Ischemia-Reperfusion Injury and Free Radical Involvement in Gastric Mucosal Disorders
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Hypoxanthine
Hydroxyl radical
The existence of uric acid in mammalian brain was recently reported, but it has not yet become a consensus. The mammalian brain has been thought to lack xanthine oxidase, which catalyzes hypoxanthine to xanthine and xanthine to uric acid as the last steps of ATP degradation in other tissue. Using high-performance liquid chromatography, we performed assays for hypoxanthine, xanthine, and uric acid in rat brain after cerebral ischemia. It was confirmed that all three substances showed significant augmentation in the removed brains and that the chronological order of those increases corresponded to the order in the metabolic pathway. Allopurinol, a specific inhibitor of xanthine oxidase, significantly suppressed the increases in uric acid and xanthine, and a compensatory accumulation of hypoxanthine was observed. From these results, it was concluded that uric acid does exist in the brain, increases after ischemia, and is possibly the end product of purine degradation in the brain. Furthermore, it is suggested that xanthine oxidase exists in the brain and catalyzes the reaction from hypoxanthine to xanthine and then to uric acid. These reactions catalyzed by xanthine oxidase are considered to be a source of free radicals and may play important roles in the pathogenesis of cerebral ischemic injury. (Neurosurgery 25:613-617, 1989)
Hypoxanthine
Allopurinol
Xanthine
Xanthine dehydrogenase
Xanthine oxidase inhibitor
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The antitumor effect of oxygen radicals produced by hypoxanthine and xanthine oxidase reaction was studied in an experimental rabbit model. VX2 carcinomas were transplanted into rabbit hind legs. Hypoxanthine was administered continuously through the ear vein, while xanthine oxidase was administered simultaneously through the femoral artery. As a result, hypoxanthine and xanthine oxidase reacted only in the hind leg, and superoxide was produced in that area. The volume of the VX2 carcinoma was measured immediately prior to treatment and 7 days later. As an index of lipid peroxidation, thiobarbituric acid-reactive substances in the tumor tissue were measured 60 min following infusion of hypoxanthine and xanthine oxidase. Tumor growth was suppressed significantly by the hypoxanthine-xanthine oxidase reaction, and thiobarbituric acid-reactive substances in the tumor tissue infused with hypoxanthine and xanthine oxidase were significantly increased. In addition, the antitumor effect of the hypoxanthine and xanthine oxidase reaction was significantly inhibited by the administration of superoxide dismutase and catalase. Pathological examination showed that oxygen radicals produced by hypoxanthine and xanthine oxidase reaction were selectively more destructive for VX2 carcinoma tissue than muscle tissue surrounding the tumor region. These results suggest that oxygen radicals produced by hypoxanthine and xanthine oxidase reaction produce an anticancer effect and that the VX2 carcinoma used in this study was more sensitive to oxygen radicals than normal muscle tissue.
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Xanthine
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Hypoxanthine
Allopurinol
Xanthine
Inosine
Xanthine dehydrogenase
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Hypoxanthine
Xanthine
Allopurinol
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Hypoxanthine
Xanthine
Muscle tissue
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Abstract A number of new hypoxanthine analogs have been prepared as substrate inhibitors of xanthine oxidase. Most noteworthy inhibitory new hypoxanthine analogs are 3‐( m ‐tolyl)pyrazolo[1,5‐ a ]pyrimidin‐7‐one ( 47 ), ID 50 0.06 μ M and 3‐phenylpyrazolo[1,5‐ a ]pyrimidin‐7‐one ( 46 ), ID 50 0.40 μ M. 5‐( p ‐Chlorophenyl)pyrazolo[1,5‐ a ]pyrimidin‐7‐one ( 63 ) and the corresponding 5‐nitrophenyl derivative 64 exhibited an ID 50 of 0.21 and 0.23 μ M , respectively. 7‐Phenylpyrazolo[1,5‐ a ]‐ s ‐triazin‐4‐one ( 40 ) is shown to exhibit an ID 50 of 0.047 μ M. The structure‐activity relationships of these new phenyl substituted hypoxanthine analogs are discussed and compared with the xanthine analogs 3‐ m ‐tolyl‐ and 3‐phenyl‐7‐hydroxypyrazolo[1,5‐ a ]pyrimidin‐5‐ones ( 90 ) and ( 91 ), previously reported from our laboratory to have ID 50 of 0.025 and 0.038 μ M , respectively. The presence of the phenyl and substitutedphenyl groups contribute directly to the substrate binding of these potent inhibitors. This work presents an updated study of structure‐activity relationships and binding to xanthine oxidase. In view of the recent elucidation of the pterin cofactor and the proposed binding of this factor to the molybdenum ion in xanthine oxidase, a detailed mechanism of xanthine oxidase oxidation of hypoxanthine and xanthine is proposed. Three types of substrate binding are viewed for xanthine oxidase. The binding of xanthine to xanthine oxidase is termed Type I binding. The binding of hypoxanthine is termed Type II binding and the specific binding of alloxanthine is assigned as Type III binding. These three types of substrate binding are analyzed relative to the most potent compounds known to inhibit xanthine oxidase and these inhibitors have been classified as to the type of inhibitor binding most likely to be associated with specific enzyme inhibition. The structural requirements for each type of binding can be clearly seen to correlate with the inhibitory activity observed. The chemical syntheses of the new 3‐phenyl‐ and 3‐substituted phenylpyrazolo[1,5‐ a ]pyrimidines with various substituents are reported. The syntheses of various 8‐phenyl‐2‐substituted pyrazolo‐[1,5‐ a ]‐ s ‐triazines, certain s ‐triazolo[1,5‐ a ]‐ s ‐triazines and s ‐triazolo[1,5‐ a ]pyrimidine derivatives prepared in connection with the present study are also described.
