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:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to clarify the possible mechanism of the interaction between theophylline (TP) and mexiletine (ME), the elimination kinetics and in vitro metabolism of TP and its metabolites were investigated in rats. The plasma elimination of TP, 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU) was significantly delayed by the intravenous (i.v.) administration of ME. The oral administration of ME also decreased the elimination rate of TP to the same extent as the i.v. dosing. The in vitro metabolic experiment showed that ME significantly inhibited the metabolic conversion of TP to 1,3-DMU and, 1,3-DMU to 1-MU, and slightly inhibited the conversion of TP to 3-methylxanthine, these processes being mediated by microsomal enzymes, with no inhibition of xanthine oxidase. Our results indicated that ME could inhibit the metabolic conversion of TP and its metabolite in rat, as reported in man.
...
PMID:Effect of mexiletine on elimination and metabolic conversion of theophylline and its major metabolites in rats. 836 52

Without the addition of any exogenous stimuli, neutrophils generated O2- and then ceased in a reversible manner that correlated with cellular swelling and contraction. The nature of the possible mechanism responsible for this O2- generation was studied and compared with that observed in the triggering of stimulant-dependent O2- generation (respiratory burst). The swelling-induced O2- generation was inhibited by diphenyliodonium, and was independent of the functional distortion of mitochondrial and/or microsomal electron transport and xanthine oxidase. This suggested that such generation was involved in respiratory-burst oxidase activation; however, this generation was not accompanied by any new phosphorylation of the 47-kDa protein or of tyrosine proteins. Dihydrocytochalasin B potentiated the O2- generation. The cellular swelling produced a priming effect on the triggering of respiratory burst with different stimuli. Cellular contraction, conversely, suppressed the respiratory burst. The structural specificity of the swelling-induced plasma membrane modulation for the O2- generation was suggested by the finding that modulation of plasma membrane structures by various non-ionic detergents per se inhibited O2- generation. Lipophilic and positively-charged agents inhibited the generation and this inhibition was abrogated by negatively-charged, but not by non-ionic agents. Negatively-charged agents potentiated the O2- generation. These results suggest that both the interaction of the plasma membrane with the cytoskeleton and an increase in net negative charges at the plasma membrane play important role in evoking O2- generation; this is discussed and compared with the signal transduction reported previously for respiratory burst.
...
PMID:Swelling-induced O2- generation in guinea-pig neutrophils. 838 42

Oxidation of the experimental anti-tumour agent N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) to the 9(10H)acridone, followed by ring hydroxylation and glucuronidation, appears to be the main pathway of detoxication of AC in the rat and mouse. The acridone formation has been further characterized in vitro using an enzyme-enriched fraction where activity per milligram protein is increased approximately 10-fold compared with the cytosolic fraction. Inhibition by amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; NSC 249992] and menadione (50% inhibition at 6.4 and 1.8 microM, respectively) but not allopurinol (to 30 microM) indicates that the activity is due to aldehyde oxidase, without the involvement of xanthine oxidase. Interestingly, acridone formation in both the cytosolic and enzyme-enriched fractions is highly sensitive to the classical cytochrome P450 inhibitor SKF-525A [proadifen hydrochloride; 2'-(diethylamino)ethyl 2,2-diphenylpentenoate] (50% inhibition at 9.2 and 1.9 microM, respectively). Further analysis indicates mixed non-competitive type inhibition by SKF-525A (K(is), 0.3 microM; K(ii), 4.9 microM). Little or no inhibition was seen with cimetidine, metyrapone or methimazole. No NADPH-dependent acridone formation was observed with the microsomal fraction. These data indicate that acridone formation previously observed in isolated rat hepatocytes and in vivo is most likely due to aldehyde oxidase rather than cytochrome P450.
...
PMID:Inhibition by SKF-525A of the aldehyde oxidase-mediated metabolism of the experimental antitumour agent acridine carboxamide. 851 97

