Applications of in vitro and in vivo hepatic models to investigate drug and chemical toxicity

Abstract

Hepatocytes are the primary cell of the liver, performing the majority of its unique functions, including the metabolism and clearance of xenobiotics and as a result, the liver plays an important role in drug and chemical toxicity. There are numerous in vitro and in vivo models currently used to investigate drug and chemical toxicity. The application of these models was used to investigate drug‐ and chemical‐induced lipid dysregulation in hepatocytes and to determine the hepatic toxicity of an ionic liquid found in the environment, 3‐methyl‐1‐octyl‐1H‐imidazol‐3‐ium (M8OI). Hepatocyte‐like B‐13/H cells have previously been shown to express functional metabolising enzymes and have been suggested as an alternative to primary hepatocytes for in vitro toxicity screening. B‐13/H cells accumulated lipids in response to being exposed to fatty acids and the liver X receptor activator T0901317. Phospholipidosis, a lipid storage disorder characterised by the accumulation of phospholipids was also observed in B‐13/H cells exposed to cationic amphiphilic drugs. This effect was reduced by the over‐ expression of lysosomal phospholipase A2. M8OI induced apoptotic cell death in several in vitro hepatic models including primary human hepatocytes and the inhibition of mitochondrial oxidative phosphorylation was determined as the cause of this toxic effect. Hepatic injury and glycogen depletion was observed in in vivo mouse models exposed to M8OI. Finally, M8OI was shown to be metabolised in primary human hepatocytes and in mice to less toxic hydroxyl and carboxyl metabolites. These data indicate that B‐13/H cells are an effective in vitro model in which to study the hepatic lipid dysregulation in response to drugs and chemicals and M8OI induces hepatotoxic effects in vitro and in vivo models.