Mechanism-based selection of compounds for the development of innovative in vitro approaches to hepatotoxicity studies in the LIINTOP project

Abstract

The 6th European Framework Programme project LIINTOP was specifically raised to optimise and provide established protocols and experimental in vitro models for testing intestinal and liver absorption, metabolism and toxicity of molecules of pharmacological interest. It has been focused on some of the most promising existing liver and intestine in vitro models with the aim of further improving their performance and thus taking them to a pre-normative research stage. Regarding the specific area of the liver, a first basic approach was the optimisation of in vitro hepatic models and the development and optimisation of in vitro approaches for toxicity screening. New advanced technologies have been proposed and developed in order to determine cellular and molecular targets as endpoints of drug exposure. A key issue in the development and optimisation of in vitro hepatotoxicity screening methods was the selection of structurally diverse suitable hepatotoxic reference model compounds to be tested. To this end, a number of solid selection criteria were defined (drugs preferably than chemical agents, well-documented hepatotoxicity in man and well-defined mechanism/s of hepatotoxicity, commercially available no volatile compounds with unequivocal CAS number and chemical structure), the strategy followed, including all resources consulted, is described and the selected compounds are extensively illustrated.