Hypoxanthine
Xanthine
Molybdenum Cofactor
Xanthine dehydrogenase
Aldehyde oxidase
Purine analogue
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AbstractThe hypoxanthine — xanthine oxidase system generates an extracellular flux of superoxide anion radical (O2−) and hydrogen peroxide (H2O2). Catalase but not superoxide dismutase (SOD) protects V79 cells exposed to the hypoxanthine — xanthine oxidase system, showing that H2O2 is the major reactive oxygen species involved in the cytotoxicity of such a system. In contrast to SOD, the lipophilic SOD like compound CuII (diisopropylsalicylate)2 (CuDIPS) exhibits some protection at non cytotoxic concentration. It is also found that methanol partially protects cells exposed to the hypoxanthine-xanthine oxidase system. It appears that in our experimental conditions (temperature, ionic strength and pH) the protective effect afforded by methanol and CuDIPS is due to the inhibition of the xanthine oxidase activity.Key Words: Reactive oxygen speciescell lethalitysuperoxide dismutasesuperoxide dismutase mimiccatalase
Hypoxanthine
Xanthine
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The existence of uric acid in mammalian brain was recently reported, but it has not yet become a consensus. The mammalian brain has been thought to lack xanthine oxidase, which catalyzes hypoxanthine to xanthine and xanthine to uric acid as the last steps of ATP degradation in other tissue. Using high-performance liquid chromatography, we performed assays for hypoxanthine, xanthine, and uric acid in rat brain after cerebral ischemia. It was confirmed that all three substances showed significant augmentation in the removed brains and that the chronological order of those increases corresponded to the order in the metabolic pathway. Allopurinol, a specific inhibitor of xanthine oxidase, significantly suppressed the increases in uric acid and xanthine, and a compensatory accumulation of hypoxanthine was observed. From these results, it was concluded that uric acid does exist in the brain, increases after ischemia, and is possibly the end product of purine degradation in the brain. Furthermore, it is suggested that xanthine oxidase exists in the brain and catalyzes the reaction from hypoxanthine to xanthine and then to uric acid. These reactions catalyzed by xanthine oxidase are considered to be a source of free radicals and may play important roles in the pathogenesis of cerebral ischemic injury.
Hypoxanthine
Xanthine
Allopurinol
Xanthine dehydrogenase
Urate Oxidase
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Thiol compounds have been reported to abolish hypoxanthine/xanthine oxidase induced luminol chemiluminescence and this effect has been attributed to scavenging of superoxide (O2‐)/(H2O2) produced from hypoxanthine/xanthine oxidase. Yet other workers have reported that thiol compounds have shown little, if any, reactivity towards O2‐/H2O2. The aim of this study was to examine the discrepancy between these two sets of findings further. Captopril (a thiol angiotensin‐converting enzyme (ACE) inhibitor) and MPG (a simple thiol) were observed to abolish hypoxanthine/xanthine oxidase induced chemiluminescence. The reactivity of captopril and MPG towards O2‐/H2O2 was then determined by measurement of thiol oxidation in captopril and MPG after their incubation with hypoxanthine/xanthine oxidase. Incubation (at 10 min, 37 degrees C) with 4 mM hypoxanthine/0.03 u ml‐1 xanthine oxidase resulted in 7% and 20% thiol oxidation in captopril and MPG (at 1 mM) respectively. Captopril and MPG, therefore, appeared to be ineffective scavengers of oxidants produced by hypoxanthine/xanthine oxidase. Captopril and MPG also did not affect urate production or oxygen consumption by xanthine oxidase which indicated that captopril and MPG quench luminol chemiluminescence by a mechanism that excludes the inhibition of xanthine oxidase. Hypoxanthine/xanthine oxidase induced luminol chemiluminescence may, therefore, be an unsuitable method for measuring free radical scavenging activity by drugs.
Hypoxanthine
Luminol
Captopril
Xanthine
Thiol
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