited to the liver. Treatment of rats with hepatoma cytosol results in a rapid increase in liver cytosolic DT diaphorase activity in a dose-dependent manner.
...
PMID:The anticancer enzyme DT diaphorase is induced selectively in liver during ascites hepatoma growth. 312 84

Paraquat (PQ++) increased cyanide-resistant univalent respiration in cell suspensions of five strains of obligately thermophilic bacteria. PQ++ was reduced by an NADH: or NADPH:paraquat diaphorase and selectivity for NADH, NADPH, or both electron donors varied among the thermophiles. Superoxide anion production that was dependent on the presence of PQ++ was shown by following the superoxide dismutase-inhibitable reduction of cytochrome c. In addition, the PQ++-dependent formation of hydrogen peroxide from superoxide anion was evident in two of the thermophilic strains. Catalase synthesis was induced by adding hydrogen peroxide to the growth medium of the thermophiles. The induction of catalase to eliminate hydrogen peroxide appears to be an important response of these thermophilic bacteria to oxygen toxicity.
...
PMID:Paraquat toxicity and effect of hydrogen peroxide on thermophilic bacteria. 391 5

Crude extracts of Methanospirillum hungatei strain GP1 contained NADH and NADPH diaphorase activities. After a 483-fold purification of the NADH diaphorase the enzyme was further separated from contaminating proteins by polyacrylamide disc gel electrophoresis. Two distinct activity bands were extracted from the acrylamide, each one having oxygen, 2,6-dichlorophenolindophenol, and cytochrome c linked activities. In these preparations NADPH could not replace NADH as electron donor. During the initial purification steps all activity was lost due to the removal of a readily released cofactor. Enzyme activity was restored by either FAD or a FAD fraction isolated from M. hungatei. Oxidase activity exhibited a broad pH optimum from 7.0 to 8.5 and apparent Km values of 26 microM for NADH and 0.2 microM for FAD. Superoxide anion, formed in the presence of oxygen, accounted for all of the NADH consumed in the reaction. The molecular weight of the diaphorase was about 117 500 by sodium dodecyl sulfate gel electrophoresis. Sulfhydryl reagents and chelating agents were inhibitory. Inactivation, which occurred during storage in phosphate buffer at 4 degrees C, was delayed by dithiothreitol. The isolated NADH diaphorase lacked NADPH:NAD transhydrogenase and NAD reductase activities.
...
PMID:Isolation and characterization of a FAD-dependent NADH diaphorase from Methanospirillum hungatei strain GP1. 626 28

Following the two-electron reduction of 2-methyl-1,4-naphthoquinone by rat liver DT-diaphorase (also called NAD(P)H: (quinone acceptor) oxidoreductase, EC 1.6.99.2), the hydroquinone product is slowly autoxidized to the quinone in buffered solutions at pH 7.0. The autoxidation, which generates the superoxide radical (O2-.) and other reactive oxygen species, is the rate-limiting step in the oxidation-reduction (redox) cycling of the quinone. The addition of ascorbate to these reaction mixtures increases the rate of redox cycling. Two mechanisms are proposed to explain this increase: (1) ascorbate reduces the quinone in a one-electron reduction and (2) if Fe(3+)-EDTA is present, ascorbate reduces the metal chelate in a one-electron reduction. Both mechanisms produce O2-. which initiates the free radical chain reaction that results in autoxidation of the hydroquinone. Although ascorbate may be a physiologically important antioxidant under some conditions, the studies reported here show that ascorbate is a prooxidant in the redox cycling of 2-methyl-1,4-naphthoquinone and, as such, could increase the potential toxicity of this quinone.
...
PMID:Effect of ascorbate on the DT-diaphorase-mediated redox cycling of 2-methyl-1,4-naphthoquinone. 773 72

The relationship between superoxide anion production and the activities of sperm specific NADH-diaphorase and isozyme LDH-C4 has been investigated in 25 normozoospermic and 17 oligozoospermic semen samples. The samples were separated into high and low density sperm populations on discontinuous, two step (40%:80%) Percoll gradients prior to analysis. Superoxide anion generation was significantly higher (P < 0.001) and diaphorase activity significantly increased (P < 0.01) in both low and high density sperm fractions from oligozoospermic patients compared to the values found in normozoospermic men. A significant positive correlation (P < 0.01) between diaphorase activity and superoxide anion production was established in the oligozoospermic samples of low density sperm fraction. A tendency of statistically insignificant increase in LDH-C4 isozyme activity was observed in the oligozoospermic samples. The activity of this isozyme appears to have no association with superoxide anion generation or diaphorase activity. These findings seem to suggest that excessive superoxide anion production along with increased diaphorase activity point to biochemical abnormalities which may affect the functional status of sperms. Hence, determination of these parameters may provide useful data in male infertility of unknown etiology.
...
PMID:Superoxide anion production and some sperm-specific enzyme activities in infertile men. 775 91

