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)

Trenimon belongs to a class of aziridinylbenzoquinone anticancer drugs that cross the blood-brain barrier. In this study we have investigated the molecular mechanisms for trenimon-induced toxicity in aerobic versus hypoxic conditions with the use of freshly isolated rat hepatocytes. The following evidence suggests the mechanisms for trenimon detoxification involves reduction by DT-diaphorase, while the cytotoxic mechanism involves macromolecular alkylation under hypoxic conditions as well as oxidative stress under aerobic conditions. (a) Hepatocyte cytotoxicity induced by trenimon (250 microM) under aerobic conditions ensued following an initial induction of cyanide-resistant respiration and partial oxidation of glutathione to oxidized glutathione. Trenimon reduction to the hydroquinone by the hepatocytes was rapid. Inhibition of hepatocyte DT-diaphorase by dicumarol increased trenimon-induced cytotoxicity by approximately 10-fold, and markedly inhibited hydroquinone formation. Furthermore, both cyanide-resistant respiration and oxidized glutathione formation were markedly increased, resulting in depletion of oxygen in the media. Trenimon reduction to the hydroquinone then occurred. This suggests that DT-diaphorase in normal hepatocytes prevents the formation of the semiquinone that causes cytotoxic protein alkylation and oxidative stress. (b) Hepatocyte cytotoxicity induced by trenimon (350 microM) under hypoxic conditions ensued following glutathione depletion without oxidized glutathione formation. Inactivation of hepatocyte DT-diaphorase by dicumarol under hypoxic conditions increased trenimon-induced cytotoxicity by approximately 3.5-fold and increased semiquinone radical levels 2-fold without affecting its reduction rate. This suggests that the cytotoxic mechanism involves protein alkylation by semiquinone radicals formed by reductases catalyzing a one-electron reduction of trenimon.
...
PMID:Modulation of trenimon-induced cytotoxicity by DT-diaphorase in isolated rat hepatocytes under aerobic versus hypoxic conditions. 137 32

Deletion mutagenesis in human NAD(P)H:Quinone Oxidoreductase (NQO1) gene and transfection studies into mammalian cells identified a segment of DNA designated as human Antioxidant Response Element (hARE) responsible for high basal expression in tumor cells and its induction by beta-naphthoflavone (beta-NF). The twenty four base pairs of the hARE contains an essential cis-element AP1 binding site and has been shown to bind to jun-D and c-fos proteins from mouse hepatoma (Hepa-1) nuclear extract. In the present report, we have identified jun-B as the third major protein in the hARE-Hepa-1 proteins complex observed in the band shift assays.
...
PMID:Identification of jun-B as third member in human antioxidant response element-nuclear proteins complex. 144 67

The respiratory chain of a marine Vibrio alginolyticus contains two types of NADH-quinone reductase (NQR): one is an Na(+)-dependent NQR functioning as an Na+ pump (NQR-1) and the other is an Na(+)-independent NQR (NQR-2). NQR-2 was purified about 55-fold from the membrane of mutant Nap-1 which is devoid of NQR-1, and its properties were compared with those of NQR-1. In contrast to NQR-1, the purified NQR-2 does not require any salts for activity and is not inhibited by up to 0.4 M salts. The optimum pH of NQR-2 is between 6.8 and 7.8, which is about 0.7 ph units lower than that of NQR-1. NQR-2 is insensitive to strong inhibitors of NQR-1 such as p-chloromercuribenzoate, Ag+ and 2-heptyl-4-hydroxyquinoline N-oxide. Using inverted membrane vesicles, it was confirmed that NQR-2 has no capacity to generate a membrane potential. NQR-2 reduces menadione and ubiquinone-1 by a two-electron reduction pathway. Since the NADH-reacting FAD-containing beta-subunit of NQR-1 reduces quinones by a one-electron reduction pathway, the mode of quinone reduction is closely related to energy coupling; the formation of semiquinone radicals as an intermediate is likely to be essential to functioning as an ion pump.
...
PMID:Properties of respiratory chain-linked Na(+)-independent NADH-quinone reductase in a marine Vibrio alginolyticus. 154 99

Bacterial respiratory chain has two types of NADH-quinone reductase (NQR): one is energy-coupled (type-1) and the other had no energy-transducing capacity, that is, energy-uncoupled (type-2). Each of the NADH-reacting flavoprotein subunits of NQR-1 from Escherichia coli and the marine Vibrio alginolyticus reduced quinone to semiquinone radicals by the one-electron transfer pathway and was very sensitive to preincubation with NADH. On the other hand, the NQR-2 from these bacteria reduced quinone to quinol by the two-electron transfer pathway and was insensitive to preincubation with NADH. Since the NQR-1 from E. coli functions as a proton pump, whereas that from the marine V. alginolyticus functions as a sodium pump, the formation of semiquinone radicals as an intermediate is likely to be a common mechanism to functioning as either proton or sodium pump.
...
PMID:Characteristic differences in the mode of quinone reduction and stability between energy-coupled and -uncoupled NADH-quinone reductases from bacterial respiratory chain. 162 43

