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)

This study was designed to evaluate the effects of dietary vitamin E and synthetic antioxidants on prostacyclin (PGI2) synthesis in isolated aorta segments and perfused hearts as well as thromboxane (TxA2) synthesis in thrombin-stimulated washed platelets. Weanling male New Zealand rabbits were fed a vitamin E-deficient basal diet or the basal diet supplemented with either all-rac-alpha-tocopherol acetate or propyl gallate or DPPD (N,N'-diphenyl-p-phenylenediamine). After 30 days on the diet, plasma tocopherol level, pyruvate kinase and liver microsomal NADPH oxidase were determined. DPPD but not propyl gallate prevented the development of myopathy. None of the synthetic antioxidants could substitute for vitamin E in decreasing enzymatic lipid peroxidation. PGI2 release by the aorta was lowered in vitamin E deficiency and was highest with DPPD supplementation. In the Langendorff perfused heart, however, PGI2 release was highest in the vitamin E-deficient group, possibly due to cardiomyopathy. TxA2 synthesis by washed platelets challenged with thrombin was independent of the antioxidant status of the animal. The data showed that dietary antioxidants selectively affect eicosanoid synthesis in different tissues.
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PMID:Differential effects of dietary vitamin E and antioxidants on eicosanoid synthesis in young rabbits. 633 92

NADPH-dependent oxygen utilization by liver microsomal fractions was stimulated by the addition of increasing concentrations of butylated hydroxyanisole concomitant with the inhibition of benzphetamine N-demethylase activity. The apparent conversion of monooxygenase activity to an oxidase-like activity in the presence of the antioxidant was correlated with the partial recovery of the reducing equivalents from NADPH in the form of increased hydrogen peroxide production. The progress curve of liver microsomal NADPH oxidase activity in the presence of butylated hydroxyanisole displayed a lag phase indicative of the formation of a metabolite capable of uncoupling the monooxygenase activity. Ethyl acetate extracts of microsomal reaction mixtures obtained in the presence of butylated hydroxyanisole, oxygen, and NADPH stimulated the NADPH oxidase activity of either liver microsomes or purified NADPH-cytochrome c (P-450) reductase. Using high performance liquid chromatography, gas chromatography, and mass spectrometry techniques, two metabolites of butylated hydroxyanisole, namely t-butylhydroquinone and t-butylquinone, were identified. The quinone metabolite and/or its 1-electron reduction product interact with the flavoprotein reductase to directly link the enzyme to the reduction of oxygen which results in an inhibition of the catalytic activity of the cytochrome P-450-dependent monooxygenase.
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PMID:Butylated hydroxyanisole-stimulated NADPH oxidase activity in rat liver microsomal fractions. 641 52

The antioxidants, BHA and BHT, inhibited the N-demethylation and ring hydroxylation of N,N-dimethyl-4-aminoazobenzene (DAB) by liver microsomes from untreated and phenobarbital (PB)-treated rats. BHA was somewhat more potent in this regard than was BHT. Microsomal NADPH oxidase from PB-treated rats was stimulated by BHA but control microsomal activity was unaffected. Glutathione did not appreciably reverse the inhibitory effect of BHA on DAB metabolism and had no effect on NADPH oxidase activity. It is concluded that inhibition of DAB metabolism by BHA cannot be accounted for by interaction with NADPH oxidase, particularly in untreated microsomes. It more likely affects one or more species of cytochrome P-450.
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PMID:Effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on metabolism of N,N-dimethyl-4-aminoazobenzene (DAB) by rat liver microsomes. 643 41

Intraperitoneal administration of chloramphenicol (100 mg/kg) to phenobarbital-treated rats causes 50% inhibition of liver microsomal 7-ethoxycoumarin and 1,1,2,2 tetrachloroethane metabolism but has no effect on the level of cytochrome P-450 detectable as its carbon monoxide complex or on the NADPH-cytochrome c reductase (EC 1.6.2.4) activity. Both the endogenous NADPH oxidase activity and the enzymatic reduction of cytochrome P-450 are inhibited by chloramphenicol treatment, whereas the Km and Ks for ethoxycoumarin and the cumene hydroperoxide- or iodosobenzene-supported deethylation of ethoxycoumarin are unaffected, suggesting that impaired electron transport to cytochrome P-450 may be the cause of the loss of enzymatic activity. Administration of [14C]chloramphenicol (100 mg/kg) leads to the covalent binding of 0.7 nmole of metabolite(s) per nanomole of the major cytochrome P-450 isozyme. Alkaline hydrolysis of a cytochrome P-450 fraction obtained by chromatography of solubilized 14C-labeled microsomes on octylamino-Sepharose releases oxalic acid and chloramphenicol oxamic acid, whereas enzymatic digestion releases N-epsilon-chloramphenicol oxamyl lysine in addition. These data obtained with radiolabeled chloramphenicol suggest that the same metabolic pathways which lead to the inactivation of cytochrome P-450 in vitro are also operative in vivo.
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PMID:Suicide inactivation of rat liver cytochrome P-450 by chloramphenicol in vivo and in vitro. 660 Dec 33

