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)

Misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol) is an experimental anticancer drug. Reductive metabolism is thought to be important for the cytotoxicity of misonidazole. In this study, the DNA binding of misonidazole was examined after chemical and enzymatic reduction. Under anaerobic conditions, both rat liver microsomes and cytosol catalyzed the reductive metabolism and DNA binding of misonidazole. The misonidazole utilized in these studies was radiolabeled on the side chain. The adduct(s) formed was too unstable for structural analysis. Little or no metabolism of misonidazole was detected in aerobic incubations. Likewise, very little DNA binding occurred in the presence of oxygen. Xanthine oxidase, a model nitroreductase, also was capable of catalyzing the DNA binding of misonidazole. However, unlike the xanthine oxidase catalyzed DNA binding of carcinogenic nitropolycyclic aromatic hydrocarbons, the DNA binding of misonidazole was not increased at slightly acidic pH. The putative reactive intermediate, the N-hydroxylamine, was synthesized by zinc reduction of misonidazole. The DNA binding of the N-hydroxylamine derivative increased with increasing pH. The observed pH dependence of the reactions with DNA is similar to other heterocyclic N-hydroxylamines, but is in contrast to the reactivity of a number of aromatic N-hydroxylamines.
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PMID:Reductive metabolism and DNA binding of misonidazole. 279 16

Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963.
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PMID:Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios. 677 Oct 29

[14C]Misonidazole (MISO) becomes bound to macromolecules of mammalian cells upon hypoxic incubation. Intracellular enzyme processes are implicated since the temperature dependence for this process showed an activation energy of 33.5 kcal/mol. The sensitizer bound to both hypoxic and aerobic cells was associated with the macromolecular fraction and the soluble fraction in the proportion, 23 and 77%, respectively. The initial rate of binding of [14C]MISO to the macromolecular (acid-insoluble) fraction of hypoxic EMT-6 mouse tumor and V-79 hamster cells increased proportionally with the square root of extracellular concentration of MISO up to at least 5mM. High concentrations of dimethyl sulfoxide (an effective OH radical scavenger), allopurinol (an effective inhibitor of xanthine oxidase), and diamide (a chemical which can deplete cellular levels of glutathione) had little or no effect on this metabolism-induced binding process. The addition of high concentrations of exogenous cysteamine to hypoxic cell cultures resulted in almost complete inhibition of binding. Extracellular bovine albumin at high concentration in hypoxic cell cultures had little effect on the production of adducts to cell macromolecules and only small amounts of [14C]MISO were found to bind to the extra-cellular bovine albumin. This result suggests that MISO preferentially binds to molecules within the cell in which it is metabolically activated. In experiments where cells labeled under hypoxic conditions with [14C]MISO were subsequently permitted to proliferate in aerobic monolayers, a half-life of the acid-insoluble addition products of approximately 55 hr was measured. A large number of [14C]MISO adducts (approximately 10(9)/cell) can be generated in hypoxic cells without any evidence of cytotoxicity, and they are slowly cleared from cells. These are favorable characteristics as regards the development of this technique as a marker for hypoxic cells in solid tumors.
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PMID:Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. 683 1