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 role of various enzymes and biological molecules on the activation and deactivation of the metabolites of phenol was investigated in vitro. Phenol, the major metabolite of benzene, is metabolized to hydroquinone and catechol. Activation of these metabolites and deactivation of their oxidized forms was assessed by the amount of covalent binding to microsomal protein. [14C]Phenol and NADPH were incubated with hepatic microsomes isolated from phenobarbital-pretreated guinea pigs, and 2.33 nmoles of hydroquinone and 0.12 nmole of catechol were formed per minute per milligram of microsomal protein. Covalent binding of the metabolites to microsomal protein incubated with microsomes isolated from guinea pigs pretreated with phenobarbital was 252 pmoles bound/min/mg; with microsomes from untreated guinea pigs, covalent binding was 146 pmoles bound/min/mg. Covalent binding was inhibited greater than 90% with the addition of N-octylamine, ascorbate, or GSH. The addition of superoxide dismutase inhibited covalent binding with microsomes isolated from phenobarbital-pretreated guinea pigs 35% but did not inhibit it with microsomes isolated from untreated animals. Partially purified guinea pig hepatic DT-diaphorase [NAD(P)H (quinone acceptor) oxidoreductase, EC 1.6.99.2] inhibited covalent binding 70%. This effect was reversed in the presence of dicumarol, a specific inhibitor of DT-diaphorase. DT-diaphorase present in the 10(5) X g supernatant fraction was also active in inhibiting covalent binding but only after the removal of endogenous reduced glutathione. This effect could also be reversed by dicumarol. The addition of diaphorase (NADH:lipoamide oxidoreductase, EC 1.6.4.3) partially purified from Clostridium kluyveri inhibited covalent binding 86%. The addition of hydrogen peroxide and horseradish peroxidase (peroxidase, EC 1.11.17) or myeloperoxidase(s) increased covalent binding 30-fold and 6-fold, respectively. Ascorbate decreased this binding greater than 95%. These results indicate that hydroquinone, catechol, and phenol as well as their oxidized forms can be activated or deactivated by several of the above model systems. These systems may play a role in the myelotoxicity of benzene by modulating covalent binding.
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PMID:DT-diaphorase and peroxidase influence the covalent binding of the metabolites of phenol, the major metabolite of benzene. 674 27

The diurnal rhythms of the microsomal flavoprotein NADPH-cytochrome c reductase activity, of diaphorase and of succinic dehydrogenase are presented. Minimum levels are ascertained at 09(00), maximum levels at 21(00). The concentration of mitochondrial radicals as a function of the time of day is also demonstrated. Here too the minimum is at 09(00) and the maximum between 15(00) and 21(00). On the other hand, GSH levels are found to be high between 09(00) and 12(00) and low in the evening. Thus a causative relationship between the concentration of cellular radicals, which originate in flavin enzymes, and the concentration of the tripeptide glutathione is assumed.
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PMID:Flavin enzymes, mitochondrial radicals and reduced glutathione in daily rhythmic dependency. 677 1

Detergent-solubilized microsomal preparations that catalyse the vitamin K-dependent gamma-carboxylation of glutamic acid residues in peptide and protein substrates, have been obtained from the livers of normal and warfarin-treated cows. The preparations from warfarin-treated animals contained more endogenous substrate than those from normal cows, but otherwise the two preparations were indistinguishable. The enzymes vitamin K reductase and gamma-glutamyl carboxylase, may function independently of each other in this system. They are, nevertheless, intimately linked in some way, so that the reduced vitamin K that is produced by the former enzyme can be used immediately by the latter.
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PMID:A comparison between vitamin K-dependent carboxylase from normal and warfarin-treated cows. 679 8

