Developing DILI models in zebrafish for screening of hepatoprotective agents

Abstract

Drug Induced Liver injury (DILI) is one of the causes of liver failure. In severe conditions, treatment for DILI is limited to liver transplant. Therefore, there is an urgent need for therapeutics that may counter DILI. Danio rerio, commonly known as zebrafish has emerged as a popular vertebrate model for drug screening. Using zebrafish, as a model system, we have successfully developed embryonic and adult zebrafish DILI models using acetaminophen (APAP) and Isoniazid (INH). Acetaminophen (paracetamol) is a known hepatotoxic molecule, extensively studied in multiple model systems and has become one of the major causes of acute liver failure. Isoniazid is a drug prescribed for Tuberculosis (TB). Since, TB is highly prevalent in India; hepatotoxicity due to INH has become a serious issue in the Indian sub-continent. Using fabp10a as a marker for liver, we have shown by multiple means that both drugs down-regulate the expression of fabp10a thus indicating damage. Other techniques were used to characterize both the DILI models and study their post-damage effects. Using the INH-induced liver-damage model, we have screened 15 small molecules for their hepatoprotective effect and have found one molecule as a potential candidate. These models can be used for further screening of novel small molecules and enable us to understand DILI as well as the mechanisms of small molecules that can revert it.