title: A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor.
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.
authors.affiliation: Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Iwano
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Hideo
authors.initials: H
authors.lastname: Akiyama
authors.forename: Satoko
authors.initials: S
authors.lastname: Takizawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nobumasa
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002853:Chromatography, Liquid; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles / Q000633:toxicity*; D012333:RNA, Messenger; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D043922:Toxicogenetics / Q000379:methods; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds
chemical_list: D005978:Glutathione; D051267:NF-E2-Related Factor 2; D009281:Naphthalenes; D011720:Pyrazoles; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; C495636:Nfe2l2 protein, mouse; C452139:doramapimod; D010671:Phenylurea Compounds