title: Th2 cytokine-mediated methimazole-induced acute liver injury in mice.
abstract: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical practice. The pathogenesis of DILI usually involves the participation of the parent drug or metabolites that either affect cellular function or elicit an immune response. However, the mechanisms leading to DILI are unknown in most cases. Methimazole (MTZ) is used as an antithyroid drug and is well known to have induced liver injuries such as cholestatic hepatitis in a small number of human cases. Immune-mediated reactions were also suggested to play a role in MTZ-induced acute liver injury, but the mechanism underlying this process has not been elucidated. To address this issue, we measured plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hepatic glutathione levels, hepatic expression of CD4⁺ Th cell-related transcriptional factors, cytokines and chemokines, plasma interleukin (IL)-4 levels and histopathological changes in the liver following MTZ (450 mg kg⁻¹ , p.o.) administration in mice. The hepatic expression of mRNA for Th2 cell-related factors, such as GATA-binding protein, macrophage inflammatory protein-2 (MIP-2) and plasma IL-4 levels, as well as plasma AST and ALT levels, was significantly increased in mice treated with MTZ. These changes were markedly enhanced by pre-treatment with L-buthionine sulfoximine (3 mmol kg⁻¹, i.p.) and MTZ (15 mg kg⁻¹, p.o.). Neutralization of IL-4 using a monoclonal anti-mouse IL-4 antibody (100 µg/mouse, single i.p.) suppressed the hepatotoxic effect of MTZ. In conclusion, this report is the first to demonstrate that Th2 cytokine-mediated immune responses are involved in MTZ-induced acute liver injury in mice.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Satonori
authors.initials: S
authors.lastname: Higuchi
authors.forename: Mika
authors.initials: M
authors.lastname: Ide
authors.forename: Satomi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D000963:Antimetabolites / Q000009:adverse effects; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000009:adverse effects*; D019328:Buthionine Sulfoximine / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008713:Methimazole / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000963:Antimetabolites; D013956:Antithyroid Agents; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D012333:RNA, Messenger; D015847:Interleukin-4; D019328:Buthionine Sulfoximine; D008713:Methimazole; D005978:Glutathione