title: IL-4 mediates dicloxacillin-induced liver injury in mice.
abstract: Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2).
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Satonori
authors.initials: S
authors.lastname: Higuchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Yoshikawa
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 / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D019138:Antibodies, Blocking / Q000494:pharmacology; D001663:Bilirubin / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004009:Dicloxacillin / Q000633:toxicity*; D005260:Female; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D019138:Antibodies, Blocking; D012333:RNA, Messenger; D015847:Interleukin-4; C034832:13,14-dihydro-15-ketoprostaglandin D2; D004009:Dicloxacillin; D000410:Alanine Transaminase; D001663:Bilirubin; D015230:Prostaglandin D2