title: Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset.
abstract: Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1(-/-) mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine and.
authors.forename: Imir G
authors.initials: IG
authors.lastname: Metushi
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.forename: Dzana
authors.initials: D
authors.lastname: Dervovic
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lobach
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000380:Agranulocytosis / Q000276:immunology*; D000410:Alanine Transaminase / Q000378:metabolism; D000655:Amodiaquine / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein; D000655:Amodiaquine; D000410:Alanine Transaminase
keywords: Covalent binding; drug-induced liver injury; immune tolerance; immune-mediated; reactive metabolite