Establishment of a mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism.

Abstract

Drug-induced liver injury is a major problem in drug development and clinical drug therapy. Troglitazone (TGZ), a thiazolidinedione antidiabetic drug for the treatment of type II diabetes mellitus, was found to induce rare idiosyncratic severe liver injury in patients, which led to its withdrawal in 2000. However, in normal experimental animals in vivo TGZ has never induced liver injury. To explore TGZ hepatotoxic mechanism, we established a novel mouse model of TGZ-induced liver injury. Administration of BALB/c female mice with a single intraperitoneal TGZ dose (300 mg/kg) significantly elevated alanine aminotransferase and aspartate aminotransferase levels 6 hours after the treatment. The ratio of oxidative stress marker glutathione/disulfide glutathione was significantly decreased. The increased hepatic mRNA levels of inflammation- and oxidative stress-related factors were observed in TGZ-treated mice. Subsequently, hepatic transcriptome profiles of TGZ-exposed liver were compared with those of non-hepatotoxic rosiglitazone. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was activated in TGZ-induced liver injury. The activation of the JAK/STAT pathway promoted phosphorylation of STAT3 in TGZ-treated mice. Consequently, upregulation of STAT3 activation increased mRNA levels of its downstream genes. In conclusion, a single intraperitoneal dose of TGZ exposure could induce liver injury in BALB/c female mice and, by a hepatic transcriptomic analysis, we found that the activation of JAK/STAT pathway might be related to TGZ-induced hepatotoxicity.

• Authors: Ru Jia, Shingo Oda, Koichi Tsuneyama, Yuya Urano, Tsuyoshi Yokoi
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) Vol. 39 Issue 11 Pg. 1541-1556 (11 2019) ISSN: 1099-1263 [Electronic] England
• PMID: 31294483 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons, Ltd.

Chemical References

• Hypoglycemic Agents
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Janus Kinases
• Troglitazone

Topics

• Animals
• Chemical and Drug Induced Liver Injury (enzymology, pathology)
• Disease Models, Animal
• Female
• Hypoglycemic Agents (toxicity)
• Janus Kinases (genetics, metabolism)
• Liver (drug effects, metabolism, pathology)
• Mice, Inbred BALB C
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction
• Transcription, Genetic (drug effects)
• Troglitazone (toxicity)