title: Effect of structural modifications on 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione-induced hepatotoxicity in Fischer 344 rats.
abstract: Glitazones, used for type II diabetes, have been associated with liver damage in humans. A structural feature known as a 2,4-thiazolidinedione (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-(3,5-dichlorophenyl)-2,4-thiazolidinedione (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-dichlorophenyl)amino]carbonyl]thio]acetic acid, DCTA}; a methylated TZD ring [3-(3,5-dichlorophenyl)-5-methyl-2,4-thiazolidinedione, DPMT]; and isomeric thiazolidinone rings [3-(3,5-dichlorophenyl)-2- and 3-(3,5-dichlorophenyl)-4-thiazolidinone, 2-DCTD and 4-DCTD, respectively]. The following phenyl ring-modified analogs were also tested: 3-phenyl-, 3-(4-chlorophenyl)-, 3-(3,5-dimethylphenyl)- and 3-[3,5-bis(trifluoromethyl)phenyl]-2,4-thiazolidinedione (PTZD, CPTD, DMPT and DFMPT, respectively). Toxicity was assessed in male Fischer 344 rats 24 h 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 mmol kg(-1) (298.6 ± 176.1 and 327.3 ± 102.9 Sigma-Frankel units ml(-1) , respectively) vs corn oil controls (36.0 ± 11.3) 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 ± 133.6, 1622.5 ± 218.5 and 2071.9 ± 217.8, respectively (1.0 mmol kg(-1) 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Niti N
authors.initials: NN
authors.lastname: Patel
authors.forename: Christine M
authors.initials: CM
authors.lastname: Crincoli
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Frederick
authors.forename: Ruy
authors.initials: R
authors.lastname: Tchao
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Harvison
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000633:toxicity; D008099:Liver / Q000187:drug effects*; D008107:Liver Diseases / Q000209:etiology* / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: C532666:3-(3,5-dichlorophenyl)-2,4-thiazolidinedione; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D000410:Alanine Transaminase