title: MicroRNA-877-5p is involved in the trovafloxacin-induced liver injury.
abstract: Trovafloxacin develops severe hepatotoxicity; however, the underlying mechanism of the trovafloxacin-induced liver injury has not been cleared. It has been shown that microRNAs (miRNAs) can be involved in the development of drug-induced liver injuries. We performed a miRNA microarray analysis to identify hepatic miRNAs that were induced or reduced by trovafloxacin in mice. It was demonstrated that miR-877-5p was the most increased miRNA in the mouse liver 24h after the trovafloxacin administration. To investigate the role of miR-877-5p in the liver, we established miR-877-5p-overexpressed HepG2 cells. Microarray analysis detected altered expressions in 2077 (>2-fold) and 1547 (<0.5-fold) genes in the miR-877-5p overexpressing cells compared to the mock cells. Especially, SLCO4C1, PEPCK, MT1M, HIST1H2BM, LGI1, and PLA2G2A were markedly increased or decreased in the miR-877-5p overexpressing cells. We conducted a correlation analysis between the expression levels of miR-877-5p and the six genes in eight miR-877-5p stably-expressed clones. It was shown that the PEPCK expression levels were correlated with miR-877-5p expression levels. PEPCK is associated with development of apoptotic cell death; therefore, the increased miR- 877-5p-induced PEPCK can be a trigger that is involved in the development of trovafloxacin-induced liver injury.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Mitsugi
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D024841:Fluoroquinolones / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D009287:Naphthyridines / Q000633:toxicity*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C570298:MIRN877 microRNA, human; C000614106:MIRN877 microRNA, mouse; D035683:MicroRNAs; D009287:Naphthyridines; C080163:trovafloxacin; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: Drug-induced liver injury; PEPCK; Trovafloxacin; miR-877-5p; miRNA