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

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.

SUBMITTER: Tani T 

PROVIDER: S-EPMC6704627 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature