期刊
JOURNAL OF APPLIED TOXICOLOGY
卷 32, 期 10, 页码 815-822出版社
WILEY
DOI: 10.1002/jat.1706
关键词
cytokines; DILI; MIP-2; IL-4; prostaglandin D2
类别
资金
- Ministry of Health, Labor and Welfare of Japan [H20-BIO-G001]
- Grants-in-Aid for Scientific Research [21390174] Funding Source: KAKEN
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patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn.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 mu g 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. Copyright (C) 2011 John Wiley & Sons, Ltd.
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