title: Involvement of immune- and inflammatory-related factors in flucloxacillin-induced liver injury in mice.
abstract: Drug-induced liver injury (DILI) is a serious problem in pre-clinical stages of drug development and clinical pharmacotherapy, but the pathogenesis of DILI has not been elucidated. Flucloxacillin (FLX), which is a β-lactam antibiotic of the penicillin class that is used widely in Europe and Australia, rarely causes DILI. Clinical features suggest that FLX-induced liver injury is caused by immune- and inflammatory-related factors, but the mechanism of FLX-induced liver injury is unknown. The purpose of this study was to elucidate the mechanisms of FLX-induced liver injury in vivo. Plasma alanine aminotransferase, aspartate aminotransferase and total-bilirubin levels were significantly elevated in FLX-administered mice [1000 mg kg(-1) , intraperitoneally (i.p.)]. Toll-like receptor 4 (TLR4) ligands, such as high-mobility group box 1 (HMGB1) and S100A8/A9, were significantly increased in FLX-administered mice, and inflammatory factors, such as interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein (MIP)-2, CXC chemokine-ligand-1 (CXCL1) and monocyte chemoattractant protein (MCP)-1, were also significantly elevated. IL-17-related transcriptional factors and cytokines were increased, and the administration of recombinant IL-17 (2 mg per body weight, i.p.) resulted in an exacerbation of the FLX-induced liver injury. TLR4-associated-signal transduction may be involved in FLX-induced liver injury, and IL-17 is an exacerbating factor.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Takai
authors.forename: Satonori
authors.initials: S
authors.lastname: Higuchi
authors.forename: Azusa
authors.initials: A
authors.lastname: Yano
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D040501:Calgranulin A / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005436:Floxacillin / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D024243:HMGB1 Protein / Q000097:blood; D020381:Interleukin-17 / Q000494:pharmacology; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D050050:Protein Carbonylation / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood
chemical_list: D000900:Anti-Bacterial Agents; D040501:Calgranulin A; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D020381:Interleukin-17; D064568:S100 Calcium Binding Protein beta Subunit; C086145:S100a8 protein, mouse; C579159:S100b protein, mouse; D005436:Floxacillin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D001663:Bilirubin
keywords: IL-17; flucloxacillin; inflammatory; toll-like receptor 4 (TLR4)