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Metabolomics Analysis Elucidates Unique Influences on Purine

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Metabolomics Analysis Elucidates Unique Influences on Purine Tani et al. Molecular Medicine (2019) 25:40 Molecular Medicine https://doi.org/10.1186/s10020-019-0109-y RESEARCHARTICLE Open Access Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia- reperfusion injury Takashi Tani1,2* , Ken Okamoto2, Megumi Fujiwara2, Akira Katayama2 and Shuichi Tsuruoka1 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. Keywords: Metabolome, Xanthine oxidoreductase inhibitor, Ischemia-reperfusion injury Background inhibition mechanisms: the purine-analog inhibitor Xanthine oxidoreductase (XOR) catalyzes the oxida- allopurinol, and non-purine-analog inhibitors, such as tion of hypoxanthine to xanthine and that of xanthine febuxostat and topiroxostat. The largest difference be- to uric acid, as well as the reduction of nicotinamide tween the purine analog and non-purine-analog inhib- adenine dinucleotide (NAD+) or molecular oxygen. itors is the specificity of the target enzyme; the non- Because they inhibit the conversion of xanthine to purine-analog inhibitors impede the activity of XOR uric acid, XOR inhibitors are used as anti-gout drugs. solely by obstructing substrate binding, and do not Clinically used XOR inhibitors are classified into two inhibit additional enzymes in purine and pyrimidine groups based on different chemical structures and metabolism pathways as reported for allopurinol (Okamoto et al. 2003;Takanoetal.2005). XOR inhibitors have shown potential organ-protective * Correspondence: [email protected] 1Department of Nephrology, Graduate School of Medicine, Nippon Medical effects in clinical trials (Sezai et al. 2015; Tanaka et al. School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan 2015; Tsuruta et al. 2014; Whelton et al. 2011) as well as 2 Department of Metabolism and Nutrition, Graduate School of Medicine, animal experiments (Sanchez-Lozada et al. 2008; Tsuda Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tani et al. Molecular Medicine (2019) 25:40 Page 2 of 13 et al. 2012; Omori et al. 2012). The mechanism of pro- The influence of XOR inhibitors on metabolic path- tection is usually explained by the oxidative-stress hy- ways may be related to their organ-protective effects pothesis: potent inhibition of XOR activity results in (Cunningham et al. 1974; Lasley et al. 1988; Khatib et al. suppression of the activity of xanthine oxidase (XO), 2001); thus, clarifying the alterations in the metabolome where XO functions in disease states by transferring may help elucidate their mechanism of action. There- − electrons to O2 to form O2 , leading to oxidative stress fore, in this study, we aimed to elucidate the mechanism and resulting in organ disorders (Tsuda et al. 2012; of XOR inhibitors using capillary electrophoresis–time- Omori et al. 2012; McCord 1985). of-flight mass spectrometry (CE-TOFMS) in a rat model There are several clinical reports indicating that of renal I/R, in which the effectiveness of XOR inhibitors the non-purine-analog inhibitor, febuxostat shows has been established (Tsuda et al. 2012). superior organ-protective effects compared to allo- purinol (Sezai et al. 2015;Kimetal.2017;Chouet Methods al. 2017;Foodyetal.2017;Shafik2013;Wangetal. Rat model of renal I/R injury 2015;Khanetal.2017;Katoetal.2016). Some in Sixty-two 6-week-old male Sprague–Dawley rats were vivo experiments revealed a superior organ-protect- randomly allocated to four groups (Table 1): (1) vehicle- ive effect of febuxostat compared to allopurinol in treatment group (Veh; n = 17); (2) febuxostat-treatment an intestinal ischemia-reperfusion (I/R) injury rat group (Feb; n = 15); (3) topiroxostat-treatment group model, a myocardial I/R injury mouse/rat model and (Top; n = 15) (4) allopurinol-treatment group (Allo; n = a mouse model of amyotrophic lateral sclerosis 15). Vehicle-treated rats orally received 0.5 ml of 0.5% (ALS) (Shafik 2013;Wangetal.2015;Khanetal. methylcellulose 60 min before surgery. Experimental rats 2017;Katoetal.2016). Most of these reports claim were orally administered 10 mg/kg febuxostat, 10 mg/kg that superiority of non-purine-analog inhibitor to topiroxostat, or 50 mg/kg allopurinol in 0.5% methylcel- allopurinol was due to significant potency of non- lulose, 60 min before operation. purine-analog inhibitor to inhibit XOR activity, and Before surgery, rats were anesthetized by intraperitoneal thus lowering oxidative-stress. However, there are no injection of 360 mg/kg chloral hydrate (Wako Pure Chem- studies in which augmentation of XO activity itself ical Industries, CAS: 302–17-0) and were placed on a was confirmed enzymatically, and the specific mech- warmed table to maintain a rectal temperature of 37 °C. anism of action remains further to be elucidated. The animals were then allowed to stabilize for 20 min. I/R One possible alternate answer to the question is that injury was initiated by left renal pedicle occlusion with a XOR inhibitors might exhibit organ-protective effects by non-traumatic vascular clamp for 30 min, during which affecting purine metabolism. Indeed, administration of time the kidney was kept warm and moist. Occlusion was allopurinol maintained tissue concentrations of ATP, ad- confirmed visually by a color change to a paler shade. Then, enosine diphosphate (ADP), and adenosine 5′-monopho- the clamp was removed, and the kidney was observed for sphate (AMP), and preserved functional organ activity return of blood flow. (Cunningham et al. 1974;Lasleyetal.1988; Khatib et al. Kidney samples were obtained at different phases 2001). As XOR is a key player in purine metabolism, ex- of the operation (Table 1): (a) stationary phase (n = haustive metabolic analysis would contribute to elucidate 21), sacrifice at 60 min after drug administration the beneficial organ-protective effect of XOR inhibitors. with no ischemic damage (S groups); (b) ischemic To survey such global alterations of metabolic pathways, phase (n = 20), sacrifice at after 30 min left renal is- metabolomics is considered an appropriate approach. The chemia (I groups); (c) reperfusion phase (n = 21), metabolome is the global collection of small molecules sacrifice after 30 min of left renal ischemia followed (typically < 1500 Da; e.g., sugars, amino acids, organic by 30 min of reperfusion (R groups). Each sample acids, nucleotides, acylcarnitines, and lipids) in a cell or a group (n = 5 or 6) was named after the administered biologic specimen (Kalim and Rhee 2017). drug and sampling phase, e.g., Feb-I represents the Animal models of I/R injury have long been used to group treated with febuxostat that underwent 30 min evaluate metabolic fluctuations in organ disorders (Cun- of I/R injury. At the time of sacrifice, the left kidney ningham et al. 1974; Lasley et al. 1988; Khatib et al. was quickly weighed, snap-frozen in liquid nitrogen, 2001; Stromski et al. 1986; Stromski et al. 1988; Okabe and stored at − 80 °C, and blood was obtained via 1996). By investigating the influence of renal I/R on the puncture of the inferior vena cava. Plasma creatinine metabolome, I/R-induced metabolic changes can be elu- and urea were measured enzymatically and by the cidated. For instance, ischemia produces a rapid loss of urease-GLDH method, respectively, on a Hitachi high-energy phosphates and accumulation of hydrolysis 7180 auto-analyzer (Hitachi High-Technologies, products, including lactate, β-hydroxybutyrate, and cit- Tokyo, Japan). Rats were euthanized through cervical rate (Weiner 1987). dislocation under anesthesia. Tani et al. Molecular Medicine (2019)25:40 Table 1 Overview of the experimental set-up and plasma biochemical
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