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 analogues. 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 analogues 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 hours 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 (298.6 ± 176.1 and 327.3 ± 102.9 Sigma-Frankel units/ml, respectively) versus corn oil controls (36.0 ± 11.3) and morphological changes in liver sections. Among the phenyl analogues, 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 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.

S-adenosyl-l-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry

“…All other chemicals were purchased from Sigma Chemical Company or Fisher Scientific (Pittsburgh, PA). Alanine aminotransferase (ALT) was assayed using a method based on the discontinued Sigma 505-P kit (Patel et al, 2012). …”

Cytotoxicity of 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) and analogues in wild type and CYP3A4 stably transfected HepG2 cells

“…In contrast, both 1-aminobenzotriazole (a non-specific CYP inhibitor) and troleandomycin (a CYP3A inhibitor) attenuated DCPT-induced hepatotoxicity. Additionally, an in vivo structure-activity relationship study with several analogues of DCPT found that hepatotoxicity is dependent on an intact TZD ring (Patel et al, 2011). …”

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

“…Since glitazones do not cause liver damage in laboratory animals, comparing these to new thiazolidinediones in order to research the mechanism of toxicity can be misleading (Patel et al, 2012). Further, it has been shown that thiazolidinediones with the N3-carboxymethyl substituent are nontoxic , which may be related to their metabolic stability due to avoidance of the ring opening, since compounds with this feature are more stable than their peers.…”