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

Citrate-Fe3+, reportedly a physiological chelate, exhibits superoxide dismutaselike activity, as evidenced by the inhibition of xanthine oxidase-dependent cytochrome c reduction; the dismutation of xanthine oxidase-generated superoxide to hydrogen peroxide and oxygen, and the enhanced disproportionation of potassium superoxide. The catalytic activity of citrate-Fe3+ corresponds, on a molar basis, to 0.03% of that of copper- and zinc-containing superoxide dismutase. Although weak, this activity enables citrate-Fe3+ to inhibit superoxide and ADP-Fe3+ -dependent peroxidation of extracted microsomal lipids. Also, the dismutase activity of citrate-Fe3+ interferes with its ability to promote lipid peroxidation. It is proposed that chelation of Fe3+ by citrate may represent a protective mechanism against the deleterious consequences of superoxide generation.
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PMID:Superoxide-dependent redox cycling of citrate-Fe3+: evidence for a superoxide dismutaselike activity. 302 73

Pyrazole, an effective inhibitor of alcohol dehydrogenase, was previously shown to be a scavenger of the hydroxyl radical. 4-Hydroxypyrazole is a major metabolite in the urine of animals administered pyrazole in vivo. Experiments were conducted to show that 4-hydroxypyrazole was a product of the interaction of pyrazole with hydroxyl radical generated from three different systems. The systems utilized were the iron-catalyzed oxidation of ascorbate, the coupled oxidation of hypoxanthine by xanthine oxidase, and NADPH-dependent microsomal electron transfer. Ferric-EDTA was added to all the systems to catalyze the production of hydroxyl radicals. A HPLC procedure employing either uv detection or electrochemical detection was utilized to assay for the production of 4-hydroxypyrazole. The three systems all supported the oxidation of pyrazole to 4-hydroxypyrazole by a reaction which was sensitive to inhibition by competitive hydroxyl radical scavengers such as ethanol, mannitol, or dimethyl sulfoxide and to catalase. The sensitivity to catalase implicates H2O2 as the precursor of the hydroxyl radical by all three systems. Superoxide dismutase inhibited production of 4-hydroxypyrazole only in the xanthine oxidase reaction system. In the absence of ferric-EDTA (and azide), microsomes catalyzed the oxidation of pyrazole to 4-hydroxypyrazole by a cytochrome P-450-dependent reaction which was independent of hydroxyl radicals. This latter pathway may be primarily responsible for the in vivo metabolism of pyrazole to 4-hydroxypyrazole. The production of 4-hydroxypyrazole from the interaction of pyrazole with hydroxyl radicals may be a sensitive, rapid technique for the detection of these radicals in certain tissues or under certain conditions, e.g., increasing oxidative stress.
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PMID:Production of 4-hydroxypyrazole from the interaction of the alcohol dehydrogenase inhibitor pyrazole with hydroxyl radical. 303 2

The effect of superoxide anion-radical and other reactive oxygen species on the metabolism of benzo(a)pyrene was studied with isolated mouse liver microsomes. Reactive oxygen species were generated in vitro by xanthine-xanthine oxidase plus Fe3+ X FeEDTA and benzo(a)pyrene metabolism was followed by reverse-phase high pressure liquid chromatography. The following results were obtained: The reactive oxygen species induced one-electron oxidation of benzo(a)pyrene and increased production of free epoxide as well as protein-binding intermediates. The reactive oxygen species triggered microsomal lipid peroxidation in the presence of Fe3+ X FeEDTA. As a result of microsomal lipid peroxidation a decreased activity of cytochrome P-450, epoxide hydrolase and UDP-glucuronyltransferase was found. It is suggested that active oxygen species changed the balance between bioactivation and conjugation of benzo(a)pyrene metabolites causing accumulation of the epoxide and protein-binding intermediates. The role of iron ions and chelates in this process is discussed.
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PMID:Action of xanthine-xanthine oxidase system on microsomal benzo(a)pyrene metabolism in vitro. 303 65

