Chapter 25: Animal Models of Idiosyncratic, Drug-Induced Liver Injury

Idiosyncratic drug reactions present a human health problem and are a major economic issue for the pharmaceutical industry. The liver has been a major target of these reactions, for which the mechanisms remain poorly understood. Several hypotheses are currently entertained, and these include roles for drug metabolism or transport polymorphisms, failure of adaptation to hepatic stresses imposed by drugs, mitochondrial toxicity, acquired immunity, and inflammatory stress during drug therapy. Proof for any of these hypotheses has been difficult to generate in humans due to the typical infrequency of the reactions and other factors. Accordingly, animal models that recapitulate drug-induced liver injury would have value in predicting which drug candidates have idiosyncrasy potential and/or in understanding mechanisms that could lead to predictive, high-throughput, in vitro assays. Animal models in which genetic and/or environmental conditions are adjusted to render animals sensitive to liver injury from drugs that produce human idiosyncratic reactions are beginning to emerge and are the focus of this chapter.