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:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Inhibition of endogenous microsomal NADPH oxidase by CO enables membrane-bound glutathione-insulin transhydrogenase (EC 1.8.4.2) to be assayed conveniently by a linked assay involving NADPH and glutathione reductase (EC 1.6.4.2). 2. The specific activity of the enzyme in rat liver microsomal preparations is of the order of 1 nmol of oxidized glutathione formed/min per mg of membrane protein. 3. The specific activity of the enzyme is comparable in rough and smooth microsomal fractions, and the activity is not affected by treatment with EDTA and the removal of ribosomes from rough microsomal fractions. 4. Membrane-bound glutathione-insulin transhydrogenase is not affected by concentrations of deoxycholate up to 0.5%, whereas protein disulphide-isomerase (EC 5.3.4.1) is drastically inhibited. 5. On these grounds it is concluded that, in rat liver microsomal fractions, glutathione-insulin transhydrogenase and protein disulphide-isomerase activities are not both catalysed by a single enzyme species.
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PMID:Thiol-protein disulphide oxidoreductases. Assay of microsomal membrane-bound glutathione-insulin transhydrogenase and comparison with protein disulphide-isomerase. 1 83

On the basis of inhibition studies of the dealkylation of morphine and norcodeine, George and Tephly concluded that O-dealkylation and N-dealkylation are catalyzed by different enzymes. We have examined the microsomal dealkylation of 3-O-[1'-14Clethylmorphine by measuring HCHO colorimetrically and [1-14C]acetaldehyde radiometrically. We find that the KM for the O-de-ethylation is 57 muM, which is quite close to the KS(71 muM) for the type I binding of ethylmorphine in similar preparations. On the other hand, the KM for N-demethylation was 250 muM. Further, the N-demethylation was stoichiometric with the stimulation of both NADPH-cytochrome P-450 reductase and NADPH oxidase, whereas the sum of the N-demethylation and O-de-ethylation was significantly greater, suggesting that the O-de-ethylase activity does not involve stimulation of either of these two activities. Induction with phenobarbital increaesed N-demethylation 118% but did not affect O-de-ethylation. Finally, D2O inhibited the N-demethylase more than the O-de-ethylase.
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PMID:Studies on the N-demethylation and O-de-ethylation of ethylmorphine by hepatic microsomes from male rats. 1 81

The addition of 125--1000 mM (NH4)2SO4 to rat hepatic washed microsomal preparations was found to stimulate markedly the rate of in vitro metabolism of the hepatocarcinogen dimethylnitrosamine. Solute treatment also stimulated the activities of NADPH-cytochrome c reductase, NADPH oxidase, the N-oxidation of N,N-dimethylaniline, and the fluorescent interaction of 8-anilino-1-naphthalenesulfonic acid (ANS) with hepatic microsomes. (NH4)2SO4 had a varied effect on the activities of a number of mixed-function oxidase (MFO) enzyme activities. Whereas the activities of aniline 4-hydroxylase and 4-nitrobenzoic acid nitroreductase were enhanced at all solute concentrations, several other MFO enzyme activities were either progressively inhibited or stimulated at low and inhibited at high (NH4)2SO4 concentrations. Solute treatment had no effect on microsomal cytochrome P-450 content but inhibited the activities of glucose 6-phosphatase and UDP-glucuronyltransferase. All of the observed changes in enzyme activities and ANS-microsome fluorescence interaction were found to be reversible when the solute was removed by centrifugation. These findings suggest that (NH4)2SO4 and certain other solutes can reversibly modify the conformation of microsomal membranes in such a manner as to affect microsomal enzyme activities.
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PMID:The effect of ammonium sulfate on the metabolism of dimethylnitrosamine and other xenobiotics by rat hepatic microsomes. 3 91

The microsomal cytochromes P-450 and b5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25-30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l-alpha-acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.
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PMID:Additional metabolic correlates of 1-alpha-acetylmethadol (LAAM)-induced cellular tolerance and physical dependence: the role of the hepatic microsomal electron transport system. 11 96

