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.

Figure 1

Structures of thiazolidinedione ring-containing compounds. Calculated log P values for DCPT and its analogues are shown in parenthesis.

Figure 2

Effect of thiazolidinedione ring modifications on serum alanine aminotransferase (ALT) levels in rats. Compounds were administered i.p. in corn oil. Controls received corn oil only (4 ml/kg). Values are means ± SE (N = 3–4). An asterisk (*) indicates that the value is significantly different (p < 0.05) from the corn oil control. Different letters within a treatment group indicate that the doses are significantly different (p < 0.05).

Figure 3

Effect of thiazolidinedione ring modifications on rat hepatic morphology. Representative photomicrographs are shown for the highest dose administered for each compound (1.0 mmol/kg for DPMT, 2-DCTD and 4-DCTD; 0.6 mmol/kg for DCTA; i.p. in corn oil). Controls received corn oil only (4 ml/kg). Vacuolated cells and swollen hepatocytes are indicated by white arrows and black arrows, respectively. Magnification is 400×.

Figure 4

Effect of phenyl ring modifications on serum alanine aminotransferase (ALT) levels in rats. Compounds were administered i.p. in corn oil. Controls received corn oil only (4 ml/kg). Values are means ± SE (N = 3–4). An asterisk (*) indicates that the value is significantly different (p < 0.05) from the corn oil control. Different letters within a treatment group indicate that the doses are significantly different (p < 0.05).

Figure 5

Effect of phenyl ring modifications on rat hepatic morphology. Representative photomicrographs are shown for the highest dose administered for each compound (1.0 mmol/kg; i.p. in corn oil). Controls received corn oil only (4 ml/kg). White arrowheads define regions of necrosis. Inflammatory cells are indicated by black arrowheads. Magnification is 400×.