Dopa was oxidized by Mn(3+)-pyrophosphate complex to the corresponding o-quinone, accompanied by the cyclization of the amino chain to form cyclized dopa ortho-quinone (cDoQ) with absorption maxima at wavelengths of 305 and 475 nm. The cyclization was found to proceed in a single step from DoQ to cDoQ without formation of cDoQH2 and oxygen consumption. DT-diaphorase catalyzes the reduction of cDoQ to the corresponding hydroquinone (cDoQH2), which was found to be unstable in the presence of oxygen. The autoxidation of the cDoQH2 was followed by recording the constant oxidation of NADH and oxygen consumption and reduction of cDoQ at a wavelength of 475 nm. It was found that three different oxidizing agents were involved in autoxidation of cDoQH2. The addition of DETAPAC resulted in a strong inhibition of NADH oxidation (65% inhibition) during the reduction of cDoQ by DT-diaphorase, suggesting that manganese was responsible for 65% of the autoxidation of cDoQH2. The addition of SOD to the incubation mixture resulted in the inhibition of NADH oxidation (79%) during the reduction of cDoQ by DT-diaphorase. In the presence of DETAPAC, the addition of SOD inhibited NADH oxidation during cDoQH2 autoxidation 75%, suggesting that superoxide radicals are responsible for 75% of the oxygen-dependent autoxidation. The remaining NADH oxidation, which was not inhibited by DETAPAC and SOD, was accompanied by a constant oxygen consumption, suggesting that this autoxidation of cDoQH2 proceeds by reducing oxygen to superoxide radical. The effect of SOD and catalase in the presence of DETAPAC was also studied. A nearly complete inhibition (90%) of oxygen consumption during the reduction of cDoQ by DT-diaphorase was observed when SOD alone or SOD and catalase were added to the incubation mixture containing DETAPAC. We conclude that SOD and catalase constitute a protective cellular system against formation of reactive oxygen species during reduction of cDoQ by DT-diaphorase.
...
PMID:Superoxide dismutase and catalase prevent the formation of reactive oxygen species during reduction of cyclized dopa ortho-quinone by DT-diaphorase. 808 30

Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, SR 4233, WIN 59075) is a bioreductive antitumor agent with a high selective toxicity for hypoxic cells. The selective hypoxic toxicity of TPZ results from the rapid reoxidation of the one-electron reduction product, the TPZ radical, in the presence of molecular oxygen with the concomitant production of superoxide radical. Under hypoxia the TPZ radical kills cells by causing DNA double-strand breaks and chromosome aberrations. However, the mechanism of aerobic cytotoxicity is still a matter of debate. In this study, we investigated the mechanism of aerobic cytotoxicity by adapting human lung adenocarcinoma A549 cells to aerobic TPZ exposure and characterizing the changes associated with drug resistance. The adapted cells were resistant to aerobic TPZ exposures (with dose-modifying factors of up to 9.2), although hypoxic sensitivity was largely unchanged. Relative to the parental A549 cell line, adaptation to continuous aerobic TPZ exposure resulted in increased levels of manganese superoxide dismutase (up to 9.4-fold), moderate increases in glutathione reductase (up to 2.1-fold), and loss of both quinone oxidoreductase (DT-diaphorase) activity and NADPH cytochrome P450 reductase activity. There was essentially no change in the activity of the cytoplasmic form of superoxide dismutase (CuZnSOD), catalase, or glutathione peroxidase. The increased activity of antioxidant enzymes in the resistant cell lines (in particular MnSOD) strongly suggests that reactive oxygen species are, in large part, responsible for the toxicity of TPZ under aerobic conditions, and is consistent with aerobic and hypoxic drug cytotoxicity resulting from different mechanisms.
...
PMID:Adaptation of human tumor cells to tirapazamine under aerobic conditions: implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity. 927 29


1 2 3 Next >>

---