Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of an antigenic challenge with sheep red blood cells (SRBC) on the activities of cytochrome P-450-dependent and -independent xenobiotic metabolizing enzymes and on lipid peroxidation in the liver was investigated. The studies were carried out using three mouse strains of C57B1/10 and three strains of C3H backgrounds which are cogenic, differing genetically at the H-2 complex. The basal levels of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase (7-Ec) were different among congenic strains. The activity of 7-Ec was lower in C3H background mice than in B10 background mice. Similarly, the difference due to the strain and the H-2 locus was detected in the activities of P-450-independent enzymes such as malathion and diethyl succinate carboxylesterases, glutathione S-transferase, and epoxide hydrolases in microsomal and cytosolic fractions. The degree of immune responsiveness in these mice was determined by a plaque forming cell assay. Within the same background, the H-2b mouse strain was a high responder and the H-2k a low responder to SRBC. However, treatment with SRBC had no significant depressive effect on P-450-dependent enzyme activities except in C3H/He. Activity of AHH was suppressed in C3H/He mice. Treatment with SRBC had no effect on P-450-independent enzyme activities except for malathion carboxylesterase: the activity was increased in C3H/He and C3H.JK, whereas it was decreased in B10. The basal level of lipid peroxidation was lower in C3H/He and C3H.JK. The treatment produced a significant enhancement in lipid peroxidation in C3H/He, B10 and B10.BR (P less than 0.05) with a concomitant increase in xanthine oxidase activity (P less than 0.05). Thus, the present study revealed that a specific antigenic challenge, unlike non-specific immunostimulants (e.g. poly IC, endotoxin), does not necessarily inhibit P-450-dependent xenobiotic metabolizing enzymes even though antigen challenge increased XO activity and lipid peroxidation. The possible roles of an increase in lipid peroxidation and xanthine oxidase activity in immune response to SRBC and xenobiotic metabolizing enzymes are discussed.
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PMID:Effect of induction of T-cell-dependent antibody with sheep red blood cells on P-450-dependent and -independent xenobiotic metabolizing enzymes. 348 42

To demonstrate whether there are any pathways of nitrite formation from N-nitrosamines other than reductive denitrosation by cytochrome P-450 we performed the following experiments. An esterified alpha-hydroxylated nitrosamine was incubated in a microsomal system to test if nitrite generation is coupled with or linked to the oxidative bioactivation pathway. Simultaneously, inhibitors of microsomal esterases were added to test if the intact molecule or a metabolite from the oxidative metabolism was responsible for nitrite formation. To check if the superoxide radical anion could be related to the mechanism of nitrite generation, nitrosamines were incubated with a xanthine oxidase/hypoxanthine system. To test if the OH radical was involved in nitrite formation, nitrosamines were incubated with an artificial hydroxy-radical generating system (xanthine oxidase/hypoxanthine system supplemented with Fe2+/EDTA). Measurable amounts of nitrite were detected after incubation of the esterified-hydroxylated N-nitrosamine when the hydrolysis by microsomal esterases was inhibited by diisopropylfluorophosphate or paraoxon and when the N-nitrosamines were incubated with the artificial hydroxy-radical generating system. Nitrite formation could not be detected in the O2(-)-generating system (xanthine oxidase/hypoxanthine) or when the esterified alpha-hydroxylated N-nitrosamine was incubated without inhibition of the microsomal esterases. These results demonstrate that besides reductive denitrosation by cytochrome P-450, nitrite generation from N-nitrosamines can also be caused by hydroxy-radicals. The importance of this possible pathway for the in vivo situation of nitrosamine metabolism is discussed.
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PMID:Metabolic nitrite formation from N-nitrosamines: are there other pathways than reductive denitrosation by cytochrome P-450? 375 94

