Precision-cut liver slices as a model for intrinsic and idiosyncratic drug-induced liver injury

PhD ceremony: Mr. M. Hadi, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Precision-cut liver slices as a model for intrinsic and idiosyncratic drug-induced liver injury

Promotor(s): prof.dr. G.M.M. Groothuis

Faculty: Mathematics and Natural Sciences

Severe liver toxicity is one of the main reasons why drugs are taken from the market. This liver toxicity was not predicted in preclinical studies, because nowadays no adequate translational strategies are available to adequately predict the safety of new drugs. Mackenzie Hadi developed novel predictive screening tools and biomarkers for better prediction of liver toxicity. His research contributes to the 3Rs (refinement, reduction and replacement) of animal experiment

Hadi developed an in vitro model with precision-cut liver slices (PCLS) from human and animal liver for intrinsic and idiosyncratic drug-induced liver injury (DILI). These PCLS retain the normal tissue architecture of an intact liver and normal cell-to-cell interactions. Although intrinsic DILI sometimes can be detected during preclinical studies, idiosyncratic DILI is up to now almost unpredictable as it occurs in a small minority of the patients taking the drug (<1 in 1000-10.000 people). Based on the hypothesis that this idiosyncratic DILI may arise when drugs are taken during inflammatory episodes, Hadi exposed PCLS from rat, mouse and human liver to a non-toxic dose of drugs known to cause IDR in patients and at the same time to an inflammation-inducing agent, LPS. Indeed under these circumstances liver toxicity could be found in the majority of the samples, indicating that this model could predict idiosyncratic DILI in vitro. Moreover marked species differences in drug metabolism and intrinsic and idiosyncratic toxicity were identified by Hadi. This underlines the importance of using human tissue in addition to animal experiments for prediction of toxicity, for the elucidation of the mechanisms of intrinsic and idiosyncratic DILI in humans and also to reduce the number of experimental animals for research and drug development.