What have we learned from animal models of idiosyncratic, drug-induced liver injury?
- 4 May 2020
- journal article
- review article
- Published by Taylor & Francis Ltd in Expert Opinion on Drug Metabolism & Toxicology
- Vol. 16 (6), 475-491
- https://doi.org/10.1080/17425255.2020.1760246
Abstract
Introduction. Idiosyncratic, drug-induced liver injury (IDILI) continues to plague patients and restrict the use of drugs that are pharmacologically effective. Mechanisms of IDILI are incompletely understood, and a better understanding would reduce speculation and could help to identify safer drug candidates preclinically. Animal models have the potential to enhance knowledge of mechanisms of IDILI. Areas covered. Numerous hypotheses have emerged to explain IDILI pathogenesis, many of which center on the roles of the innate and/or adaptive immune systems. Animal models based on these hypotheses are reviewed in the context of their contributions to understanding of IDILI and their limitations. Expert opinion. Animal models of IDILI based on an activated adaptive immune system have to date failed to reproduce major liver injury that is of most concern clinically. The only models that have so far resulted in pronounced liver injury are based on the multiple determinant hypothesis or the inflammatory stress hypothesis. The liver pathogenesis in IDILI animal models involves various leukocytes and immune mediators such as cytokines. Insights from animal models are changing the way we view IDILI pathogenesis and are leading to better approaches to preclinical prediction of IDILI potential of new drug candidates.Keywords
Funding Information
- National Institute for Diabetes and Digestive and Kidney Diseases (R01DK112695)
This publication has 124 references indexed in Scilit:
- Neutrophil–cytokine interactions in a rat model of sulindac-induced idiosyncratic liver injuryToxicology, 2011
- Amiodarone Exposure During Modest Inflammation Induces Idiosyncrasy-like Liver Injury in Rats: Role of Tumor Necrosis Factor-alphaToxicological Sciences, 2011
- Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II AllelesGastroenterology, 2011
- Natural Killer Cells Mediate Severe Liver Injury in a Murine Model of Halothane HepatitisToxicological Sciences, 2011
- Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatmentToxicology, 2010
- Trovafloxacin Enhances TNF-Induced Inflammatory Stress and Cell Death Signaling and Reduces TNF Clearance in a Murine Model of Idiosyncratic HepatotoxicityToxicological Sciences, 2009
- Synergistic drug–cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicityToxicology and Applied Pharmacology, 2009
- Hepatotoxic Interaction of Sulindac with Lipopolysaccharide: Role of the Hemostatic SystemToxicological Sciences, 2008
- Coexposure of Mice to Trovafloxacin and Lipopolysaccharide, a Model of Idiosyncratic Hepatotoxicity, Results in a Unique Gene Expression Profile and Interferon Gamma–Dependent Liver InjuryToxicological Sciences, 2008
- Effect of polyI:C cotreatment on halothane-induced liver injury in miceJournal of Hepatology, 2008