Dinitropyrenes are contaminants in diesel emissions that are mutagenic in bacteria and mammalian cells, and tumorigenic in laboratory animals. In this project, we investigated the factors that contributed to the extreme genotoxicity of dinitropyrenes in bacteria and determined if these factors were important in mammalian cells. Xanthine oxidase, a mammalian nitroreductase, catalyzed the conversion of the dinitropyrenes to DNA-bound products, but the level of binding did not exceed that observed with 1-nitropyrene. This suggested that factors in addition to nitroreduction were important in the metabolic activation of dinitropyrenes. 1-Nitro-6-nitrosopyrene and 1-nitro-8-nitrosopyrene were synthesized and reacted with DNA under reducing conditions. The same C8-substituted deoxyguanosine adducts were formed that were found in the xanthine oxidase-catalyzed reactions, which confirmed that incubation with this nitroreductase generated reactive N-hydroxy arylamine intermediates. In incubations with rat and human liver microsomes and cytosol, 1-nitropyrene and 1,3-dinitropyrene were reduced to a lesser extent than 1,6- and 1,8-dinitropyrene, which was in accord with their relative mutagenicities. Each of the cytosolic incubations were similar in that oxygen decreased aminopyrene, but not nitrosopyrene, formation. The data indicated that reduced derivatives of the nitrosopyrenes were redox cycling with oxygen, which decreased cytosolic aminopyrene formation. In cytosolic incubations, oxygen inhibited the reduction of 1-nitropyrene and 1,3-dinitropyrene to a greater extent than 1,6- and 1,8-dinitropyrene. By comparison, in microsomal investigations, the nitroreduction of each nitrated pyrene was equally oxygen-sensitive. This apparently was caused by the initial nitroanion radicals reacting with oxygen to decrease nitrosopyrene formation. Although more extensive nitroreduction of each compound was detected in anaerobic incubations, aerobic reduction of these compounds did occur and may be important during in vivo exposure to nitrated pyrenes. When rat liver cytosol was incubated with the nitrated pyrenes, very low levels of DNA binding were detected. Addition of acetyl coenzyme A (AcCoA) to these incubations increased the binding of the dinitropyrenes 20- to 40-fold, while the binding of 1-nitropyrene was not affected. The extent of AcCoA- dependent binding of the dinitropyrenes reflected the amount of nitroreduction; however, the increase in binding did not occur with dog liver cytosol, which was known to be deficient in N-acetylases. These results indicated that cytosolic nitroreductases catalyzed the formation of N-hydroxy arylamine intermediates, which in the case of dinitropyrenes were converted to reactive N-acetoxy arylamines by cytosolic AcCoA-dependent acetylases.
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PMID:The metabolic activation and DNA adducts of dinitropyrenes. 307 23

Lipid peroxidation has been invoked as a mechanism of alcoholic liver injury but its role has been controversial and the mechanism by which it occurs is unclear. Catalytic iron is known to play an important role in cellular injury and is produced during mobilization of ferritin iron. In vivo administration of a large acute dose of ethanol (5 g/kg) which produces hepatic lipid peroxidation in chow-fed rats resulted in mobilization of non-heme iron. The generation of NADH from alcohol metabolism via ADH or superoxide from acetaldehyde-xanthine oxidase mobilized iron from horse spleen ferritin in vitro. Chronic feeding of alcohol as 36% of energy for 6 weeks does not itself produce peroxidation in the rat but potentiates acute effects of ethanol. It produced microsomal induction which enhanced iron-stimulated lipid peroxidation and increased hepatic non-heme iron. Carbon monoxide increased rather than decreased accumulation of microsomal peroxidation products in vitro suggesting that cytochrome P-450 reductase mediates peroxidation but cytochrome P-450 may metabolize products. Incubation at lowered oxygen tensions equivalent to those observed in the perivenular zone (pO2 = 24 mmHg) enhanced in vitro iron mobilization but decreased peroxidation. Lipid peroxidation and its stimulation by iron mobilization and microsomal induction may be an important contributory mechanism of alcohol-induced liver injury.
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PMID:Lipid peroxidation as a mechanism of alcoholic liver injury: role of iron mobilization and microsomal induction. 313 9

A method for measuring the content of two groups of microsomal cytochrome P-450 isozymes--cytochromes P-450W and P-450L--with the active sites directed into the water phase and membrane lipids, respectively, has been developed. The method is based on the ability of the xanthine oxidase-menadione complex to reduce microsomal cytochromes b5 and P-450 under anaerobic conditions by transferring electrons to hemoproteins with the active sites directed into the water phase. Cytochrome b5 is completely reduced (to the dithionite level) and cytochrome P-450 is reduced partially (only a group of cytochromes P-450W). The amount of cytochromes P-450L is estimated using the difference between the total content of cytochrome P-450 reduced by sodium dithionite and the content of cytochromes P-450W. The possibility of controlling the ratio of these two isozyme groups in cytochrome P-450 in vivo in membranes of the endoplasmic reticulum by pretreatment of animals with a variety of chemicals has been demonstrated. The ratio of cytochromes P-450W and P-450L has been shown to decrease two-fold 18 days after three injections of phenobarbital into mice. Carbon tetrachloride and cyclophosphamide also decrease this ratio in vivo.
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PMID:The ratio of two isozyme groups in microsomal cytochrome P-450 under exogenous influence of carbon tetrachloride and cyclophosphamide. 323 47

Male C57Bl/10 mice were chronically fed hexachlorobenzene (HCB) (0.02% of the diet) alone or in combination with a single subcutaneous dose of iron (12.5 mg iron per mouse). After eight weeks the group of mice pretreated with the iron overload was highly sensitized to the porphyrogenic effect of HCB, as shown by liver porphyrin accumulation. A synergistic effect of iron was evident on other parameters too, such as HCB-induced hepatic damage, activation of type O of xanthine oxidase, and decreased activity of copper zinc superoxide dismutase and glutathione peroxidase(s). None of these parameters was affected by iron alone. Iron alone and in association with HCB markedly raised the level of lipid peroxides, the increase in the HCB group being smaller. The combined treatment resulted in a significant reduction of HCB's inductive effects on microsomal heme and cytochromes P-450 and b5 and on the activity of aryl hydrocarbon hydroxylase. The content of nonprotein sulfhydryl groups was reduced to the same extent in mice treated with HCB or HCB plus iron. The results suggest that reactive intermediates such as are formed by lipid peroxidation are not sufficient on their own to create the conditions for uroporphyrinogen decarboxylase impairment, as evident in the group of mice receiving iron overload alone. Conversely, HCB administration induced a specific condition of imbalance in the liver between formation and inactivation of reactive intermediates which was associated with hepatic porphyrin accumulation and was potentiated by concomitant administration of iron.
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PMID:Investigations on the role of free radical processes in hexachlorobenzene-induced porphyria in mice. 323 39

