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Abstract: TH-PO365

Metabolomics Analytic Approach Reveals Global Metabolic Influences by Xanthine Oxidoreductase Inhibitors in a Rat Model of Unilateral Renal Ischemia-Reperfusion Injury

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Tani, Takashi, Nippon Medical School, Tokyo, Japan
  • Okamoto, Ken, Tokyo University, Bunkyo-Ku, Japan
  • Fujiwara, Megumi, Nippon Medical School, Tokyo, Japan
  • Katayama, Akira, Nippon Medical School, Tokyo, Japan
  • Tsuruoka, Shuichi, Nippon Medical School, Tokyo, Japan
Background

Xanthine oxidoreductase (XOR) inhibitors are clinically applied as anti-gout drugs to inhibit the conversion of xanthine to uric acid by XOR. They reportedly exert an organ-protective effect, especially the potent and selective XOR inhibitors, febuxostat and topiroxostat. We aimed to verify the hypothesis that preservation of tissue high-energy phosphate concentrations contributes to these positive effects in a rat model of unilateral renal ischemia-reperfusion (I/R) injury through global metabolic pathway analysis.

Methods

Six-week-old male Sprague–Dawley rats were orally administrated either 10 mg/kg of febuxostat, 10 mg/kg of topiroxostat, 50 mg/kg of allopurinol, or vehicle 60 min before they were subjected to 30 min of unilateral renal I/R injury. Kidney samples were collected at three time points; before I/R injury (stationary group), 30 min left renal ischemia (ischemic group), 30 min after I/R injury (reperfusion group). Metabolites in kidney lysates were analyzed by HPLC and CE-TOFMS metabolomics.

Results

Metabolomics analysis revealed global impact of I/R injury on metabolic pathways. In XOR-selective-inhibitor-treated groups, tissue concentrations of high-energy phosphates were higher before and after I/R injury, and renal adenine compounds were better preserved throughout I/R injury than in vehicle and allopurinol groups. The XOR-selective inhibitors were also shown to uniquely influence glycolysis, glycogenesis, and the tricarboxylic acid cycle metabolic pathways.

Conclusion

These findings were well in accordance with the proposed hypothesis that the recomposition of high-energy phosphates, such as ATP and ADP, is promoted by the XOR-selective 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. The unique global metabolic alterations by the XOR-selective inhibitors, presumably by a change in the ATP/AMP ratio, acting as an allosteric effector, remained further to be investigated. This study revealed novel findings of the XOR inhibitors` influences on global metabolic pathway, and sheds light on the undetermined physiology of the organ-protective effects of XOR inhibitors.