Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury

• Main Authors: Takashi Tani (Author), Ken Okamoto (Author), Megumi Fujiwara (Author), Akira Katayama (Author), Shuichi Tsuruoka (Author)
• Format: Book
• Published: BMC, 2019-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1186/s10020-019-0109-y; 1076-1551; 1528-3658
• Keywords: Metabolome; Xanthine oxidoreductase inhibitor; Ischemia-reperfusion injury; Therapeutics. Pharmacology; RM1-950; Biochemistry; QD415-436
• Source: Molecular Medicine, Vol 25, Iss 1, Pp 1-13 (2019)

Abstract Background Clinically 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. Methods Rats 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. Results In 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. Conclusions This metabolic approach shed light on the physiology of the organ-protective effects of XOR inhibitors.