Since the cure of solid tumors is limited by the presence of cells with low oxygen contents, we have approached the development of treatment regimens and of new drugs for these tumors by investigating agents which are preferentially bioactivated under hypoxia. Major emphasis has been directed at studying the mode of action of the mitomycin antibiotics, as bioreductive alkylating agents. Using primarily the EMT6 mouse mammary carcinoma as a solid tumor model, we have found that mitomycin C and porfiromycin are preferentially toxic to cells with low oxygen contents. The mitomycin analog BMY-25282 is more toxic to hypoxic cells than are mitomycin C and porfiromycin; however, unlike these antibiotics, BMY-25282 is preferentially toxic to well-oxygenated cells. With these three mitomycins, we have observed a correlation between cytotoxicity to hypoxic cells, the rate of generation of reactive products, and the redox potentials of the drugs. Investigations of the enzymes in EMT6 cells that could possibly activate mitomycin C have revealed that cytochrome P-450 and xanthine oxidase are not present in measurable quantities and therefore are not responsible for activation of mitomycin C. Activities representative of NADPH-cytochrome c reductase and DT-diaphorase are present in these neoplastic cells. Comparison of these enzymatic activities in EMT6, CHO, and V79 cells with the rate of generation of reactive products under hypoxia shows a direct correlation between these two parameters, but there is no quantitative correlation between these two parameters and the amount of cytotoxicity. Use of purified NADPH-cytochrome c reductase and inhibitors of this enzyme demonstrated that NADPH-cytochrome c reductase can activate mitomycin C, but that it is probably not the only enzyme participating in this bioactivation in EMT6 cells. The DT-diaphorase inhibitor dicoumarol was employed to show that this enzyme is not involved in the activation of mitomycin C to a cytotoxic agent. Instead, DT-diaphorase appears to metabolize mitomycin C to a nontoxic product. This property has been exploited to develop a new treatment regimen for solid tumors. Using X-rays to eliminate well oxygenated cells of a solid tumor implant of the EMT6 carcinoma, we have found that the combination of dicoumarol plus mitomycin C is more toxic to hypoxic tumor cells in vivo than mitomycin C alone. Furthermore, knowledge of the biochemical mechanism of mitomycin C activation permits a prediction of which tumors can best be treated with this combination of drugs by measuring enzymatic activities in biopsy specimens.
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PMID:Chemotherapeutic attack of hypoxic tumor cells by the bioreductive alkylating agent mitomycin C. 393 22

Synthetic antioxidants lead in vitro to increased H2O2 formation in rat liver and lung microsomes and in guinea pig and hamster liver microsomes. Butylated hydroxyanisole and ethoxyquin are more potent than propyl-, octyl-, and dodecyl gallate; butylated hydroxytoluene is only weakly active. Extra production of H2O2 is maximal at antioxidant concentrations between 50 and 500 microM and is dependent on the concentration of NADPH. It is paralleled by increased microsomal oxygen consumption and decreased concentration of oxycytochrome P-450 and is enhanced by pretreatment of the animals with phenobarbital. Both the endogenous and the antioxidant-stimulated H2O2 production are inhibited by metyrapone. In vivo administration of ethoxyquin and butylated hydroxyanisole in the diet leads to decreased oxycytochrome P-450 concentrations but not to increased H2O2 formation in liver microsomes. No extra production of H2O2 was observed in a glucose oxidase or xanthine oxidase system; rather, inhibition occurred in the latter system. Our data suggest that antioxidants enhance the oxidase function of cytochrome P-450. This effect is discussed in view of the known toxicity of these food additives.
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PMID:Effect of synthetic antioxidants on hydrogen peroxide formation, oxyferro cytochrome P-450 concentration and oxygen consumption in liver microsomes. 396 81