1. Ethanol metabolism in slices or homogenates of transplantable hepatocellular carcinoma HC-252 (HC-252) was 50 to 60% of the rate found in host liver slices or homogenates when they were expressed per gram of tissue wet weight and 70 to 80% of the liver when the rates were expressed per milligram of tissue protein. At 10 mM ethanol, the activities of alcohol dehydrogenase in tumor and liver supernatants were comparable. 2. Tumor microsomes did not oxidize ethanol in the presence of a NADPH-generating system, indicating the absence of the microsomal ethanol-oxidizing system and catalase-mediated peroxidation of ethanol. The HC-252 microsomes were contaminated with catalase, and acetaldehyde production occurred in the presence of a H2O2-generating system (xanthine oxidase). The virtual absence of ethanol oxidation and drug metabolism (aminopyrine demethylase and aniline hydroxylase) in HC-252 microsomes may be due to the low activities of NADPH-cytochrome c reductase, NADPH oxidase, and NADPH-dependent oxygen uptake. 3. Microsomal oxidation of ethanol was present in Morris hepatoma 5123C, a well-differentiated tumor of intermediate growth rate, while activity was negligible in microsomes from Morris hepatoma 7288CTC, a less differentiated tumor. Microsomal NADPH oxidase was present in the well differentiated tumor 5123C but was lacking in the less differentiated tumor 7288CTC. Several microsomal, mitochondrial, and cytosolic properties of HC-252 are similar to those of Morris hepatoma 7288CTC but differ from those of the more differentiated 5123C tumor and normal liver. 4. The content of mitochondrial protein in HC-252 was only 25% that of liver, and oxygen consumption per gram of tumor was only 28% that of the liver. When corrected for the mitochondrial protein content, oxygen uptake in tumor HC-252 and liver homogenates was comparable. Isolated tumor and liver mitochondria displayed comparable State 4 and 3 rates of oxygen consumption with succinate and glutamate as substrates. The activities of the reconstituted malate-aspartate and alpha-glycerophosphate shuttles were only slightly lower in isolated HC-252 mitochondria compared to liver mitochondria, when shuttles were reconstituted with purified enzymes. 5. Antimycin inhibited alcohol metabolism,and pyruvate stimulated alcohol metabolism, much less in tumor slices than in liver slices, suggesting the presence of an augmented mitochondria-independent, cytosolic mechanism for oxidizing reducing equivalents in the tumor. These factors suggest that oxidation of NADH is the limiting factor in ethanol metabolism. Whereas, in the liver mitochondrial reoxidation is predominant, in HC-252, cytosolic reoxidation of NADH also plays a major role.
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PMID:Ethanol metabolism by a transplantable hepatocellular carcinoma. Role of microsomes and mitochondria. 13 37

Thiourea and diethylthiourea, two compounds which react with hydroxyl radicals, inhibited NADPH-dependent microsomal oxidation of ethanol and 1-butanol. Inhibition by both compounds was more effective in the presence of the catalase inhibitor, azide. Inhibition by thiourea was noncompetitive with respect to ethanol in the absence of azide but was competitive in the presence of azide. Urea, a compound which does not react with hydroxyl radicals or H2O2, was without effect. Thiourea had no effect on NADH- and NADH-cytochrome c reductase, NADPH oxidase, and NADH- and NADPH-dependent oxygen uptake. Thiourea inhibited the activities of aniline hydroxylase and aminopyrine demethylase. Thiourea, but no other hydroxyl radical scavengers, e.g., dimethyl sulfoxide, mannitol, and benzoate, reacted directly with H202 and decreased H2O2 accumulation in the presence of azide. Therefore the actions of thiourea are complex because it can react with both hydroxyl radicals and H2O2. Differences between the actions of thiourea and those previously reported for dimethyl sulfoxide, mannitol, and benzoate, e.g., effects on drug metabolism, effectiveness of inhibition in the absence of azide, or kinetics of the inhibition, probably reflect the fact that thiourea reacts directly with H2O2 whereas the other agents do not. The current results remain consistent with the concept that microsomal oxidation of alcohols involves interactions of the alcohols with hydroxyl radicals generated from microsomal electron transfer.
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PMID:Effect of thiourea on microsomal oxidation of alcohols and associated microsomal functions. 42 8