It has been shown that NAD(P)H dehydrogenase (EC 1.6.99.2) reduces vitamin K1 and can support the [vitamin K1 + NADH]-dependent carboxylation reaction in rat liver microsomes (Wallin, R., Gebhardt, O., and Prydz, H. (1978) Biochem. J. 169, 95-101). Antibodies were raised in rabbits against the purified enzyme from liver cytosol and used to study the importance of NAD(P)H dehydrogenase in the vitamin K-dependent carboxylation reaction. The antibodies neutralized the warfarin-sensitive NAD(P)H dehydrogenase activity in Triton X-100-solubilized microsomes; however, they neutralized only 45% of the total [vitamin K1 + NADH]-dependent carboxylation activity. Chromatography on protein A-sepharose showed that the remaining carboxylase activity was not the result of soluble antigen-antibody complexes. The data presented support the conclusion that the microsomal preparation also contains a non-warfarin-sensitive dehydrogenase(s) that, in addition to NAD(P)H dehydrogenase, can reduce vitamin K1 to support the carboxylation reaction.
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PMID:Vitamin K-dependent carboxylation. Evidence that at least two microsomal dehydrogenases reduce vitamin K1 to support carboxylation. 679 8

Effects of feeding mice and rats with 2(3)-tert-butyl-4-hydroxyanisole (BHA) and 3,5-di-tert-butyl-4-hydroxytoluene (BHT), the two most commonly used food-additive phenolic antioxidants with known anticarcinogenic properties but with only minor differences in their chemical structures, have been compared to search for common effects between the two agents in two different rodent species and then applied toward better understanding of the mechanisms involved in their protective actions. In liver microsomes of treated mice, both BHA and BHT enhanced the relative activity of aniline ring hydroxylation but decreased the relative benzo(a)pyrene monooxidase activities. However, in rats, although aniline ring hydroxylation activity was decreased by both compounds, the decrease of benzo(a)pyrene monooxidase activity was observed only with BHT. Thus, common effects could not be recognized at the microsomal mixed-function oxidase level. Contrary to expectations based on chemical structures, BHT feeding elevated by epoxide hydrolase activity to an even greater extent than that produced by BHA, especially in rats. However, enzyme activities involved in the glucuronide conjugation system (uridine diphosphate:glucuronyl transferase, uridine diphosphate:glucose dehydrogenase, and quinone reductase) are all elevated by both antioxidants in both rodent species. With BHA treatment, the levels of acid-soluble thiols were increased in both rats and mice. However, with BHT, the level was increased only in mice but not in rats. Similar trends were produced for glucose-6-phosphate dehydrogenase activity, but glutathione reductase activity was increased even for BHT-treated rats. Additionally, the glutathione S-transferase activities were also increased by both antioxidant treatments and in both rodent species. Based on these results, the elevations of epoxide hydrolase activity along with the enhanced glucuronide conjugation and glutathione oxidation and reduction conjugation system enzyme activities were common to both compounds in both rodent species. This suggests their involvement in anticarcinogenic mechanisms. Increases of these detoxification enzyme activities appeared to be all designed to accelerate the elimination of administered antioxidants but, inadvertantly, conferring protective effects from xenobiotics such as carcinogens.
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PMID:Comparative effects of dietary administration of 2(3)-tert-butyl-4-hydroxyanisole and 3,5-di-tert-butyl-4-hydroxytoluene on several hepatic enzyme activities in mice and rats. 680 43

The in vitro effects of two coumarin anticoagulants, warfarin and difenacoum, on rat liver microsomal vitamin K dependent carboxylase, vitamin K epoxidase, vitamin K epoxide reductase, and cytosolic vitamin K reductase (DT-diaphorase) from the livers of normal and a warfarin-resistant strain of rats have been determined. Millimolar concentrations of both coumarins are required to inhibit the carboxylase and epoxidase activities in both strains of rats. Sensitivity of DT-diaphorase to coumarin inhibition differs when a soluble or liposomal-associated substrate is used, but the diaphorases isolated from both strains of rats have comparable sensitivity. The anticoagulant difenacoum is an effective rodenticide in the warfarin-resistant strain of rats, and the only enzyme studied from warfarin-resistant rat liver that demonstrated a significant differential inhibition by the two coumarins used was the vitamin K epoxide reductase. This enzyme also showed the greatest sensitivity to coumarin inhibition among the enzymes studied. These results support the hypothesis that the physiologically important site of action of coumarin anticoagulants is the vitamin K epoxide reductase.
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PMID:Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver. 680 39

