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| Status |
Public on Jul 14, 2021 |
| Title |
Establishment of a novel mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Drug-induced liver injury (DILI) 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. In experimental animals in vivo, however, TGZ has never induced liver injury. In this study, administration of BALB/c female mice with TGZ alone significantly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 6 h after the treatment. Co-administration of L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, unexpectedly restrained the TGZ-dependent increase of ALT and AST. Furthermore, the ratio of oxidative stress marker glutathione/disulfide glutathione was significantly decreased in TGZ-alone- and BSO plus TGZ-administered mice, and increased hepatic mRNA levels of inflammation- and oxidative stress-related factors in liver were observed. Subsequently, microarray studies were performed 6 h after administration and we discovered that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was activated in TGZ-induced liver injury. Moreover, the activation of JAK/STAT pathway promoted phosphorylation of STAT3 in TGZ-alone- and BSO plus TGZ-administered mice. Consequently, upregulation of STAT3 activation increased mRNA levels of its downstream genes. In conclusion, the present study is the first time to establish a mouse model of TGZ-induced liver injury with BALB/c mouse for assessing DILI in drug development and the activation of JAK/STAT signaling pathway might be as an important role involved in hepatotoxic mechanisms of TGZ.
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| Overall design |
Liver samples were collected 6 hours after the administration of TGZ or RGZ and vehicle. Total RNA was extracted from these liver samples and equal amount of RNA was pooled from 6 animals in each group.
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| Contributor(s) |
Jia R, Oda S, Tsuneyama K, Urano Y, Yokoi T |
| Citation missing |
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| Submission date |
Jul 17, 2018 |
| Last update date |
Jul 16, 2021 |
| Contact name |
Ru JIA |
| E-mail(s) |
newjiaru@med.nagoya-u.ac.jp
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| Phone |
+81-52-744-2110
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| Organization name |
Nagoya University Graduate School of Medicine
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| Department |
Department of Drug Safety Sciences
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| Street address |
65 Tsurumai-cho, Showa-ku
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| City |
Nagoya |
| State/province |
Aichi |
| ZIP/Postal code |
466-8550 |
| Country |
Japan |
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| Platforms (1) |
| GPL21163 |
Agilent-074809 SurePrint G3 Mouse GE v2 8x60K Microarray [Probe Name version] |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA481545 |
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