title: A novel mouse model for phenytoin-induced liver injury: involvement of immune-related factors and P450-mediated metabolism.
abstract: Drug-induced liver injury is an important issue for drug development and clinical drug therapy; however, in most cases, it is difficult to predict or prevent these reactions due to a lack of suitable animal models and the unknown mechanisms of action. Phenytoin (DPH) is an anticonvulsant drug that is widely used for the treatment of epilepsy. Some patients who are administered DPH will suffer symptoms of drug-induced liver injury characterized by hepatic necrosis. DPH-induced liver injury occurs in 1 in 1000 or 1 in 10 000 patients. Clinically, 75% of patients who develop liver injury develop a fever and 63% develop a rash. In this study, we established a mouse model for DPH-induced liver injury and analyzed the mechanisms for hepatotoxicity in the presence of immune-related or inflammation-related factors and metabolic activation. Female C57BL/6 mice were administered DPH for 5 days in combination with L-buthionine-S,R-sulfoximine. Then, the plasma alanine aminotransferase (ALT) levels were increased, hepatic lesions were observed during the histological evaluations, the hepatic glutathione levels were significantly reduced, and the oxidative stress marker levels were significantly increased. The inhibition of cytochrome P450-dependent oxidative metabolism significantly suppressed the elevated plasma ALT levels and depleted hepatic glutathione. Among the innate immune factors, the hepatic mRNA levels of NACHT, LRR, pyrin domain-containing protein 3, interleukin-1β, and damage-associated molecular patterns were significantly increased. Prostaglandin E₁ treatment ameliorated the hepatic injury caused by DPH. In conclusion, cytochrome P450-dependent metabolic activation followed by the stimulation of the innate immune responses is involved in DPH-induced liver injury.
authors.affiliation: * Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Eita
authors.initials: E
authors.lastname: Sasaki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Azumi
authors.initials: A
authors.lastname: Iida
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
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; D019328:Buthionine Sulfoximine; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D058847:Inflammasomes / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018384:Oxidative Stress; D010672:Phenytoin / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D058847:Inflammasomes; D018836:Inflammation Mediators; D019328:Buthionine Sulfoximine; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione
keywords: IL-17; glutathione; hepatotoxicity; mouse model.; phenytoin