This laboratory has recently reported that, in a reconstituted enzyme system containing alcohol-induced isozyme 3a of liver microsomal cytochrome P-450, the sum of acetaldehyde generated by the monooxygenation of ethanol and of hydrogen peroxide produced by the NADPH oxidase activity is inadequate to account for the O2 and NADPH consumed. Studies on the stoichiometry have revealed the occurrence of an additional reaction involving an overall 4-electron transfer to molecular oxygen which is presumed to yield water: O2 + 2 NADPH + 2H+----2 H2O + 2 NADP+. The occurrence of a peroxidase reaction in which free H2O2 is reduced to water by NADPH was ruled out. When the 4-electron oxidase activity is taken into account, measurements of NADPH oxidation and O2 consumption are in accord with the amounts of products formed in the presence of various P-450 isozymes, either in the absence or presence of typical substrates, including those which undergo hydroxylation, N- or O-demethylation, or oxidation of hydroxymethyl to aldehyde groups. Of the substrates examined, some had no effect on the oxidase reaction yielding hydrogen peroxide or the 4-electron oxidase reaction, some were inhibitory, and some were stimulatory, but the same substrate did not necessarily have the same effect on the two reactions.
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PMID:On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450. Products of oxygen reduction. 672 72

The hepatic microsomal cytochromes P-450 and b5, as well as the enzymes of the hepatic microsomal electron-transport system (HMETS), including NADPH oxidase and NAPDH cytochrome c reductase, were monitored in male ICR mice (25 - 30 g) over a six-day period following repeated oral administration of methadone hydrochloride 12.5, 25, or 50 mg/kg per day, or an equivalent volume of water. Cytochrome P-450 content, when expressed per milligram of microsomal protein, was elevated as early as day 1 of administration. This increase in cytochrome P-450, which lasted throughout the period of administration, appeared to correlate with the previously reported increase in the hepatic microsomal enzyme methadone N-demethylase and tolerance to methadone lethality. The activities of the enzymes NADPH cytochrome c reductase and NADPH oxidase were both elevated significantly by day 2 of administration. However, these increases returned to control levels by day 6 of treatment. The only other cytochrome in the HMETS, cytochrome b5, showed no significant change following repeated oral methadone administration. Further, methadone administration depressed the hepatic microsomal protein content following two days of treatment and no elevation above control values was noted. The significance of these findings with respect to the role of the HMETS in the development of tolerance is discussed in some detail for methadone, as well as the findings previously reported by this laboratory for its acetylated congener, l-alpha-acetylmethadol.
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PMID:The role of the hepatic microsomal electron-transport system in the development of metabolic tolerance from repeated oral methadone administration in mice. 676 37

Spironolactone pretreatment (10mg/100g, twice daily for 4 days, orally) caused a significant decrease in cytochrome P-450 levels in the liver microsomes in female rats but male rats were unaffected. NADH oxidase activity was significantly decreased in both sexes by this pretreatment but NADPH oxidase and NADH cytochrome C reductase activities were not altered. NADPH cytochrome c reductase activity was increased more markedly in female rats. Despite the decrease in P-450 levels, aminopyrine N-demethylase activity was increased in female rats, while it remained unchanged in males. 7-Ethoxycoumarin O-deethylase activity was markedly increased in male and slightly decreased in female rats. The azoreductase activity was slightly reduced in treated male rats and remained unaltered in female rats when it was expressed in activity per mg microsomal protein, but the activity did show a significant increase in female rats when it was expressed as a P-450 specific rate. Sex associated differences in the effect of spironolactone on the rat liver microsomal drug metabolizing enzyme system demonstrated in the present study cannot be simply explained by the previously reported effect on adrenal and testicular steroids in male rats. It also seems unlikely that these effects were caused by an alteration in P-450 quality by selective destruction of certain species of P-450.
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PMID:Effect of spironolactone on hepatic microsomal monooxygenase and azoreductase activities. 707 90

