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.

A Combination of In Silico ADMET Prediction, In Vivo Toxicity Evaluation, and Potential Mechanism Exploration of Brucine and Brucine N-oxide—A Comparative Study

“…At the same time, endoplasmic reticulum stress-induced upregulation of STARD1 could promote APAP-induced acute liver failure via SH3BP5 and phosphorylation of JNK1 and JNK2 [ 42 , 43 ]. Troglitazone-induced hepatotoxicity is related to the activation of JAK/STAT pathway [ 44 ]. As overwhelming oxidative stress plays a critical role in DILI, signal transduction pathways activated/inhibited during oxidative stress proved to be one of the critical factors in DILI [ 45 , 46 ].…”

Structure-Based Reactivity Profiles of Reactive Metabolites with Glutathione

“…In recent years, screening the formation of metabolites has been of considerable importance in the early stages of drug discovery. , There are increasing clinical reports of drug metabolism-induced organ toxicities. − For example, the glucose-lowering drug troglitazone and anti-depressant nefazodone have been withdrawn from the market successively as they have been shown to produce reactive metabolic intermediates leading to severe hepato­toxicity. Some medicinal plant ingredients, such as aristolochia acid, pyrrolizidine alkaloids, and isoquinoline alkaloids, have also been shown to produce reactive metabolites with toxicity.…”

In silico prediction of drug‐induced liver injury with a complementary integration strategy based on hybrid representation

“…Drugs containing such structures, such as troglitazone, pioglitazone and rosiglitazone, have been reported to be associated with hepatotoxicity. Troglitazone was withdrawn from the market in the United States in 2000 after causing severe hepatotoxicity [58]. These compounds are common hypoglycemic agents and often used clinically with hepatoprotective drugs because of the potential risk of liver injury.…”