title: Acyl-glucuronide as a Possible Cause of Trovafloxacin-Induced Liver Toxicity: Induction of Chemokine (C-X-C Motif) Ligand 2 by Trovafloxacin Acyl-glucuronide.
abstract: Trovafloxacin is an antibiotic that was withdrawn from the market relatively soon after its release due to the risk of hepatotoxicity. Trovafloxacin is mainly metabolized to its acyl-glucuronide by uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1. In this study, we examined whether the acyl-glucuronide is involved in the development of hepatotoxicity. A UGT1A1-induced cell model was developed and the toxicity of trovafloxacin acyl-glucuronide was evaluated. The UGT1A1-induced cell model was developed by treating HepG2 cells with chrysin for 48 h. Chemokine (C-X-C motif) ligand 2, a cytokine involved in drug-induced liver injury, was uniquely induced by trovafloxacin in the UGT1A1-induced HepG2 cells. Induction of UGT1A1 resulted in a decrease in cell viability. An in vivo animal study further demonstrated the importance of UGT1A1 in the trovafloxacin-induced liver toxicity. Although the complete mechanism of trovafloxacin-induced liver injury is still unknown, trovafloxacin acyl-glucuronide can be involved in the development of toxic reactions in vitro and in vivo.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Kitasato University.
authors.forename: Ryo
authors.initials: R
authors.lastname: Mitsugi
authors.forename: Kyohei
authors.initials: K
authors.lastname: Sumida
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujie
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D024841:Fluoroquinolones / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008822:Mice, Transgenic; D009287:Naphthyridines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D054426:Chemokine CXCL2; D005419:Flavonoids; D024841:Fluoroquinolones; D020719:Glucuronides; D014453:Glucuronosyltransferase; D009287:Naphthyridines; D012333:RNA, Messenger; D000099148:UGT1A1 Enzyme; C043561:chrysin; C080163:trovafloxacin