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...
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BMC
2019-08-01
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| Series: | Molecular Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s10020-019-0109-y |
| _version_ | 1818285582066909184 |
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| author | Takashi Tani Ken Okamoto Megumi Fujiwara Akira Katayama Shuichi Tsuruoka |
| author_facet | Takashi Tani Ken Okamoto Megumi Fujiwara Akira Katayama Shuichi Tsuruoka |
| author_sort | Takashi Tani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T01:10:59Z |
| format | Article |
| id | doaj.art-f45ce37d13a54e15b566432b41790116 |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-13T01:10:59Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-f45ce37d13a54e15b566432b417901162022-12-22T00:04:28ZengBMCMolecular Medicine1076-15511528-36582019-08-0125111310.1186/s10020-019-0109-yMetabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injuryTakashi Tani0Ken Okamoto1Megumi Fujiwara2Akira Katayama3Shuichi Tsuruoka4Department of Nephrology, Graduate School of Medicine, Nippon Medical SchoolDepartment of Metabolism and Nutrition, Graduate School of Medicine, Nippon Medical SchoolDepartment of Metabolism and Nutrition, Graduate School of Medicine, Nippon Medical SchoolDepartment of Metabolism and Nutrition, Graduate School of Medicine, Nippon Medical SchoolDepartment of Nephrology, Graduate School of Medicine, Nippon Medical SchoolAbstract 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.http://link.springer.com/article/10.1186/s10020-019-0109-yMetabolomeXanthine oxidoreductase inhibitorIschemia-reperfusion injury |
| spellingShingle | Takashi Tani Ken Okamoto Megumi Fujiwara Akira Katayama Shuichi Tsuruoka Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury Molecular Medicine Metabolome Xanthine oxidoreductase inhibitor Ischemia-reperfusion injury |
| title | Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury |
| title_full | Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury |
| title_fullStr | Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury |
| title_full_unstemmed | Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury |
| title_short | Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury |
| title_sort | metabolomics analysis elucidates unique influences on purine pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia reperfusion injury |
| topic | Metabolome Xanthine oxidoreductase inhibitor Ischemia-reperfusion injury |
| url | http://link.springer.com/article/10.1186/s10020-019-0109-y |
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