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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE117257 | GEO | 2021/07/14

REPOSITORIES: GEO

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Project description:BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK)1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated, via phosphorylation, in response to acetaminophen- or CCl4-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissues from patients and in mice with genetic deletion of JNK in hepatocytes. METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, non-steroidal anti-inflammatory drugs or autoimmune hepatitis), or patients without acute liver failure (controls), collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1Îhepa) or combination of Jnk1 and Jnk2 (JnkÎhepa), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray, and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes. RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to JnkÎhepa mice produced a greater level of liver injury than that observed in Jnk1Îhepa or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in JnkÎhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared to Jnk1Îhepa or control mice. Hepatocytes from JnkÎhepa mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of AMPK, total protein AMPK levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected JnkÎhepa and control mice from liver injury. CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects. Livers and primary hepatocytes were isolated from wild type and JNKÎhepa (Jnk1Îhepa/global Jnk2-/-) double-knockout mice and subjected to gene expression profiling.

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

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