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Abstract
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.
Highlights
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
XOR activity and western blotting analysis of kidney extracts during I/R injury Western blotting for XOR expression in kidney lysates showed a single 150-kDa band in each group, and the amount enzyme protein was not changed throughout the I/R process, this indicates that no limited proteolysis of XOR nor enzyme induction occurred (Fig. 1c)
No significant differences in the expression of adenine phosphoribosyltransferase (APRT), XOR, pyruvate kinase (PK), phosphofructokinase (PFK), pyruvate dehydrogenase kinase (PDH), pyruvate carboxylase (PC), and phosphoenolpyruvate carboxykinase (PEPCK) within groups in either the stationary or reperfused state were observed (Additional file 1: Figure S1A, C–H)
Summary
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. Some in vivo experiments revealed a superior organ-protective effect of febuxostat compared to allopurinol in an intestinal ischemia-reperfusion (I/R) injury rat model, a myocardial I/R injury mouse/rat model and a mouse model of amyotrophic lateral sclerosis (ALS) (Shafik 2013; Wang et al 2015; Khan et al 2017; Kato et al 2016). Most of these reports claim that superiority of non-purine-analog inhibitor to allopurinol was due to significant potency of nonpurine-analog inhibitor to inhibit XOR activity, and lowering oxidative-stress. There are no studies in which augmentation of XO activity itself was confirmed enzymatically, and the specific mechanism of action remains further to be elucidated
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