A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor

✍ Scribed by Shunsuke Iwano; Yoshiji Asaoka; Hideo Akiyama; Satoko Takizawa; Hitoshi Nobumasa; Hisashi Hashimoto; Yohei Miyamoto

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 461 KB
• Volume: 31
• Category: Article
• ISSN: 0260-437X
• DOI: 10.1002/jat.1622

✦ Synopsis

ABSTRACT

BIRB‐796, a selective inhibitor of p38 mitogen‐activated protein kinase, has entered clinical trials for the treatment of autoimmune diseases. Levels of alanine transaminase, a biomarker of hepatic toxicity in clinical pathology, were found to be increased in Crohn's disease patients treated with BIRB‐796. The purpose of the present study was to clarify the molecular mechanism(s) of this hepatotoxicity. A toxicogenomic analysis using a highly sensitive DNA chip, 3D‐Gene™ Mouse Oligo chip 24k, indicated that BIRB‐796 treatment activated the nuclear factor (erythroid‐derived 2)‐like 2 signaling pathway, which plays a key role in the response to oxidative stress. A reactive intermediate of BIRB‐796 was detected by the glutathione‐trapping method using mouse and human liver microsomes. The production of this reactive metabolite in the liver may be one of the causes of BIRB‐796's hepatotoxicity. Copyright © 2011 John Wiley & Sons, Ltd.