期刊
JOURNAL OF APPLIED TOXICOLOGY
卷 31, 期 7, 页码 671-677出版社
WILEY-BLACKWELL
DOI: 10.1002/jat.1622
关键词
BIRB-796; DNA microarray; hepatotoxicity; p38 MAPK; toxicogenomics
类别
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 (TM) 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 (C) 2011 John Wiley & Sons, Ltd.
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