title: Involvement of Th2 cytokines in the mouse model of flutamide-induced acute liver injury.
abstract: Drug-induced liver injury is a growing concern for pharmaceutical companies and patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn. Flutamide rarely causes liver dysfunction in humans, and immune allergic reactions have been suggested in some cases. In this study, we investigated the mechanisms of flutamide-induced liver injury in BALB/c mice. Plasma alanine aminotransferase and aspartate aminotransferase levels were significantly increased 3, 6 and 9 h after flutamide (1500 mg kg⁻¹ , p.o.) administration. The biomarker for oxidative stress was not changed, but Th2-dominant immune-related factors, such as interleukin (IL)-4, IL-5, STAT6 and GATA-binding protein (GATA)-3, were induced in flutamide-administered mice. The pre-administration of monoclonal-IL-4 antibody suppressed the hepatotoxicity of flutamide. In addition, we investigated the effect of 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂; 10 µg per mouse, i.p.) administration on flutamide-induced acute liver injury. Coadministration of DK-PGD₂ and flutamide resulted in a significant increase in alanine aminotransferase and a remarkable increase of macrophage inflammatory protein-2. In conclusion, we demonstrated that flutamide-induced acute liver injury is mediated by Th2-dominant immune responses in mice.
authors: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors: Satonori
authors: S
authors: Higuchi
authors: Masanori
authors: M
authors: Kobayashi
authors: Azusa
authors: A
authors: Yano
authors: Koichi
authors: K
authors: Tsuneyama
authors: Tatsuki
authors: T
authors: Fukami
authors: Miki
authors: M
authors: Nakajima
authors: Tsuyoshi
authors: T
authors: Yokoi
mesh_terms: D000726:Androgen Antagonists / Q000009:adverse effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005485:Flutamide / Q000009:adverse effects*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D015230:Prostaglandin D2 / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; C034832:13,14-dihydro-15-ketoprostaglandin D2; D005485:Flutamide; D015230:Prostaglandin D2