{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:41:32Z","timestamp":1760575292764,"version":"build-2065373602"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,2,21]],"date-time":"2011-02-21T00:00:00Z","timestamp":1298246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Glitazones, used for type II diabetes, have been associated with liver damage in humans. A structural feature known as a 2,4\u2010thiazolidinedione (TZD) ring may contribute to this toxicity. TZD rings are of interest since continued human exposure via the glitazones and various prototype drugs is possible. Previously, we found that 3\u2010(3,5\u2010dichlorophenyl)\u20102,4\u2010thiazolidinedione (DCPT) was hepatotoxic in rats. To evaluate the importance of structure on DCPT toxicity, we therefore studied two series of analogs. The TZD ring was replaced with: a mercaptoacetic acid group {[[[(3,5\u2010dichlorophenyl)amino]carbonyl]thio]acetic acid, DCTA}; a methylated TZD ring [3\u2010(3,5\u2010dichlorophenyl)\u20105\u2010methyl\u20102,4\u2010thiazolidinedione, DPMT]; and isomeric thiazolidinone rings [3\u2010(3,5\u2010dichlorophenyl)\u20102\u2010 and 3\u2010(3,5\u2010dichlorophenyl)\u20104\u2010thiazolidinone, 2\u2010DCTD and 4\u2010DCTD, respectively]. The following phenyl ring\u2010modified analogs were also tested: 3\u2010phenyl\u2010, 3\u2010(4\u2010chlorophenyl)\u2010, 3\u2010(3,5\u2010dimethylphenyl)\u2010 and 3\u2010[3,5\u2010bis(trifluoromethyl)phenyl]\u20102,4\u2010thiazolidinedione (PTZD, CPTD, DMPT and DFMPT, respectively). Toxicity was assessed in male Fischer 344 rats 24\u2009h after administration of the compounds. In the TZD series only DPMT produced liver damage, as evidenced by elevated serum alanine aminotransferase (ALT) activities at 0.6 and 1.0\u2009mmol\u2009kg<jats:sup>\u22121<\/jats:sup> (298.6\u2009\u00b1\u2009176.1 and 327.3\u2009\u00b1\u2009102.9 Sigma\u2010Frankel units ml<jats:sup>\u22121<\/jats:sup>, respectively) vs corn oil controls (36.0\u2009\u00b1\u200911.3) and morphological changes in liver sections. Among the phenyl analogs, hepatotoxicity was observed in rats administered PTZD, CPTD and DMPT; with ALT values of 1196.2\u2009\u00b1\u2009133.6, 1622.5\u2009\u00b1\u2009218.5 and 2071.9\u2009\u00b1\u2009217.8, respectively (1.0\u2009mmol\u2009kg<jats:sup>\u22121<\/jats:sup> doses). Morphological examination revealed severe hepatic necrosis in these animals. Our results suggest that hepatotoxicity of these compounds is critically dependent on the presence of a TZD ring and also the phenyl substituents. Copyright \u00a9 2011 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.1639","type":"journal-article","created":{"date-parts":[[2011,2,27]],"date-time":"2011-02-27T12:49:05Z","timestamp":1298810945000},"page":"108-117","source":"Crossref","is-referenced-by-count":6,"title":["Effect of structural modifications on 3\u2010(3,5\u2010dichlorophenyl)\u20102,4\u2010thiazolidinedione\u2010induced hepatotoxicity in Fischer 344 rats"],"prefix":"10.1002","volume":"32","author":[{"given":"Niti N.","family":"Patel","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of the Sciences in Philadelphia  Philadelphia PA 19104 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine M.","family":"Crincoli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of the Sciences in Philadelphia  Philadelphia PA 19104 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas M.","family":"Frederick","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of the Sciences in Philadelphia  Philadelphia PA 19104 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruy","family":"Tchao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of the Sciences in Philadelphia  Philadelphia PA 19104 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Harvison","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of the Sciences in Philadelphia  Philadelphia PA 19104 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,2,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02980259"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.104.002683"},{"key":"e_1_2_6_4_1","unstructured":"BrouwerWG BlemAR.1987.Substituted thiazolidinones useful as plant growth regulators. 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