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)

A number of model systems have been developed to study the initiating and promoting phases of neoplastic development in rats liver. Four of these protocols use diethylnitrosamine (DEN) initiation, but employ different methods of promotion. The present studies were designed to evaluate these systems under standardized laboratory conditions to determine their relative ability to induce histochemically identifiable gamma-glutamyl transpeptidase positive (GGT+) foci. Studies were also performed to examine the effects of the four promoting regimens on liver-derived serum enzymes and hepatic drug metabolism. Under standardized laboratory conditions, including the use of a single rat strain, all four systems induced GGT+ foci following DEN initiation. Within the maximum time period evaluated (8 weeks) promotion with 2-acetylaminofluorene and partial hepatectomy resulted in the highest number of GGT+ foci/cm2. In addition, the hepatic mixed-function oxidase system was markedly affected by the promoting regimens. Cytochrome P-450 content was decreased (50% of control) by three of four systems. All four promotion regimens reduced benzphetamine-N-demethylase activity (20-50% of control). Ethoxycoumarin-O-deethylase activity (P-448 related) was not changed by the promotion regimens. Three of four regimens increased epoxide hydrolase activity (150-600% of control) and DT-diaphorase activity (150-200% of control). Combining DEN initiation and each of the four promotion protocols had little additional effect on hepatic drug metabolizing enzymes. It is concluded that the four systems evaluated are reproducible under standard conditions and that the promotion regimens employed cause striking alterations in hepatic microsomal drug metabolism that are largely independent of the presence or absence of focal GGT+ lesions.
...
PMID:Comparison of hepatic carcinogen initiation-promotion systems. 612 70

The mechanism of salicylate-induced hypoprothrombinaemia has been investigated in the rat. Salicylate administration produced an increase in the percentage of the total liver vitamin that was present as vitamin K 2,3-epoxide, but the addition of salicylate did not influence vitamin K epoxide reductase activity in-vitro. Neither did it influence vitamin K-dependent carboxylase or vitamin K epoxidase activity. Both cytosolic and microsomal DT-diaphorase activities were, however, inhibited about 50% by 75 microM sodium salicylate. Salicylate inhibition was also observed when vitamin K quinone and NADH or dithiothreitol were used to support carboxylation. To achieve 50% inhibition required 0.5 mM salicylate with NADH as a reductant and 4 mM salicylate when dithiothreitol was the reductant. These results suggest that the main effect of salicylate on vitamin K metabolism is to inhibit quinone reductases and may be useful in explaining the inhibition of the biosynthesis of vitamin K-dependent clotting factors that occurs in salicylate-induced hypothrombinaemia. These data also demonstrate that the percentage of total liver vitamin present as vitamin K epoxide can be increased by agents that do not have a direct effect on the vitamin K epoxide reductase in-vitro.
...
PMID:The effects of salicylate on enzymes of vitamin K metabolism. 613 82

The effect of tris-(2-chloroethyl)-amine (HN-3) on RNA and DNA was investigated spectrophotometrically. The shift in the absorbance spectrum caused by the addition of HN-3 was used to test a variety of compounds for their ability to inhibit RNA alkylation. The effect of HN-3 on the activity of several enzymes was also investigated. The activities of ribonuclease A, desoxyribonuclease I, acetylcholinesterase, diaphorase, glutathione reductase, adenosine desaminase, glyoxalase I, 3-hydroxyacyl-CoA-dehydrogenase, xanthine oxidase, glucose-6-phosphate dehydrogenase, hexokinase and the microsomal N-oxygenation of aniline were not changed by HN-3, whereas the activity of cytochrome-c-reductase exhibited a dose dependent diminution in the presence HN-3. Of 105 compounds tested only 14, namely, sodium thiosulfate, dithioxanthine, thiosalicylic acid, 1,2,4-triazole-5-thiol, 2-thiocytosine, 2-thiohistadine, 2,3-dithiosuccinic acid, thioglycolic acid, 3-mercapto-D-valine,6-amino-2-thiouracil, thionicotine amide, dithiothreitol, sodium sulfite, and ergothioneine prevented the alkylation of RNA. All of them also reacted with HN-3 in absence of RNA. No correlation was found between the reaction constant of the reaction compound:HN-3 in the absence of RNA and the concentration of the compound which inhibited RNA alkylation by 50%. The compounds which were effective in vitro were also tested in mice for their ability to reduce HN-3 toxicity in vivo. Only sodium thiosulfate, d-penicillamine, and dithiosuccinic acid were effective. A 3.9fold increase in the LD50 of HN-3 was achieved in mice treated with sodium thiosulfate 3330 mg/kg i.p., a 1.7fold with 2125 mg dithiosuccinic acid/kg, and a 2fold increase with 2500 mg/kg d-penicillamine. The compound tested was injected i.p. 0.5 to 1 min after the s.c. injection of HN-3.
...
PMID:Effect of various compounds on the reaction of tris-(2-chloroethyl)amine with ribonucleic acid in vitro and on its toxicity in mice. 617 33

