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In Vitro Models to Study Hepatotoxicity

Department of Pediatric Pneumology and Immunology, david.groneberg{at}charite.de, Department of Medicine

Christian Grosse-Siestrup

Department of Comparative Medicine and Experimental Animal Sciences, Charité School of Medicine, Humboldt-University Berlin, Germany

Axel Fischer

Department of Pediatric Pneumology and Immunology

Drug discovery and development consists of a series of processes starting with the demonstration of pharmacologica l effects in experimental cell and animal models and ending with drug safety and effi cacy studies in patients. A main limitation is often the unacceptabl e level of toxicity with the liver as the primary target organ. Therefore, approaches to study hepatic toxicity in the early phase of drug discovery represent an important step towards rational drug development. A variety of in vitro liver model s have been developed in the past years. Next to their use in drug development, they can also be applied to study environmental toxins and their hepatotoxicity. The 3 main approache s are ex vivo isolated and perfused organ models, precision-cut liver slices and cell culture models. Although the advantage of whole organ perfusions is based on the assessment of physiologic parameters such as bile production and morphologic parameters such as tissue histology, cell culture models can be effi ciently used to assess cellular metabolism, cytotoxicity and genotoxicity. The advantage of precision-cut liver slices is based on the juxtaposition of cellular assays and tissue morphology. None of these model s can be compared as they all focus on different fi elds of hepatoxicolog y. For the future, the ideal setup for testing the hepatic toxicity of a new compound could of primary studies in cell or slice cultures to assess cellular effects and secondary studies using ex vivo perfused organs to examine gross organ function parameters and histology.

Key Words: Liver • toxicology • liver slices • cell culture • perfusion.

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