The cellular source(s) and mechanisms of generation of reactive oxygen species (ROS) in nonphagocytic cells stimulated by cytokines are unclear. In this study, we demonstrate that transforming growth factor beta 1 (TGF-beta 1, 1 ng/ml) induces the release of H2O2 from human lung fibroblasts within 8 h following exposure to this cytokine. Elevation in H2O2 release peaked at 16 h (approximately 22 pmol/min/10(6) cells) and gradually declined to undetectable levels at 48 h after TGF-beta 1 treatment. NADH consumption by these cells was stimulated by TGF-beta 1 while that of NADPH remained unchanged. NADPH oxidase activity as measured by diphenyliodonium (DPI)-inhibitable NADH consumption in TGF-beta 1-treated cells followed a time course similar to that of H2O2 release. DPI, an inhibitor of the NADPH oxidase complex of neutrophils and other flavoproteins, also inhibited the TGF-beta 1-induced H2O2 production. Inhibitors of other enzymatic systems involving flavoproteins that may be responsible for the production of H2O2 in these cells, including xanthine oxidase, nitric oxide synthase, and both mitochondrial and microsomal electron transport systems, failed to inhibit TGF-beta 1-induced NADH oxidation and H2O2 production. The delay (> 4 h) following TGF-beta 1 exposure along with the inhibition of this process by cycloheximide and actinomycin D suggest the requirement of new protein synthesis for induction of NADH oxidase activity in TGF-beta 1-stimulated fibroblasts.
...
PMID:Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. 853 Apr 57

Mitomycin C (MMC), an alkylating anti-tumor agent, was activated by non-enzymatic and enzymatic mechanisms leading to DNA binding and adduct formation. However, it was enzymatically, not non-enzymatically, activated MMC which induced inter-strand DNA cross-linking, a major determinant of cell death. The enzymatic activation of MMC was catalyzed by microsomal NADPH:cytochrome P450 reductase (P450 reductase) and cytosolic enzyme activities. Human P450 reductase, transiently expressed from its cDNA in the COSI cells, metabolically activated MMC to generate 9 specific MMC-DNA adducts and induced inter-strand DNA cross-linking. Co-chromatography of the MMC-DNA adducts generated by P450 reductase and sodium borohydride in separate experiments indicated that MMC was metabolized by P450 reductase to produce 2,7-diaminomitosenes that exhibited binding to deoxyguanosine. Several experiments indicated that cytosolic enzymes which catalyzed reductive activation of MMC and DNA cross-linking included NAD(P)H:quinone oxidoreductaseI (NQOI or DT diaphorase) when present in extremely high concentrations and a unique cytosolic activity. The unique cytosolic activity was present in several mammalian cells and mouse colon and liver but absent in mouse kidney. The unique activity had properties of a diaphorase but was distinct from NQOI because of a lack of correlation between NQOI (2,6-dichlorophenolindophenol reduction) activity and the amount of MMC-reductive activation leading to DNA cross-linking. This activity was also distinct from xanthine oxidoreductase and NADH-cytochrome b5 reductase, 2 other enzymes that catalyze metabolic activation of MMC, because the unique activity was not inhibited by allopurinol (an inhibitor of xanthine oxidoreductase) and its activity was the same with NADH and NADPH (cytochrome b5 reductase is specific to NADH).
...
PMID:Non-enzymatic and enzymatic activation of mitomycin C: identification of a unique cytosolic activity. 856 27

The pathways participating in the metabolism of the nitrofuran antimicrobial drug N-[5-nitro-2-furfurylidene]-3-amino-2-oxazolidinone (furazolidone) in intact cells were investigated in the human intestinal cell line Caco-2. One-electron reduction of furazolidone led to the formation of a free radical intermediate that could be monitored in dense cell suspensions by noninvasive electron spin resonance spectroscopy. The effects of enzyme inhibitors on the kinetics of radical production and decay were used to estimate the relative contribution of different enzymes to the reductive activation of the drug. Although many enzymes are known to reduce nitrofurans in vitro (e.g., xanthine oxidase, aldehyde oxidase, DT-diaphorase, mitochondrial redox chain components), their contributions were insignificant in living Caco-2 cells. The first reducing equivalent required for the formation of the nitroanion derivative of furazolidone appeared to be provided essentially by the microsomal cytochrome P450 reductase. This was confirmed through studies of the NADPH-dependent radical formation by microsomes. Differentiated Caco-2 cells, an established enterocyte model, showed only modestly increased radical formation and the same enzyme-specificity pattern as undifferentiated cells. Consistently, only a small increase in P450 reductase activity was found in differentiated cells, in contrast to the 10-fold increase seen in typical differentiation marker enzymes. With the electron spin resonance method that we describe, it is possible to distinguish between sites of bioactivation of redox active drugs in intact cells.
...
PMID:N-[5-nitro-2-furfurylidene]-3-amino-2-oxazolidinone activation by the human intestinal cell line Caco-2 monitored through noninvasive electron spin resonance spectroscopy. 864 95

