Premium
Involvement of Th2 cytokines in the mouse model of flutamide‐induced acute liver injury
Author(s) -
Higuchi Satonori,
Kobayashi Masanori,
Yano Azusa,
Tsuneyama Koichi,
Fukami Tatsuki,
Nakajima Miki,
Yokoi Tsuyoshi
Publication year - 2012
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1706
Subject(s) - flutamide , liver injury , immune system , medicine , pharmacology , endocrinology , immunology , cancer , androgen receptor , prostate cancer
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patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn.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‐PGD 2 (DK‐PGD 2 ; 10 µg per mouse, i.p.) administration on flutamide‐induced acute liver injury. Coadministration of DK‐PGD 2 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. Copyright © 2011 John Wiley & Sons, Ltd.