Involvement of Th2 cytokines in the mouse model of flutamide-induced acute liver injury

Satonori Higuchi; Masanori Kobayashi; Azusa Yano; Koichi Tsuneyama; Tatsuki Fukami; Miki Nakajima; Tsuyoshi Yokoi

doi:10.1002/jat.1706

Involvement of Th2 cytokines in the mouse model of flutamide-induced acute liver injury

J Appl Toxicol. 2012 Oct;32(10):815-22. doi: 10.1002/jat.1706. Epub 2011 Jul 7.

Authors

Satonori Higuchi¹, Masanori Kobayashi, Azusa Yano, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima, Tsuyoshi Yokoi

Affiliation

¹ Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.

PMID: 21735453
DOI: 10.1002/jat.1706

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patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn.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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Antagonists / adverse effects*
Animals
Antibodies, Monoclonal / therapeutic use
Antibodies, Neutralizing / therapeutic use
Antineoplastic Agents, Hormonal / adverse effects*
Chemical and Drug Induced Liver Injury / immunology*
Chemical and Drug Induced Liver Injury / metabolism
Chemical and Drug Induced Liver Injury / physiopathology
Chemical and Drug Induced Liver Injury / prevention & control
Cytokines / antagonists & inhibitors
Cytokines / genetics
Cytokines / metabolism*
Female
Flutamide / adverse effects*
GATA3 Transcription Factor / genetics
GATA3 Transcription Factor / metabolism
Gene Expression Regulation / drug effects
Interleukin-4 / antagonists & inhibitors
Interleukin-4 / metabolism
Liver / drug effects*
Liver / immunology
Liver / metabolism
Liver / physiopathology
Mice
Mice, Inbred BALB C
Oxidative Stress / drug effects
Prostaglandin D2 / adverse effects
Prostaglandin D2 / analogs & derivatives
Prostaglandin D2 / metabolism
RNA, Messenger / metabolism
STAT6 Transcription Factor / genetics
STAT6 Transcription Factor / metabolism
Th2 Cells / drug effects*
Th2 Cells / immunology
Th2 Cells / metabolism

Substances

Androgen Antagonists
Antibodies, Monoclonal
Antibodies, Neutralizing
Antineoplastic Agents, Hormonal
Cytokines
GATA3 Transcription Factor
Gata3 protein, mouse
RNA, Messenger
STAT6 Transcription Factor
Stat6 protein, mouse
Interleukin-4
13,14-dihydro-15-ketoprostaglandin D2
Flutamide
Prostaglandin D2