A biphenyl compound, 3,4,3',4'-tetrahydroxy-5,5'-diisopropyl-2,2'-dimethylbiphenyl (1), and a flavonoid, eriodicytol (2), were isolated as antioxidative components from the leaves of Thymus vulgaris by bioassay-directed fractionation. These compounds inhibited superoxide anion production in the xanthine/xanthine oxidase system. Mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH were also inhibited by these compounds. Compound 1 is an extremely potent antioxidant; complete inhibition was observed at 1 microM against both microsomal and mitochondrial peroxidation. Furthermore, compound 1 protected red cells against oxidative hemolysis. These phenolic compounds were shown to be effective to protect biological systems against various oxidative stresses.
...
PMID:Antiperoxidative components in Thymus vulgaris. 869 32

We investigated the inhibition mechanism of lipid peroxidation by estrogens. Estradiol and 2-hydroxyestradiol showed strong inhibitory activities toward NADPH and ADP-Fe(3+)-dependent lipid peroxidations in the microsomes from rat livers only when the steroids were added to the reaction system before the start of the peroxidation reaction. These steroids also strongly inhibited oxygen uptake only when added before the start of the reaction. These results suggest that estradiol and 2-hydroxyestradiol inhibit the initial stage of microsomal lipid peroxidation. Lipid peroxidation of erythrocyte membranes induced by the systems of xanthine oxidase-hypoxanthine and ascorbate was strongly inhibited by 2-hydroxyestradiol, but not by estradiol. Lipid peroxidation of erythrocyte membranes induced by 2.2'-azobis- (amidinopropane) dihydrochloride was not markedly inhibited by estradiol and 2-hydroxyestradiol, suggesting that the steroids have low reactivity with lipid peroxyl radicals. However, lipid peroxidation induced by t-butyl hydroperoxide-Fe3+ was strongly inhibited only by 2-hydroxyestradiol. It seems that 2-hydroxyestradiol may interact with alkoxyl rather than with peroxyl radicals during lipid peroxidation.
...
PMID:Inhibition of lipid peroxidation by estradiol and 2-hydroxyestradiol. 877 1

The antioxidant activity of marchantin H was investigated using various experimental models. Marchantin H inhibited nonenzymatic iron-induced lipid peroxidation in rat brain homogenates with an IC50 value of 0.51 +/- 0.03 microM. It was more potent than desferrioxamine or other classical antioxidants. Marchantin H also suppressed NADPH-dependent microsomal lipid peroxidation with an IC50 value of 0.32 +/- 0.01 microM without affecting microsomal electron transport of NADPH-cytochrome P450 reductase. Marchantin H could scavenge the stable free radical 1,1-diphenyl-2-picrylhydrazyl and peroxyl radical derived from 2,2 '-azobis(2-amidinopropane) dihydrochloride in aqueous phase, but not the peroxyl radical derived from 2,2 '-azobis(2,4-dimethylvaleronitrile) in hexane. The oxygen consumption during peroxyl radical-induced human erythrocyte ghost oxidation was decreased in a concentration-dependent manner by marchantin H. Furthermore, it was reactive toward superoxide anion generated by the xanthine/xanthine oxidase system. On the other hand, marchantin H inhibited copper-catalyzed oxidation of human low-density lipoprotein, as measured by fluorescence intensity, thiobarbituric acid-reactive substance formation, and electrophoretic mobility in a concentration-dependent manner. Our results indicate that marchantin H is a potentially effective and versatile antioxidant and can be used as a chaperone protecting biomacromolecules against peroxidative damage.
...
PMID:Marchantin H as a natural antioxidant and free radical scavenger. 883 34

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.
...
PMID:Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. 889 26


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

---