The dithiothreitol-dependent vitamin K and vitamin K 2,3-epoxide hepatic microsomal reductase activities of warfarin-susceptible and warfarin-resistant rats were compared to gain insight into the role(s) of these activities in vitamin K metabolism and function. In microsomes from resistant rats, 3- to 4-fold more warfarin was required to produce 50% inhibition (I50) of vitamin K reduction to vitamin K hydroquinone than in microsomes from susceptible rats. For the reduction of vitamin K 2,3-epoxide to vitamin K a 6-fold higher warfarin concentration was required. In microsomes from resistant rats, the I50 warfarin concentration required to inhibit gamma-carboxylation of microsomal precursor protein was also 4-fold higher with vitamin K as substrate and was 6-fold higher with the epoxide as substrate than in microsomes from susceptible rats. Collectively, these data suggest that the vitamin K reductase contributes to the metabolism of vitamin K in intact rats and that warfarin inhibition of both the vitamin K and vitamin K 2,3-epoxide reductases is involved in its anticoagulant effect.
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PMID:Evidence that warfarin anticoagulant action involves two distinct reductase activities. 681 77

A number of drug-metabolizing systems were measured in hyperplastic noduli from the livers of rats receiving 2-acetyl-aminofluorene in their diet and compared with corresponding activities in control liver. The level of microsomal cytochrome P-450 is reduced 54% in the nodular tissue, while 5 activities catalyzed by the cytochrome P-450 system (i.e., aminopyrine N-demethylase, benzo[a]pyrene monooxygenase, ethoxyresorufin O-deethylase, ethoxycoumarin O-deethylase, and 2-acetylaminofluorene N-hydroxylase) are all present at levels corresponding to 5-44% of the control levels. The pattern of 2-acetylaminofluorene metabolites formed by nodule microsomes also differs from the pattern observed with control microsomes. Microsomal epoxide hydrolase is increased 415%, cytosolic glutathione S-transferases 203-576%, microsomal UDP-glucuronyltransferase activity about 200%, and cytosolic DT-diaphorase 1210% in the nodules. The same changes are seen in nodules of different sizes and in individual nodules of the same size. Finally, of all of these changes only the full increase in epoxide hydrolase can be seen after 1-3 weeks of exposure to 2-acetylaminofluorene.
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PMID:Characterization of drug-metabolizing systems in hyperplastic nodules from the livers of rats receiving 2-acetylaminofluorene in their diet. 685 Sep 90

2(3)-tert-Butyl-4-hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarol-inhibited NAD(P)H:quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2] activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones and may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protective effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.
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PMID:Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. 693 53

Reduction of vitamin K 2,3-epoxide and vitamin K catalyzed by hepatic microsomal enzymes is required for normal, postribosomal, gamma-carboxyglutamate formation in the prothrombin complex Factors II, VII, IX, and X. The R- and S-warfarin enantiomers differentially inhibit (S-warfarin is 2 to 5 times more active) vitamin K function by mechanisms which have not been unambiguously determined. As a step toward determining the physiologically relevant site(s) of warfarin-antivitamin K activity we investigated in Wistar rats the effects of R- and S-warfarin on vitamin K 2,3-epoxide and vitamin K reductase activities and correlated them with effects on plasma concentrations of the Factors II, VII, and X. Based on the results of these studies we conclude that: 1) warfarin inhibition of the vitamin K 2,3-epoxide and vitamin K reductases is essentially irreversible; 2) S-warfarin stereoselectively inhibits both reductases in vivo but not in vitro; 3) the vitamin K reductase which utilizes dithiothreitol as cofactor in vitro is primarily responsible for vitamin K reduction to vitamin K hydroquinone under physiological conditions; 4) warfarin initially inhibits gamma-carboxyglutamate formation by inhibiting simultaneously the vitamin K 2,3-epoxide and vitamin K reductases; and 5) following enantiomer administration there is an apparent lack of correlation between the restoration of the reductase activities and the reinitiation of coagulation factor synthesis.
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PMID:R- and S-Warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat. 706 69


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