For most commonly used mouse strains there is either no sex difference in drug metabolism, or females have a higher rate of metabolism than males of the same strain. In the CRL:CD-1 strain, for example, the males have a lower Vmax and a higher Km than females for ethylmorphine N-demethylation. By contrast, kinetic analysis for this pathway of drug metabolism in the BALB/cJ mouse strain demonstrated that males have a higher Vmax and a lower Km than females. Although gonadal hormones appear to play a similar role in both the strains with respect to body weight, liver weight, microsomal protein content, and the weights of sex hormone responsive organs, a strict dependence of the sex differences in ethylmorphine (EM) metabolism on gonadal hormones could not be demonstrated. A systematic analysis of the spectral interactions of EM with cytochrome P-450 (P-450), the activities of NADPH P-450 reductase and NADPH oxidase in these mouse strains did not reveal a common regulatory site for gonadal hormones. Moreover, sex differences in EM N-demethylase activity are not a direct function of the total P-450 present in hepatic microsomes since, for both strains, males have higher P-450 content than females. We conclude, therefore, that sex differences in hepatic EM N-demethylase activity in the BALB/cJ and CRL:DC-1 mouse strains may depend on the relative quantities of the individual forms of microsomal P-450 which appear to be under genetic and/or hormonal control.
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PMID:Effects of endogenous sex hormones on mouse liver ethylmorphine N-demethylase. 721 71

A series of naphthalene diols, quinones, and related compounds were examined for their ability to inhibit mixed-function oxidase in liver microsomes obtained from rats which had been pretreated with 3-methylcholanthrene (3-Mc) or phenobarbital (PB). Using benzo(a)pyrene monooxygenase as a measure of mixed-function oxidase activity, it was found that phenanthrene-9, 10-quinone was the most active compound tested with a K1 = 0.79 microM. Phenanthrene-9, 10-quinone did not affect cytochrome c reductase but did inhibit aminopyrine N-demethylase and p-nitroanisole-O-demethylase in both 3-MC and PB-induced microsome with almost identical inhibition constants. 1,2-Naphthoquinone exerted similar effects as phenanthrene-9,10-quinone on cytochrome c reductase, aminopyrine N-demethylase and p-nitroanisole-O-demethylase. Both quinones stimulated NADPH oxidase activity but the extent of this stimulation did not explain their inhibition of microsomal oxidation. Kinetic studies using benzo(a)-pyrene monooxygenase with phenanthrene-9, 10-quinone and 1,2-naphthoquinone indicated that they were noncompetitive with benzo(a)pyrene and mixed noncompetitive with NADPH. Both of these quinones inhibited benzo(a)pyrene induced oncogenic transformation in C3H10T1/2CL8 cells in culture in a dose response manner, presumably by inhibition of the cellular microsomal enzyme which activate benzo(a)pyrene. Phenanthrene-9, 10-quinone and 1,2-naphthoquinone seem to inhibit microsomal oxidative processes by interaction at the level of cytochrome P-450 possibly with a cytochrome P-450-substrate-oxygen complex.
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PMID:Inhibition of microsomal metabolism and chemical oncogenesis in culture by naphthalene quinones. 721 45

Parameters related to oxidative stress in rat liver and erythrocytes were studied after short-term administration (60 and 90 days) of 1000 ppm of lindane in the diet. Lindane induced an oxidative stress condition in the liver, which is related to an enhancement in microsomal NADPH-cytochrome c reductase and NADPH oxidase activities, superoxide radical formation and cytochrome P450 content, produced independently of the time of treatment. Also, decreased activities of glutathione peroxidase and catalase were concomitantly observed. Although these changes were paralleled by an increase in lipid peroxidation indices, such as production of thiobarbituric acid reactants and spontaneous chemiluminescence, no evidence of liver injury was obtained. Lindane treatment did not exert quantitatively important changes in the pro-oxidant/anti-oxidant status of the erythrocyte, with reduction in the red blood cell mass possibly reflecting actions of the insecticide on the erythropoietic process.
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PMID:Differential effects of short-term lindane administration on parameters related to oxidative stress in rat liver and erythrocytes. 750 13


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