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)

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole acetamide) is a drug used against Chagas' disease, a parasitic disease afflicting several millions of Latin Americans. Bz administration to Sprague-Dawley male rats at 100 mg/kg p.o. caused subcellular alterations in the adrenal cortex involving fasciculata and reticularis zones but not in the glomerulosa. There is Bz nitroreductase activity in the adrenal microsomal and mitochondrial fractions but most of it is localized in mitochondria. Activity in the two fractions requires NADPH under anaerobic conditions. Mitochondrial Bz nitroreductase activity was inhibited by oxygen. A minor but statistically significant inhibition was observed in mixtures incubated under carbon monoxide. Microsomal Bz nitroreductase activity was not detected under oxygen atmosphere and was not inhibited under carbon monoxide. No Bz nitroreductase activity mediated by xanthine oxidase or aldehyde oxidase was detected in the cytosolic fraction from rat adrenals. Electron microscopic examination of the adrenal cortex from Bz-treated animals revealed cells with marked lipid accumulation and alterations in nuclei, endoplasmic reticulum and mitochondria in the reticularis and fasciculata zones. In vitro results suggest a Bz nitroreductive activation, with minor or null P-450 participation, leading to reactive metabolites able to cause damage in various organelles.
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PMID:Benznidazole-induced ultrastructural alterations in rat adrenal cortex. Mechanistic studies. 151 44

Xanthine/xanthine oxidase and H2O2 stimulated sugar transport. Application of superoxide dismutase and catalase to the cells showed an inhibitory effect on these agent-stimulated sugar transports. Addition of amiloride and 4-acetamide-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), which abolish the cytoplasmic alkalinization, inhibited the stimulation of sugar transport by xanthine/xanthine oxidase in the presence of catalase. The calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and trifluoperazine inhibited H2O2-stimulated sugar transport. These results suggest that O2- stimulates sugar transport in an intracellular pH-dependent manner and that H2O2 stimulates sugar transport in a calcium-calmodulin-dependent manner. These mechanisms may be involved in sugar-transport stimulation in mouse fibroblast BALB/3T3 cells by the tumor-promoting phorbol ester phorbol-12,13-dibutyrate and insulin, since the stimulatory effects of these agents were inhibited by scavengers of oxygen radicals.
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PMID:Mechanism of O2- (-) and H2O2-induced stimulation of sugar transport in mouse fibroblast BALB/3T3 cells. 284 89

The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt., was shown to act as an initiator in a dose-dependent fashion in rat liver using the Solt-Farber method. Acetamide and its putative metabolite N-hydroxy-acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for genotoxicity in tests for mutations in Salmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. In contrast, N-hydroxy-acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N-hydroxy-acetamide induced transformation of primary Syrian hamster embryo cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabelled acetamide and N-hydroxy-acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N-Hydroxy-acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N-hydroxy-acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N-hydroxy-acetamide and acetic acid. No significant excretion of N-hydroxy-acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initiating effect of acetamide is obscure.
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PMID:Studies on the mechanism of acetamide hepatocarcinogenicity. 355 Jul 69

The initial metabolite formed by most mammalian nitroreductases is the nitro anion free radical. We, as well as others, have proposed that nitroheterocyclic anion radicals covalently bind to protein, DNA, or thiol compounds such as reduced glutathione (GSH). Our results indicate that even at 100 mM GSH does not affect the steady-state concentration of the nitro anion free radical of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) in rat hepatic microsomal or xanthine oxidase incubations. The steady-state ESR amplitude of the anion radical is also unchanged by the addition of BSA or DNA. Similar results are obtained with nitrofurazone and nitrofurantoin. The reactive chemical species which binds to tissue macromolecules and GSH upon the reduction of nitrofurans remains unknown, but the anion free radical metabolite can be excluded from consideration.
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PMID:No detectable reaction of the anion radical metabolite of nitrofurans with reduced glutathione or macro-molecules. 609 28

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole-acetamide) is a drug used against Chagas' disease. Rat liver microsomal and cytosolic fractions, but not mitochondria, exhibited Bz nitroreductase activity under anaerobic conditions in the presence of NADPH. Microsomal nitroreductase activity was enhanced by FAD and was inhibited totally by oxygen and partially by carbon monoxide. Liver cystosol fraction was able to reduce Bz nitrogroups in the presence of either N-methylnicotinamide or hypoxanthine as substrates. These enzyme activities were inhibited by menadione or allopurinol respectively. Under every experimental condition leading to enzymatic reduction of Bz nitrogroups and its inhibition or enhancement, reactive metabolites that bind covalently to proteins were also produced. This covalent binding was effectively prevented by reduced glutathione. Results suggest the participation of cytochrome P-450 and cytochrome c reductase in liver microsomal processes and of xanthine oxidase and aldehyde oxidase in liver cytosolic processes of Bz nitroreduction and activation to reactive metabolites that bind covalently to proteins. Possible pharmacological and toxicological implications of the described observations were discussed.
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PMID:Reductive metabolism and activation of benznidazole. 671 14

A stable nitroxide radical named Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) was synthesized and its antioxidant and antitumor properties were investigated and compared with these of another nitroxide derivatives previously designed in our laboratories. Three experimental models were used: xanthine/xanthine oxidase system, pulse radiolysis and experimental rat cancer (Yoshida Sarcoma) in vivo. In this work we measured the rate constant of the reactions of Metexyl with enzymatically generated O2.- or radiolytically produced .OH. For comparison, the reactions of non radical derivative (4-acetamide-2,2,6,6-tetramethylpiperidinium acetate) or nitroxide Tempace (4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl) with the above mentioned reactive oxygen radicals were also studied. The comparative ability of Metexyl to act as an inducer of apoptosis in vivo was also investigated in pharmacological test. The ring substituent (-OCH3) at position 4 of the Metexyl molecule had significant influence on its properties as antioxidant and apoptosis inducer. The results in this study suggest that Metexyl is a promising nitroxide antioxidant, which can induce apoptosis of tumor cells in vivo, thus providing a base for its further investigations in vitro and pharmacological applications.
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PMID:Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) as an oxygen radicals scavenger and apoptosis inducer in vivo. 1069 46