Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma
Yanhong WangYanqing LeJie WuWenqu ZhaoQian ZhangGuiling XuZhaoqian GongMaosheng XuYanyan MaChanghui YuShaoxi CaiHaijin Zhao
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Abstract:
Extracellular high mobility group box 1 (HMGB1) is a key mediator in driving allergic airway inflammation and contributes to asthma. Yet, mechanism of HMGB1 secretion in asthma is poorly defined. Pulmonary metabolic dysfunction is recently recognized as a driver of respiratory pathology. However, the altered metabolic signatures and the roles of metabolic to allergic airway inflammation remain unclear.Keywords:
Allopurinol
HMGB1
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
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Allopurinol
Hypoxanthine
Xanthine
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Allopurinol
Xanthine oxidase inhibitor
Xanthine
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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.
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Xanthine oxidase inhibitor
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Although the protection against myocardial ischemia-reperfusion injury by allopurinol has previously been attributed to inhibition of xanthine oxidase, the demonstration of protective effects in species devoid of detectable myocardial xanthine oxidase activity argues against this hypothesis. In the present study, the effects of allopurinol pretreatment in a model of heart-lung transplantation were examined in swine, a species devoid of myocardial xanthine oxidase activity. Twenty-eight experiments were performed utilizing the heartlung transplantation model—seven controls (14 animals, 7 donors and 7 recipients) with no preoperative pharmacological intervention, and twenty-one in the experimental group (42 animals, 21 donors and 21 recipients) with donor and recipient pretreated with allopurinol 50 mg/kg/day for 3 days. The effect of allopurinol was determined on day 2 blood samples assessing red cell antioxidant status by measurement of malondialdehyde (MDA) formation in response to in vitro peroxidative challenge. The experimental group was divided into subgroups—namely, nonresponders (8 pairs of animals) and responders (13 pairs of animals) based on the range (mean ± 2 SD) of erythrocyte MDA levels in the control group. Heart-lung transplantation was performed in the three groups (control [7], nonresponders [8], and responders [13]) on day 3 following the final dose of allopurinol administration in the experimental group. Based on postsurgical assessments of cardiac and pulmonary function integrity, animals showing the greatest red cell antioxidant response following allopurinol treatment showed significantly better recovery
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Xanthine oxidase inhibitor
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高血圧自然発症ラット (SHR) を用いて両側総頚動脈3時間結紮後, 30分間の血行再開通を行い, 予めxanthine oxidase阻害作用を有するallopurinol, 400mg/kgを経口投与した群と対照群における脳組織内の過酸化脂質をmalonyldialdehyde (MDA) を指標として測定し, 比較検討した.結果はsham群, 対照群でそれぞれ68.90±3.46, 83.27±5.18 (nmol/gm) であったのに対し, allopurinol投与群では67.62±3.28 (nmol/gm) となり, 対照群に比べて有意に低値を示した (p<0.05).以上の結果よりallopurinolは脳虚血および血行再開通により惹起されるxanthine oxidase-linked free radicalによる脂質過酸化反応を抑制することが示唆された.
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Xanthine oxidase inhibitor
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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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