Recessive congenital methemoglobinemia (RCM) is due to the homozygous deficiency of NADH-cytochrome b5 reductase (EC 1.6.2.2.). In type I disease, in which the patients are only methemoglobinemic, the enzyme defect is fully expressed in the erythrocytes, whereas the leukocytes are much less affected. In type II disease, in which the patients are, in addition, mentally retarded, the defect is generalized to all the tissues including cultured fibroblasts. In the present study we have investigated Epstein-Barr virus (EBV) transformed lymphoid cell lines (LCL) derived from patients with both types of cytochrome b5 reductase deficiency and from nondeficient individuals. The total cytochrome b5 reductase activity of the control LCL was found to be similar whatever the LCL origin, except for one lymphoma line (Daudi). The enzyme from the control LCL (c 252/B 95) was found to be immunologically related to the human soluble erythrocyte cytochrome b5 reductase, indicating that it is the product of the same gene: the DIA1 (diaphorase) locus. The LCL derived from one patient with the type I disease and two patients with the type II disease were investigated.l In the former the defect was expressed to a lesser degree than in the cases with mental retardation in which the defect was much pronounced, and involved both the mitochondrial and the microsomal fraction. This indicated that all the subcellular forms of the cytochrome b5 reductase are under the same genetic control. Altogether, these data show that the LCL are a favorable material for studying both types of cytochrome b5 reductase deficiency and for investigating in depth the molecular aspects of this metabolic disease.
...
PMID:NADH cytochrome b5 reductase activity in lymphoid cell lines. Expression of the defect in epstein Barr virus transformed lymphoblastoid cell lines from patients with recessive congenital methemoglobinemia. 626 99

The reduction and the potential autoxidation of quinoid compounds may be viewed as taking place in three cell compartments. In microsomal fractions (endoplasmic reticulum) one-electron reduction by NAPDH-cytochrome P450 reductase leads to the formation of semiquinones which rapidly react with oxygen to form the parent quinone and superoxide anions. The formation of superoxide through this futile cycle leads ultimately to other damaging species (H2O2 and .OH). A similar futile cycle in mitochondria involves NADH dehydrogenase. In this instance, mitochondria initiation of such a cycle with quinones results not only in the formation of toxic radical species but also in the diversion of electrons from phosphorylating pathways. The consequent diminution of cellular ATP may have as important a consequence with respect to the toxicity of quinones as the generation of radicals. Finally, cytosolic DT diaphorase, which carries out a two-electron reduction of quinones to more stable hydroquinones, may compete with the one-electron systems and participate in the detoxification of quinones by supplying hydroquinones for conjugation reactions. The extent of quinone-induced damage may thus vary from cell to cell depending on the integration of these pathways.
...
PMID:Futile redox cycling: implications for oxygen radical toxicity. 631 61

Rat liver microsomal activation of the anthracycline antitumor drug, Adriamycin, in the presence of reduced pyridine nucleotide under anaerobic conditions produces reactive species that bind covalently to cellular macromolecules including DNA. Since the nuclear membrane contains enzymes capable of activating Adriamycin, we have examined activation of Adriamycin by isolated nuclei. The anaerobic incubation of Adriamycin with rat hepatic nuclei resulted in the formation of the Adriamycin semiquinone free radical. Moreover, this activation resulted in the covalent binding of Adriamycin to nuclear DNA. The binding of Adriamycin to DNA was reduced pyridine nucleotide and time dependent and was significantly decreased in the presence of reduced glutathione or ethylxanthate . Dicumerol , an inhibitor of DT-diaphorase, in contrast, had no effect on this binding. When the incubation was carried out in the presence of oxygen, no semiquinone radical was detected; however, superoxide and hydroxyl radicals were readily detected by a spin-trapping technique. Furthermore, little binding of Adriamycin to nuclear DNA was observed under aerobic conditions. These observations suggest that the nuclear activation and covalent binding of Adriamycin to DNA may be important in the biochemical actions of this drug.
...
PMID:Enzymatic activation and binding of adriamycin to nuclear DNA. 632 28

