BackgroundClinically applied as anti-gout drugs, xanthine oxidoreductase (XOR) inhibitors, especially the potent, selective, non-purine-analog XOR inhibitors febuxostat and topiroxostat, exert organ-protective effects. We tested the hypothesis that preservation of tissue concentrations of high-energy phosphates, such as ATP and ADP, contributes to organ-protective effects through CE-TOFMS metabolomics.MethodsRats were subjected to 30 min of renal ischemia-reperfusion (I/R) injury 60 min after oral administration of 10 mg/kg febuxostat, 10 mg/kg topiroxostat, 50 mg/kg allopurinol, or vehicle.ResultsIn non-purine-analog XOR inhibitor-treated groups, renal concentrations of high-energy phosphates were greater before and after I/R injury, and renal adenine compounds were less depleted by I/R injury than in the vehicle and allopurinol groups. These findings were well in accordance with the proposed hypothesis that the recomposition of high-energy phosphates is promoted by non-purine-analog XOR inhibitors via the salvage pathway through blockade of hypoxanthine catabolism, whereas non-specific inhibitory effects of allopurinol on purine/pyrimidine enzymes impede this re-synthesis process.ConclusionsThis metabolic approach shed light on the physiology of the organ-protective effects of XOR inhibitors.

中文翻译：

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代谢组学分析阐明了黄嘌呤氧化还原酶抑制剂对肾缺血再灌注损伤大鼠模型中嘌呤/嘧啶代谢的独特影响

背景临床上作为抗痛风药物应用的黄嘌呤氧化还原酶（XOR）抑制剂，尤其是强效、选择性、非嘌呤类异或抑制剂非布司他和托吡司他具有器官保护作用。我们通过 CE-TOFMS 代谢组学检验了组织中高能磷酸盐（如 ATP 和 ADP）浓度的保存有助于器官保护作用的假设。 方法大鼠受到 30 分钟的肾缺血再灌注 (I/R) 损伤口服 10 毫克/千克非布司他、10 毫克/千克托吡司他、50 毫克/千克别嘌呤醇或载体后 60 分钟。结果在非嘌呤类似物 XOR 抑制剂治疗组中，高能磷酸盐的肾脏浓度在在 I/R 损伤后，肾腺嘌呤化合物因 I/R 损伤而耗竭的程度低于赋形剂和别嘌呤醇组。