Kinetics of High-Energy Phosphates in Allopurinol-Pretreated Ischaemic and Post-lschaemic Skeletal Muscle: An in vivo Magnetic Resonance Spectroscopy Study
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Allopurinol (AP) protects skeletal muscle function against ischaemia-induced injury, but the mechanism is not yet clear. As AP acts as a competitive xanthine oxidase inhibitor, both a reduction of oxygen-derived free radicals and an enhancement of purine resynthesis (salvage pathway) might be involved. We investigated the in vivo kinetics of high-energy phosphates in skeletal muscle after AP pretreatment using 31P-magnetic resonance spectroscopy during 2 h of ischaemia and 3 h of reperfusion in rat hindlimbs. Three animals (group A) were pretreated with a total of 160 mg/kg AP i.p., 3 control animals (group B) received the same amount of 0.9% saline solution. ATP decreased to 18.6 +/- 1.3% of the pre-ischaemic value in group A and to 17.3 +/- 2.8% in group B after 2 h of ischaemia, and rose to only 47.7 +/- 1.5 and 50.5 +/- 1.8%, respectively, after 3 h of reperfusion. Phosphocreatine fell to 7.2 +/- 2.9 and 7.6 +/- 2.2% of pre-ischaemic values after 2 h of ischaemia and rose again to 36.5 +/- 12.9 and 45.4 +/- 20.4% after 3 h of reperfusion. Inorganic phosphate (Pi) increased 5-fold after 2 h of ischaemia, irrespective of the treatment. After 3 h of reperfusion, Pi was still 4 times the pre-ischaemic value. The kinetics of ATP, PCr, and Pi levels were not statistically different between the two groups. These results indicate that the ATP salvage pathway does not play an important role in AP-induced attenuation of ischaemia/reperfusion-induced muscle damage.Keywords:
Allopurinol
High-energy phosphate
Xanthine
사염화탄소에 의한 간손상시 CCl₄대사에 xanthine oxidase(XO)가 관련되어지는 규명하기 위한 일환으로 allopurinol을 흰쥐 체중 Kg당 50㎎을 전처치한 다음 CCl₄를 투여한 후 처치하여 다음과 같은 결과를 얻었다. CCl₄투여로 인한 간조직의 postmitochondria 분획의 XO활성은 allopurinol을 전처치하므로서 현저히 감소되었으나 투석한 경우에는 오히려 증가되었으며 type D로부터 type O로의 전환율은 감소되었다. 또한, 투석한 간조직의 XO를 반응속도적인 측면에서 관찰해볼때 allopurinol을 전처치후 CCl₄투여군이 CCl₄단독투여군보다 Vmax가 크게 나타났다. CCl₄투여로 인한 체중당 간무게의 증가율과 혈청 alanine aminotransferase활성증가율은 allopurinol을 전처치하므로서 저하되었다. 한편 CCl₄투여로 인한 간조직중 aniline hydroxylase 및 glucose 6 phosphatase활성감소율은 allopurinol을 전처치하므로서 저하되었다. 이상의 실험결과를 종합하여볼때 실험동물에 CCl₄와 allopurinol을 병행투여시 allopurinol이 사염화탄소에 의한 간손상을 억제시키는 현상을 XO와 사염화탄소대사간에 관련성이 있음을 시사해주고 있다.
Allopurinol
Xanthine oxidase inhibitor
Xanthine
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Allopurinol
Xanthine oxidase inhibitor
Xanthine
Active metabolite
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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. (Neurosurgery 25:613-617, 1989)
Hypoxanthine
Allopurinol
Xanthine
Xanthine dehydrogenase
Xanthine oxidase inhibitor
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Fetal brain hypoxic injury remains a concern in high-risk delivery. There is significant clinical interest in agents that may diminish neuronal damage during birth asphyxia, such as in allopurinol, an inhibitor of the prooxidant enzyme xanthine oxidase. Here, we established in a rodent model the capacity of allopurinol to be taken up by the mother, cross the placenta, rise to therapeutic levels, and suppress xanthine oxidase activity in the fetus. On day 20 of pregnancy, Wistar dams were given 30 or 100 mg kg(-1) allopurinol orally. Maternal and fetal plasma allopurinol and oxypurinol concentrations were measured, and xanthine oxidase activity in the placenta and maternal and fetal tissues determined. There were significant strong positive correlations between maternal and fetal plasma allopurinol (r = 0.97, P < 0.05) and oxypurinol (r = 0.88, P < 0.05) levels. Under baseline conditions, maternal heart (2.18 ± 0.62 mU mg(-1)), maternal liver (0.29 ± 0.08 mU mg(-1)), placenta (1.36 ± 0.42 mU mg(-1)), fetal heart (1.64 ± 0.59 mU mg(-1)), and fetal liver (0.14 ± 0.08 mU mg(-1)) samples all showed significant xanthine oxidase activity. This activity was suppressed in all tissues 2 h after allopurinol administration and remained suppressed 24 h later (P < 0.05), despite allopurinol and oxypurinol levels returning toward baseline. The data establish a mammalian model of xanthine oxidase inhibition in the mother, placenta, and fetus, allowing investigation of the role of xanthine oxidase-derived reactive oxygen species in the maternal, placental, and fetal physiology during healthy and complicated pregnancy.
Allopurinol
Xanthine oxidase inhibitor
Xanthine
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Allopurinol
Hypoxanthine
Xanthine
Xanthine oxidase inhibitor
Purine metabolism
Inosine
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Allopurinol has been employed as a "specific" inhihitor of xanthine oxidase in studies of hypoxic/ reoxygenation injury. Pulse radiolysis was used to establish rate constants for the reactions of allopurinol and its major metabolite oxypurinol with hydroxyl radicals: values were (1.45 ± 0.241 × 109 M-1 s-1 for allopurinol and (4.95 ± 0.84) × 109 M-1 s-1 for oxypurinol. These rate constants show that, in view of the amounts of allopurinol that have been used in animal studies. hydroxyl radical scavenging by this molecule could contribute to its biological actions. especially if animals are pre-treated with allopurinol. so allowing oxypurinol to form. The ability of allopurinol to protect tissues not containing xanthine oxidase against reoxygenation injury may be related to radical scavenging by allopurinol and oxypurinol.
Allopurinol
Xanthine oxidase inhibitor
Xanthine
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Allopurinol
Xanthine oxidase inhibitor
Coronary occlusion
Xanthine
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Allopurinol
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1. Hypoxanthine, xanthine, uric acid, allopurinol and oxipurinol have been determined in skeletal-muscle biopsies by quantitative high-resolution mass spectrometry. 2. The results obtained in six untreated gout patients and in seven gout patients who had been treated with the xanthine oxidase inhibitor allopurinol for periods of about 2 years, have been compared with those obtained on muscle tissue from non-gouty subjects and with the results of previous microscopical studies of the same biopsies. 3. Measurable amounts of xanthine were detected more frequently in the allopurinol-treated gout patients than in the untreated patients. The concentration of uric acid was generally lower in the allopurinol-treated than in the untreated gout patients' muscle; and all except one of the allopurinol-treated subjects' tissue contained a measurable amount of oxipurinol. Allopurinol was detected less frequently than oxipurinol. 4. The concentrations of hypoxanthine and xanthine in the allopurinol-treated patients' muscle tissue are very much less than those which have been reported in congenital xanthine oxidase deficiency. 5. It is concluded that allopurinol can still be recommended as a useful drug in the treatment of gout but that longer studies during the clinical use of the drug would be of value.
Allopurinol
Hypoxanthine
Xanthine
Xanthine oxidase inhibitor
Sulfinpyrazone
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