A highly active preparation of rat liver dihydrodiol/3 alpha-hydroxysteroid dehydrogenase was obtained using a newly developed, rapid purification scheme involving affinity chromatography on Red Sepharose. Depending on the coenzyme present, the purified enzyme was found to catalyse the oxidation of dihydrodiols and steroids or the reduction of substrates with carbonyl or quinone moieties. Using a wide range of synthetic quinones derived from polycyclic aromatic hydrocarbons (PAHs), we observed a pronounced regioselectivity of the quinone reductase activity. Good substrates were the o-quinones of phenanthrene, benz(a)anthracene, chrysene and benzo(a)pyrene with the quinonoid moiety in the K-region which were reduced at rates of 1-10 mumol/min.mg enzyme. 1,4-Benzoquinone, naphthalene-1,2-quinone and benz(a)anthracene-8,9-quinone were also reduced at high rates. In contrast, alkyl-substituted quinones such as duroquinone and menadione were poor substrates for the enzyme. During the enzymatic reduction of several o-quinones, but not 1,4-benzoquinone, we observed the oxidation of large amounts of NADPH and the consumption of molecular oxygen which is indicative of a redox-cycling process. Thus, the reduction of quinones of PAHs may lead to a facilitated conjugation and excretion of these highly lipophilic compounds, but may also initiate toxic processes due to the formation of reactive oxygen species.
...
PMID:Quinone reduction and redox cycling catalysed by purified rat liver dihydrodiol/3 alpha-hydroxysteroid dehydrogenase. 164 48

Quinone metabolites of catechol estrogens have been postulated to mediate estradiol-induced carcinogenesis. In this study, this postulate was examined by investigating the effect of modulators of quinone metabolism on estradiol-induced tumor incidence in male Syrian hamsters. 2(3)-t-Butyl-4-hydroxyanisol (BHA) and dicumarol which are known to stimulate or inhibit respectively, the activity of quinone reductase, lowered tumor incidence by 33 and 42% respectively (3/9 and 5/12 tumor-free animals/total respectively), from 100% (13/13) observed with 17 beta-estradiol (E2) treatment only. Ebselen, a substance with glutathione peroxidase-like activity, and sodium 2-mercaptoethanesulfonate (Mesna), a cytoprotective thiol-containing agent, were only marginally effective in decreasing the estradiol-induced kidney tumor incidence (3/11 and 4/19 tumor-free animals/total respectively). The lowering of tumor incidence by BHA and dicumarol correlated well with a 40-45% decrease in renal peroxidatic activity of cytochrome P450 in hamsters treated with these substances plus estradiol for 1 month. In addition, these compounds also inhibited the oxidation of diethylstilbestrol to its corresponding quinone in vitro. An influence on quinone reductase or other detoxifying enzymes in chronically treated male Syrian hamsters could not be detected. These data support a mediation of estradiol-induced carcinogenesis by quinones formed by metabolic oxidation of catechol estrogens.
...
PMID:Inhibition of estrogen-induced kidney carcinogenesis in Syrian hamsters by modulators of estrogen metabolism. 169 Oct 52

Quinones can be metabolized by various routes: substitution or reductive addition with nucleophilic compounds (mainly glutathione and protein thiol groups), one-electron reduction (mainly by NADPH: cytochrome P-450 reductase) and two-electron reduction (by D,T-diaphorase). During reduction semiquinone radicals and hydroquinones are formed, which can transfer electrons to molecular oxygen, resulting in the formation of reactive oxygen intermediates and back-formation of the parent quinone (redox cycling). Reaction of semiquinones and reactive oxygen intermediates with DNA and other macromolecules can lead to acute cytotoxicity and/or to mutagenicity and carcinogenicity. The enhanced DNA-alkylating properties of certain hydroquinones are exploited in the bioreductive alkylating quinones. Acute cytotoxicity of quinones appears to be related to glutathione depletion and to interaction with mitochondria and subsequent disturbance of cellular energy homoeostasis and calcium homoeostasis. These effects can to a certain extent be predicted from the electron-withdrawing and electron-donating effects of the substituents on the quinone nucleus of the molecule. Prediction of cytostatic potential remains much more complicated, because reduction of the quinones and the reactivity of the reduction products with DNA are modulated by the prevailing oxygen tension and by the prevalence of reducing enzymes in tumour cells.
...
PMID:Bioreductive activation of quinones: a mixed blessing. 192 1

