title: Kupffer cell-mediated exacerbation of methimazole-induced acute liver injury in rats.
abstract: Methimazole (MTZ), an anti-thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ-induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine-mediated immune responses; however, there is little evidence for immune responses associated with MTZ-induced liver injury in rats. To investigate species differences in MTZ-induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high-mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune-related genes significantly increased in BSO- and MTZ-treated rats, but the change in Th2-related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK) proteins were accompanied by an increase in Toll-like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1-TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell-mediated immune responses are crucial factors for the exacerbation of MTZ-induced liver injury in rats, indicating apparent species differences in the immune-mediated exacerbation of liver injury between mice and rats.
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Akai
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences Tokushima University Graduate School, Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D019328:Buthionine Sulfoximine; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005682:Gadolinium / Q000494:pharmacology; D024243:HMGB1 Protein / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008713:Methimazole / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D013956:Antithyroid Agents; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D019328:Buthionine Sulfoximine; D008713:Methimazole; D005682:Gadolinium; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C038958:gadolinium chloride; D001663:Bilirubin
keywords: Kupffer cell; drug-induced liver injury; methimazole; rat; species differences