{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T06:22:11Z","timestamp":1774938131253,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech and App Biochem"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Methylglyoxal (MGO), a byproduct produced in the process of glycolysis, has cytotoxicity and forms advanced glycation endproducts (AGEs), which cause cell failure in several tissues. Because MGO is mainly removed by the action of glyoxalase I (GLO1), the activity of this enzyme contributes to the accumulation of MGO. We recently found that quinetazone, a diuretic pharmaceutical agent, has the potential to inhibit GLO1 activity. Therefore, we explored whether diuretics that have a similar structure to quinetazone inhibit GLO1. The inhibitory characteristics of diuretics with recombinant GLO1 were spectrophotometrically determined. Cell proliferation and accumulation of MGO\u2010derived AGEs were evaluated by MTT assay and Western blotting. Among the thiazide, thiazide\u2010like, and loop diuretics, metolazone and azosemide were found to inhibit GLO1 activity by 97% at 100\u00a0\u00b5M. Furthermore, we examined whether the substructures of these diuretics have inhibitory activity, quinazolinone or phenyltetrazole were determined to be the minimal structures of metolazone or azosemide required for inhibition of GLO1, respectively. In proximal renal tubule\u2010like HK\u20102 and vascular endothelial cell\u2010like EA.hy926 cells, these diuretics were shown to inhibit cell proliferation and induce accumulation of MGO\u2010derived AGEs. In contrast, the substructures of these diuretics that did not affect GLO1 activity did not cause these changes. Metolazone and azosemide have inhibitory effects against GLO1. Considering that these diuretics are clinically employed as pharmaceutical agents, high or prolonged dosages may contribute to pathogenesis through GLO1 inhibition, followed by MGO and\/or AGE accumulation.<\/jats:p>","DOI":"10.1002\/bab.2760","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T06:37:05Z","timestamp":1744180625000},"page":"1537-1545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metolazone and Azosemide, Clinically Utilized Diuretics, Exhibit Inhibitory Activity for Glyoxalase I"],"prefix":"10.1002","volume":"72","author":[{"given":"Masahiro","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Shujitsu University  Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Toyomura","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of 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