The biochemical properties of putative preneoplastic hepatocyte nodules as they relate to the metabolism of xenobiotics have been reviewed briefly. A common pattern with low phase I components and elevated phase II components appears evident. The phase I components included microsomal cytochromes P-450 in composite and four different mixed function oxygenase activities. The activities in the nodules were 50% or less of the control values. The phase II components included glutathione, glutathione S-transferases and UDP-glucuronyl transferase 1 and showed two- to five-fold elevations. In addition, activities of microsomal epoxide hydrolase, cytosolic DT-diaphorase, and gamma-glutamyl transferase were all elevated in nodules. The possible significance of this biochemical pattern in analyzing the diversity of biochemical expressions of cancer, in the mechanism of cancer development, and in understanding the suggested role of physiological adaptation in carcinogenesis is discussed.
...
PMID:The biochemistry of preneoplastic liver: a common metabolic pattern in hepatocyte nodules. 638 Jun 87

Reductive metabolism of carcinogenic 1-nitropyrene by rat liver microsomes and reconstituted cytochrome P-450 systems was investigated. Under the nitrogen atmosphere, 1-aminopyrene was the only detected metabolite of 1-nitropyrene. The reductase activity in liver 105,000 X g supernatant fraction was ascribed to DT-diaphorase, aldehyde oxidase, and other unknown enzyme(s) from the results of cofactor requirements and inhibition experiments. The microsomal reductase activity was inhibited by oxygen, carbon monoxide, 2,4-dichloro-6-phenylphenoxyethylamine, and n-octylamine. Flavin mononucleotide markedly enhanced the activity, and 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride also enhanced it, but slightly. The microsomal activity was induced by the pretreatment of rats with 3-methylcholanthrene, sodium phenobarbital, or polychlorinated biphenyl, and the increments of the activity correlated well with those of the specific contents of cytochrome P-450 in microsomes. The reductase activity could be reconstituted by NADPH-cytochrome P-450 reductase and forms of cytochrome P-450 purified from liver microsomes of polychlorinated biphenyl-induced rats. Among four forms of cytochrome P-450 examined, an isozyme P-448-IId which showed high activity in hydroxylation of benzo(a)pyrene catalyzed most efficiently the reduction of 1-nitropyrene. The results of this study indicate the central role of cytochrome P-450 in the reductive metabolism of 1-nitropyrene in liver microsomes.
...
PMID:Participation of cytochrome P-450 in reductive metabolism of 1-nitropyrene by rat liver microsomes. 643 May 44

Two procedures have been developed for the solubilization of vitamin K epoxide reductase from rat liver microsomal membranes using the detergent Deriphat 160 at pH 10.8. The methods are applicable to both normal and Warfarin-resistant-strain rat liver microsomes and yield material suitable for further purification. The preparations retain dithiothreitol-dependent vitamin K quinone reductase activity as well as vitamin K epoxide reductase and are free of vitamin K-dependent carboxylase and epoxidase activities. Optimal epoxide reductase activity is obtained at 0.1 M KCl and pH 9 in the presence of sodium cholate. Artifactual formation of vitamin K metabolites was eliminated through the use of mercuric chloride to remove excess dithiothreitol prior to extraction and metabolite assay. Using the solubilized enzyme, valid initial velocities were measured, and reproducible kinetic data was obtained. The substrate initial velocity patterns were determined and are consistent with a ping-pong kinetic mechanism. The kinetic parameters obtained are a function of the cholate concentration, but do not vary drastically from those obtained using intact microsomal membranes. At 0.8% cholate, the enzymes solubilized from normal Warfarin-sensitive- and Warfarin-resistant-strain rat livers exhibit respective values of Vmax = 3 and 0.75 nmol/min/g liver; Km for vitamin K epoxide = 9 and 4 microM; and Km for dithiothreitol of 0.6 and 0.16 mM.
...
PMID:Solubilization and characterization of vitamin K epoxide reductase from normal and warfarin-resistant rat liver microsomes. 669 43

The NADH-dependent vitamin K-reductase activity of liver microsomes from three closely related rat strains has been studied. One strain (TAS) is susceptible and two strains (HW and HS) resistant to the anticoagulant and lethal effects of warfarin. The effects of cofactors, temperature, detergent and dithiothreitol on vitamin K1 reduction and solvent extraction of substrate and product have been investigated. Vitamin K-reductase activity was inhibited by approximately 13 and 8% respectively when microsomal preparations from TAS and HW animals were incubated with 50 microM vitamin K1 and 10 microM warfarin. In HS rat liver microsomes the enzyme was highly resistant to inhibition by warfarin. Evidence is presented and discussed that suggests that NADH-dependent vitamin K-reductase may be inhibited in the anticoagulant effect of warfarin and may be altered as a result of expression of the warfarin-resistance gene in HS rats. The enzyme activity studied was probably not a DT-diaphorase although both NADH and NADPH acted as cofactors for the reaction.
...
PMID:Inhibition by warfarin of liver microsomal vitamin K-reductase in warfarin-resistant and susceptible rats. 671 38


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---