Evaluation of zebrafish as a model to predict human hepatotoxicity

Drug-induced hepatotoxicity is one of the most important causes of drug withdrawal in the process of drug discovery. The low correlation of the in vitro cytotoxicity studies, with human hepatotoxicity, especially in the early stages of drug discovery, make human hepatotoxicity difficult to predict. Therefore the finding of new methods and models to predict hepatotoxicity is a growing area of research. The zebrafish model has been extensively studied in the last decades for their ability to regenerate. Specifically, the liver is one of the organs with the highest regenerative capacity and research over the past 10 years have characterized many of the mechanisms that occur during this process leading to an important knowledge of the signaling pathways that govern zebrafish liver function and development. Therefore, because of the functional similarities as well as of development between the liver of zebrafish and mammals, we propose to analyze the potential of zebrafish for prediction of hepatotoxic agents. For this purpose, the following aspects have been studied: (i) the stage at which adult liver markers are expressed has been identified. (ii) Several techniques have been developed for assessing the hepatotoxicity of a compound in zebrafish. (iii) These techniques have been validated by testing different drugs. (iv) The results were compared with those obtained in mammals. Our results indicate that zebrafish embryos could be used as an alternative model in the drug development process complementing the information of in vitro models and mammals and providing pharmaceutical industry of new assays which might decrease the current huge gap between in vitro and in vivo assays.