The recently characterized environmental mutagen and potential carcinogen 1-nitropyrene (NP) is known to bind DNA in Salmonella typhimurium, and also in anaerobic incubations catalyzed by purified xanthine oxidase. In this study we show that rat liver S9 supernatant, microsomal and cytosolic subcellular fractions are also able to catalyze the binding of 1-nitropyrene labeled with 14C to calf thymus DNA in vitro. In incubations conducted under air, S9 and microsomes from Charles River CD rats were the most active fractions, and NADPH was required for maximum activity (25-100 pmole NP bound/mg DNA/mg protein in 1 hr). S9 and microsomes had about one-fourth the activity under nitrogen, although less of this activity was NADPH-dependent. Binding in cytosolic incubations was generally low (1 to 5 pmole NP/mg DNA/mg protein in 1 hr), was somewhat enhanced under N2, and was more extensive in the absence of NADPH. Treatment of rats (Harlan Sprague-Dawley) with the inducing agents phenobarbital (PB), Aroclor 1254 (A), or 3-methylcholanthrene (3-MC) enhanced NADPH-dependent binding in aerobic S9 (2- to 5-fold) and microsomal (10- to 20-fold) incubations. The effects of induction regimen on binding assays conducted under N2 were more equivocal: 3-MC produced a 2-fold increase in binding in both S9 and microsomes, while the other two agents decreased binding from 50 to 75%. These results indicate that classic cytochrome P-450 inducers were able to stimulate activation of NP, but that this activation is not mediated solely by cytochrome P-450.
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PMID:Rat liver subcellular fractions catalyze aerobic binding of 1-nitro[14C]pyrene to DNA. 408 23

1. The topography of cytochrome P-450 in vesicles from smooth endoplasmic reticulum of rat liver has been examined. Approx. 50% of the cytochrome is directly accessible to the action of trypsin in intact vesicles whereas the remainder is inaccessible and partitioned between luminal-facing or phospholipid-embedded loci. Analysis by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis reveals three major species of the cytochrome. Of these, the variant with a mol.wt. of 52000 is induced by phenobarbitone and this species is susceptible to trypsin. 2. After trypsin treatment of smooth membrane, some NADPH-cytochrome P-450 (cytochrome c) reductase activity remains and this remaining activity is enhanced by treatment with 0.05% deoxycholate, which renders the membranes permeable to macromolecules. In non-trypsin-treated control membranes the reductase activity is increased to a similar extent. These observations suggest an asymmetric distribution of NADPH-cytochrome P-450 (cytochrome c) reductase in the membrane. 3. As compared with dithionite, NADPH reduces only 44% of the cytochrome P-450 present in intact membranes. After tryptic digestion, none of the remaining cytochrome P-450 is reducible by NADPH. 4. In the presence of both a superoxide-generating system (xanthine plus xanthine oxidase) and NADPH, all the cytochrome P-450 in intact membrane (as judged by dithionite reducibility) is reduced. The cytochrome P-450 remaining after trypsin treatment of smooth vesicles cannot be reduced by this method. 5. The superoxide-dependent reduction of cytochrome P-450 is prevented by treatment of the membranes with mersalyl, which inhibits NADPH-cytochrome P-450 (cytochrome c) reductase. Thus the effect of superoxide may involve NADPH-cytochrome P-450 reductase and cytosolically orientated membrane factor(s).
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PMID:Asymmetric distribution of cytochrome P-450 and NADPH--cytochrome P-450 (cytochrome c) reductase in vesicles from smooth endoplasmic reticulum of rat liver. 625 76

Uninduced rat liver microsomes and NADPH-Cytochrome P-450 reductase, purified from phenobarbital-treated rats, catalyzed an NADPH-dependent oxidation of hydroxyl radical scavenging agents. This oxidation was not stimulated by the addition of ferric ammonium sulfate, ferric citrate, or ferric-adenine nucleotide (AMP, ADP, ATP) chelates. Striking stimulation was observed when ferric-EDTA or ferric-diethylenetriamine pentaacetic acid (DTPA) was added. The iron-EDTA and iron-DTPA chelates, but not unchelated iron, iron-citrate or iron-nucleotide chelates, stimulated the oxidation of NADPH by the reductase in the absence as well as in the presence of phenobarbital-inducible cytochrome P-450. Thus, the iron chelates which promoted NADPH oxidation by the reductase were the only chelates which stimulated oxidation of hydroxyl radical scavengers by reductase and microsomes. The oxidation of aminopyrine, a typical drug substrate, was slightly stimulated by the addition of iron-EDTA or iron-DTPA to the microsomes. Catalase inhibited potently the oxidation of scavengers under all conditions, suggesting that H2O2 was the precursor of the hydroxyl radical in these systems. Very high amounts of superoxide dismutase had little effect on the iron-EDTA-stimulated rate of scavenger oxidation, whereas the iron-DTPA-stimulated rate was inhibited by 30 or 50% in microsomes or reductase, respectively. This suggests that the iron-EDTA and iron-DTPA chelates can be reduced directly by the reductase to the ferrous chelates, which subsequently interact with H2O2 in a Fenton-type reaction. Results with the reductase and microsomal systems should be contrasted with results found when the oxidation of hypoxanthine by xanthine oxidase was utilized to catalyze the production of hydroxyl radicals. In the xanthine oxidase system, ferric-ATP and -DTPA stimulated oxidation of scavengers by six- to eightfold, while ferric-EDTA stimulated 25-fold. Ferric-desferrioxamine consistently was inhibitory. Superoxide dismutase produced 79 to 86% inhibition in the absence or presence of iron, indicating an iron-catalyzed Haber-Weiss-type of reaction was responsible for oxidation of scavengers by the xanthine oxidase system. These results indicate that the ability of iron to promote hydroxyl radical production and the role that superoxide plays as a reductant of iron depends on the nature of the system as well as the chelating agent employed.
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PMID:The role of iron chelates in hydroxyl radical production by rat liver microsomes, NADPH-cytochrome P-450 reductase and xanthine oxidase. 633 21

