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. Electronic supplementary material The online version of this article (10.1186/s10020-019-0109-y) contains supplementary material, which is available to authorized users.

Association of Coronary Artery Disease and Metabolic Syndrome: Usefulness of Serum Metabolomics Approach

“…On the other hand, hypoxanthine could aggravate myocardial and renal graft ischemia/reperfusion injury by ROS (36,37). It is considered that xanthine oxidoreductase (XOR) leads to reduced uracil and hypoxanthine and increased uric acid in our study (38,39).…”

Antioxidant-Based Therapy Reduces Early-Stage Intestinal Ischemia-Reperfusion Injury in Rats

“…In contrast, there are also studies in which its oral administration prior to ischemia instauration does demonstrate an antioxidant effect, as evidenced by a reduction in HID and a decrease in the production of oxidative stress markers such as malondialdehyde (MDA) [33]. Other studies performed in a renal IRI mode have shown the beneficial effect of XO inhibition [34][35][36][37][38]. After prophylactic administration of allopurinol, a decrease of up to 75% in the damage was noticed, both biochemical and anatomopathological.…”

Febuxostat, a Xanthine Oxidoreductase Inhibitor, Decreases NLRP3-dependent Inflammation in Macrophages by Activating the Purine Salvage Pathway and Restoring Cellular Bioenergetics

“…The purine salvage pathway plays an important role in ATP maintenance, as evidenced by the low levels of ATP in Lesch-Nyhan syndrome patients who have a mutation of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a crucial enzyme in the salvage pathway 22 . XOR inhibition results in the accumulation of hypoxanthine, which in turn leads to the activation of salvage pathway via HGPRT 23,24 . Given these previous reports, the restoration of iATP by febuxostat is mainly due to the activation of salvage pathway because febuxostat increased not only ATP but also GTP (see Supplementary Fig.…”