Bone marrow stroma consists predominately of two cell types, macrophages and fibroblastoid stromal cells, which regulate the growth and differentiation of myelopoietic cells via the production of growth factors. We have previously shown that macrophages are more sensitive than fibroblastoid stromal cells (LTF cells) to the toxic effects of the benzene metabolite hydroquinone. In this study, the role of selective bioactivation and/or deactivation in the macrophage-selective effects of hydroquinone was examined. LTF and macrophage cultures were incubated with 10 microM [14C]hydroquinone to examine differential bioactivation. After 24 hr, the amount of 14C covalently bound to acid-insoluble macromolecules was determined. Macrophages had 16-fold higher levels of macromolecule-associated 14C than did LTF cells. Additional experiments revealed that hydroquinone bioactivation to covalent-binding species was hydrogen peroxide dependent in macrophage homogenates. Covalent binding in companion LTF homogenates was minimal, even in the presence of excess hydrogen peroxide. These data suggest that a peroxidative event was responsible for bioactivation in macrophages and, in agreement with this, macrophages contained detectable peroxidase activity whereas LTF cells did not. Bioactivation of [14C]hydroquinone to protein-binding species by peroxidase was confirmed utilizing purified human myeloperoxidase in the presence of hydrogen peroxide and ovalbumin as a protein source. High performance liquid chromatographic analysis of incubations containing purified myeloperoxidase, hydroquinone, and hydrogen peroxide showed that greater than 90% of hydroquinone was removed and could be detected stoichometrically as 1,4-benzoquinone. 1,4-Benzoquinone was confirmed as a reactive metabolite formed from hydroquinone in macrophage incubations using excess GSH and trapping the reactive quinone as its GSH conjugate, which was measured by high performance liquid chromatography with electrochemical detection. The activity of DT-diaphorase, a quinone reductase that has been invoked as a protective mechanism in quinone-induced toxicity, was 4-fold higher in LTF cells than macrophages. These data suggest that the macrophage-selective toxicity of hydroquinone results from higher levels of peroxidase-mediated bioactivation and/or lower levels of DT-diaphorase-mediated detoxification.
...
PMID:Bone marrow stromal cell bioactivation and detoxification of the benzene metabolite hydroquinone: comparison of macrophages and fibroblastoid cells. 215 73

NAD(P)H:(quinone-acceptor) oxidoreductase (EC 1.6.99.2) is a widely distributed enzyme which promotes two-electron reductions of quinones and thereby protects cells against damage by reactive oxygen species generated during oxidative cycling of quinones and semiquinone radicals. Quinone reductase activity represents a minor component (about 0.006%) of mouse liver cytosolic proteins under basal (uninduced) conditions. Two isofunctional forms of this quinone reductase have been purified to homogeneity (1700-fold) in 30% yield from the liver cytosols of female CD-1 mice in which the enzymes were induced by administration of 2(3)-tert-butyl-4-hydroxyanisole. The purification involved ion exchange, hydrophobic, and affinity chromatographies. The two enzyme forms have been designated "hydrophilic" and "hydrophobic" based on the order of elution from phenyl-Sepharose. The more abundant hydrophilic form has been crystallized in the presence of FAD in the form of macroscopic tetragonal crystals. The two forms have similar isoelectric points (pI 9.2) and subunit molecular weights (Mr = 30,000) and probably exist as dimers in the native state. Purified preparations of the enzymes are equiactive with NADH and NADPH and show almost complete dependence on added FAD for catalytic activity. The Km values for FAD of the hydrophilic and hydrophobic forms are 2.72 and 1.72 nM, respectively. Their catalytic activities are the same and are remarkably high for nicotinamide nucleotide-linked dehydrogenases; maximum velocities (expressed per mg of pure enzyme) approach 4000 units/mg of protein under appropriate assay conditions. When menadione is the electron acceptor, the Km value for this quinone is very low (Km congruent to 2 microM). Both enzyme forms are potently inhibited by dicoumarol. Rabbit antisera against the hydrophilic quinone reductase precipitate quantitatively the entire quinone reductase activity of mouse liver cytosols obtained from animals maintained on a standard diet or those induced with 3-tert-butyl-4-hydroxyanisole. The quinone reductase activity of rat liver cytosols is also quantitatively precipitated by this antiserum.
...
PMID:Purification and characterization of two isofunctional forms of NAD(P)H: quinone reductase from mouse liver. 241 14

Previous electron spin resonance studies have demonstrated that the decay of ascorbyl plus semiquinone radicals, produced in an aqueous mixture of ascorbate and 2,6-dimethoxy-p-quinone, is accelerated by ascites cells. This effect was concluded to involve a sulfhydryl-containing NAD(P)H-enzyme, and work on cultured cell lines showed that on neoplastic transformation the activity against the radicals was increased. We show here that at least three disulfide-oxidoreductases are able to quench the radicals in a similar way to that of viable cells. Glutathione reductase (EC 1.6.4.2) in the presence of NADPH and oxidised glutathione, and dihydrolipoamide dehydrogenase (EC 1.8.1.4) with NADH and lipoamide, are found to accelerate the radical decay by reducing the quinone or semiquinone. DT-diaphorase (EC 1.6.99.2) in the presence of NAD(P)H can also achieve this by reducing the quinone directly. Lipoamide dehydrogenase and glutathione reductase are also capable of reducing nitroxide spin labels, a finding considered of relevance to the reported reduction of such spin labels by neuroblastoma cells.
...
PMID:Electron spin resonance studies of the interaction of oxidoreductases with 2,6-dimethoxy-p-quinone and semiquinone. 302 90


1 2 3 4 5 6 Next >>

---