title: Immunization with amodiaquine-modified hepatic proteins prevents amodiaquine-induced liver injury.
abstract: Amodiaquine (AQ) has been reported to cause severe idiosyncratic drug-induced liver injury (IDILI) in humans. There is evidence that AQ-induced idiosyncratic drug reactions are immune mediated, but their exact mechanism is not fully understood. AQ is oxidized to a reactive quinoneimine metabolite, and it has been suggested that covalent binding of this metabolite leads to an immune response and liver injury. A valid animal model would greatly facilitate mechanistic studies. This laboratory had previously reported that chronic treatment of C57BL/6 mice with AQ induced a delayed-onset mild liver injury that appeared to resolve with immune tolerance. The current study attempted to prevent immune tolerance by first immunizing mice with AQ-modified hepatic proteins. This study used a soluble adjuvant known as 'covax' that has been reported to produce a better immune response than Freund's adjuvant. After immunization, the mice were treated with 0.2% AQ in food for 5 weeks, as previously done. Paradoxically, the immunization protected animals from AQ-induced liver injury instead of exacerbating it. Consistent with this protection, immunization also appeared to lead to a tolerogenic response with an increase in myeloid derived suppressor cells, M2 macrophages, and FoxP3(+) T-cells. This attempt to develop an animal model of IDILI was unsuccessful and illustrated the complexity of the immune response and the difficulty of inducing a sustained immune response in the liver. It also reinforces the hypothesis that the key determinant of IDILI is immune tolerance.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto , Toronto, Ontario , Canada.
authors.forename: Alastair
authors.initials: A
authors.lastname: Mak
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007114:Immunization; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000655:Amodiaquine
keywords: Adjuvant; animal model; drug-induced liver injury; idiosyncratic adverse drug reaction; reactive metabolite