The effects of chloroform on some rat microsomal enzyme activities were studied in vitro. Maximum inhibition of oxygen consumption, NADPH oxidase and NADPH-cytochrome c reductase was observed at 0.5 mM chloroform; prior metabolization of CHCl3 by microsomal monooxygenases increased inhibition by about 50% at 0.2-0.5 mM chloroform. Higher concentrations produced a paradoxical reversal of inhibition, whereas p-nitroanisole demethylase was steadily inhibited by about 50% up to 10 mM chloroform. Irreversible binding of 14CHCl3 was confirmed to depend on chloroform metabolization by monooxygenases. The increased irreversible binding due to phenobarbital induction is accompanied by a diminished affinity towards chloroform as shown by increased KM of irreversible binding, and a higher spectral dissociation constant KS. Aminoacids with nucleophilic functions (histidine, cysteine) partially prevented the irreversible binding of chloroform metabolites to microsomes; non-volatile radioactive derivatives were recovered in trichloracetic acid supernatants when microsomes were incubated with cysteine, but not with histidine. Phosgene has been demonstrated as a biological metabolite of chloroform: its possible reactions with nucleophilic groups of macromolecules, water and added aminoacids partly explain these experimental data. Similar results were obtained with human microsomes, showing that chloroform hepatotoxicity in man could involve the same mechanisms.
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PMID:Biotransformation of chloroform by rat and human liver microsomes; in vitro effect on some enzyme activities and mechanism of irreversible binding to macromolecules. 42 6

The electrophilic properties of the quinone-hydroquinone configuration of anthracycline antibiotics suggests a possible influence on cytochrome P-450-mediated mono-oxygenase reactions. Both doxorubicin and triferric-doxorubicin (a derivative in which the quinone groups are blocked with iron) showed a similar dose-dependent inhibition of liver microsomal drug metabolism. A doxorubicin concentration-related stimulation of NADPH oxidase activity was found to be linear but that for triferric-doxorubicin was asymptotic. Neither inhibitor affected the activity of cytochrome c reductase, cytochrome b5 reductase or cytochrome P-450 reductase. However, doxorubicin did potentiate the inhibitory effect of aniline on cytochrome P-450 reductase and on ethylmorphine metabolism. It is concluded that these anthracyclines inhibit drug metabolism in vitro not by their electron-withdrawing potential but in a manner more similar to that described for type II compounds.
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PMID:Inhibition of drug oxidation and stimulation of NADPH oxidase in vitro by doxorubicin and triferric-doxorubicin. 51 68

Low concentration (0.1--1 mM) of ascorbate and erythorbate (isoascorbate) caused lipid peroxidation and lysosome labilization ("cofactor" action). In addition, they acted additively on microsomal NADPH oxidase-induced lipid peroxidation at the low concentration. The "cofactor" action, however, was dependent reciprocally on the density of lysosomes; the more dilute was the lysosomal fraction, the more susceptible the lysosomes were. On the other hand, ascorbate and erythorbate at concentration more than 1 mM inhibited microsomal NADPH oxidase-induced lipid peroxidation and lysosome labilization. Their antioxidant effect was revealed to be clear especially when the "cofactor" action was eliminated by such a basic protein as protamine. Considering that the "cofactor" action was observed only at the lower density of lysosomes and might be inhibited by physiologically occurring basic proteins, ascorbate and erythorbate may mostly act as antioxidant on lysosomes in vivo. Ascorbate- or erythorbate- induced lysosome labilization was certified to be mediated by lipid peroxidation.
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PMID:On the dual action of ascorbate and erythorbate on rat liver lysosomes. 54 20

The effect of glucagon on the components of the hepatic microsomal electron transport chain (NADPH oxidase, NADPH cytochrome c reductase (EC 1.6.2.4), cytochrome P-450, and NADPH cytochrome P-450 reductase), and on two representative oxidative pathways (aminopyrine N-demethylation, a type I substrate oxidation; and aniline p-hydroxylation, a type II substrate oxidation) was determined. Microsomes from rats pretreated with glucagon (300 mug/kg per day for 3 days) showed a significant decrease in NADPH oxidation and in aminopyrine N-demethylation with a prolonged hexobarbital sleeping time, and a significant increase in aniline p-hydroxylation. Microsomes from rats pretreated with a lower dose of glucagon (30 mug/kg per day for 3 days) showed a significant decrease in the microsomal N-demethylation of aminopyrine. Glucagon had no effect when added in vitro to microsomes, suggesting that the in vivo effects of glucagon are mediated indirectly in the intact animal.
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PMID:Alterations of hepatic microsomal drug metabolism by glucagon. 81 38


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