title: Involvement of miRNAs in the early phase of halothane-induced liver injury.
abstract: MicroRNAs (miRNA) form a class of small non-coding RNA molecules that negatively regulate gene expression. Most cellular pathways are modulated by miRNAs. However, the pathophysiological role of miRNAs during drug-induced liver injury (DILI) remains largely unknown. In this study, the possible involvement of miRNAs in DILI caused by the hepatotoxic drug halothane (HAL) was investigated. Toward this purpose, miRNA microarray studies of HAL-induced liver injury were performed in mice at five different time points up to 24h after dosing. To exclude any pharmacological effects on miRNA expression, isoflurane was used as a low hepatotoxic drug because it is structurally similar to HAL. Approximately 30-50% of the miRNA expression levels changed more than two-fold at every time point. In silico biological pathway analysis was performed to predict the targeted genes. Consequently, the miRNA gene down-regulation that occurred 1h after HAL administration was primarily related to inflammation, immune systems and liver injury. Based on additional in silico analyses, we identified miR-106b. Subsequently target of miR-106b was investigated using liver samples from mice with HAL-induced liver injury. Among the predicted targets, we discovered that a signal transducer and activator of transcription 3 (STAT3) was particularly up-regulated beginning during the early phase of HAL-induced liver injury. Collectively, the suppressed miR-106b expression, as well as the subsequent up-regulation of STAT3, was critical for the pathogenesis of HAL-induced liver injury.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: sendo@stu.kanazawa-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Endo
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: azu.y02@stu.kanazawa-u.ac.jp.
authors.forename: Azusa
authors.initials: A
authors.lastname: Yano
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: tatsuki@p.kanazawa-u.ac.jp.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: nmiki@p.kanazawa-u.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; Department of Drug Safety Sciences, Nagoya University School of Medicine, Nagoya 466-8550, Japan. Electronic address: tyokoi@med.nagoya-u.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics; D005260:Female; D006221:Halothane; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D035683:MicroRNAs; C543896:Mirn106 microRNA, mouse; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000410:Alanine Transaminase; D006221:Halothane
keywords: Drug-induced liver injury; Halothane; STAT3; miR-106b; miRNA