2,4-Dinitrotoluene (2,4-DNT) is an important industrial nitroaromatic compound. 2,4-Diaminotoluene (2,4-DAT), one of the urinary metabolites of 2,4-DNT, is carcinogenic when fed to rats. The objectives of these studies were to determine whether 2,4-DAT was formed from 2,4-DNT in rat liver and to clarify the nature of enzymes responsible for reduction of 2,4-DNT to 2,4-DAT. Data obtained from thin-layer and high-pressure liquid chromatography indicated that metabolites produced by microsomal preparations were 2-amino-4-nitrotoluene (2A4NT) and its isomer (4A2NT). This microsomal activity is probably mediated by cytochrome P-450 because the reduction is blocked by carbon monoxide and primary amines [aniline, n-octylamine, and 2,4-dichloro-6-phenylphenoxyethylamine (DPEA)]. In contrast, 2,4-DNT was metabolized via 2A4NT and 4A2NT to 2,4-DAT by cytosolic preparations. The greatest part of the reduction activity was due to cytosolic xanthine oxidase because the reduction was blocked by allopurinol. The results of this investigation suggest that reduction of 2,4-DNT to 2,4-DAT by cytosolic xanthine oxidase may play a role in 2,4-DNT hepatocarcinogenicity.
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PMID:Reduction of 2,4-dinitrotoluene by Wistar rat liver microsomal and cytosol fractions. 654 24

Oral administration of phthalazine (50 mg/kg/day) or 1-hydroxyphthalazine (10 mg/kg/day) to female rabbits caused an increase in the specific activity of the hepatic molybdenum hydroxylases aldehyde oxidase and xanthine oxidase, whereas no effect on microsomal cytochrome P-450 activity was observed. The rise in the specific activity of purified aldehyde oxidase fractions was accompanied by a similar increase in molybdenum content. A significant lowering of the Km value for phthalazine was demonstrated with enzyme from treated rabbits whereas Km values for structurally similar substrates such as isoquinoline were unchanged from control values. Iso-electric focusing of DEAE-cellulose fractions showed the presence of an additional band of activity indicating that genuine induction of aldehyde oxidase had occurred in rabbits treated with phthalazine or 1-hydroxyphthalazine.
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PMID:Elevation of molybdenum hydroxylase levels in rabbit liver after ingestion of phthalazine or its hydroxylated metabolite. 654 14

Urinary metabolites excreted after oral caffeine were quantified in a healthy sample (n = 68) from the Toronto population by HPLC analyses. The profile of metabolites, assessed by examining particular metabolite ratios, was found to differ widely among subjects. Ratios denoting cytochrome P-450-dependent activities were shown to be interethnically variable between oriental and Caucasian groups, whereas those indicative of xanthine oxidase activity exhibited neither significant interindividual variation nor an ethnic difference. It was also shown that a ratio providing an index of polymorphic N-acetyltransferase activity holds promise as a simple marker for acetylator status in man.
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PMID:Variability in caffeine metabolism. 668 5


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