The role of nonprotein thiols (NPSH) in the enzymatic reduction of the nitro function in 2-nitroimidazoles (2-NI) has been investigated. The addition of NPSH has been shown previously to protect cells from the hypoxic cytotoxicity of 2-NI, whereas depletion of NPSH enhances the hypoxic cytotoxicity. In this report, we have investigated the effects of thiol depleting agents, N-ethylmaleimide (NEM) and diethyl maleate (DEM), on the enzymatic reduction of the nitro group. Cytosolic and microsomal fractions of rat hepatic tissue and xanthine oxidase were employed as sources of nitro reductases. Addition of NPSH caused an enhancement in the reduction of the nitro group of 2-NI; cysteine was significantly more effective than glutathione (GSH) in stimulating the enzymatic reduction. The reduction of the nitro function was decreased markedly in the presence of NEM or DEM. Addition of cysteine or GSH reversed the inhibition with NEM. Both NEM and DEM also attenuated the enhancement of reduction observed after the addition of NPSH. These results suggest that the addition of NPSH facilities the reduction of the nitro function to the reduced intermediates that may be inactivated by an excess of NPSH, whereas the depletion of NPSH allows the accumulation of the toxic nitro radicals causing increased cytotoxicity.
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PMID:Role of nonprotein thiols in enzymatic reduction of 2-nitroimidazoles. 333 46

Intercellular communication through gap junctions functions in electrical synapsing, homeostasis, hormonal response, embryogenesis, and growth control. Many neurotoxicants, teratogens, and carcinogens are capable of inhibiting gap junctional intercellular communication and this effect may be related to their toxic activity. In addition, many of these toxic agents are capable of stimulating oxygen free radical production in cells. The purpose of this study was to determine if oxygen free radicals at noncytotoxic levels could inhibit intercellular communication in primary cultured mouse hepatocytes. Intercellular communication was evaluated in 24-hr-old cultures of male B6C3F1/Cr1BR mouse hepatocytes by microinjection of fluorescent Lucifer Yellow CH dye and visualization of dye spread to adjacent hepatocytes (dye-coupling). Dye-coupling was rapidly established in freshly plated primary cultured hepatocytes reaching a level of over 90% after 24 hr of culture. After 24 hr, dye-coupling paralleled hepatocyte survival. Treatment of hepatocyte cultures with noncytotoxic concentrations of paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride; PQ) (0.5-5 mM), hydrogen peroxide (0.5-2 mM), glucose oxidase (0.1 U/ml), or xanthine oxidase (0.2 U/ml plus 1 mM xanthine) for exposure durations of 2-8 hr resulted in concentration-dependent decreases in dye-coupling. Addition of the antioxidants DPPD (N,N-diphenyl-p-phenylenediamine; 25 microM) and vitamin E (D,L-alpha-tocopherol acetate; 100 microM) decreased the inhibitory effect of PQ on dye-coupling. In contrast, addition of the catalase inhibitor 3-amino-1,2,4-triazole or the glutathione depletor diethylmaleate to PQ-treated cultures potentiated PQ-induced inhibition of dye-coupling. PQ stimulated NADPH-dependent mouse liver microsomal superoxide radical production. Thus, one effect of prooxidant compounds appears to be the inhibition of IC. This effect may be important in the sublethal toxicity of oxygen radical generating compounds.
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PMID:Inhibition of mouse hepatocyte intercellular communication by paraquat-generated oxygen free radicals. 340 94

The depletion of superoxide dismutase in the liver of rats held on a copper-deficient diet for 8 weeks induces two profound modifications in microsomal membrane characteristics. These membranes show: (1) a low degree of peroxidation induced in vitro by both endogenous (NADPH and tert-butylhydroperoxide) and exogenous sources (xanthine/xanthine oxidase) of oxygen radicals as revealed by malondialdehyde and diene-conjugate production; (2) a strong decrease of polyunsaturated and an increase of monounsaturated fatty acid content. These alterations are similar to those found in microsomal membranes from fast-growing hepatomas which exhibit a pronounced saturation of fatty acid pattern and lack superoxide dismutase. These observations support the hypothesis that during hepatocarcinogenesis the loss of superoxide dismutase causes an oxidative stress that increases cellular membrane lipid peroxidation, as a consequence of which the cell responds by synthesizing more saturated fatty acids that permanently modify cell membrane structure and properties.
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PMID:Superoxide dismutase depletion and lipid peroxidation in rat liver microsomal membranes: correlation with liver carcinogenesis. 340 6


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