Hepatotoxicity is one of the major reason for drug withdrawal from pharmaceutical development and clinical use. In vitro hepatotoxicity assays mimic in vivo tissue studies and in turn provide a reliable tool for safety assessment in the early stages of drug development. Creative Bioarray has developed standard and innovative in vitro models to address the need for early stage hepatotoxicity testing.
Liver Slices
Liver tissue slices can be a beneficial model as they contain all the cell types found in vivo, have good in vitro/in vivo correlation of xenobiotic metabolism, and maintain zone-specific cytochrome activity and toxicity mechanisms.
Immortalized Cell Lines
Common used immortalized liver-derived cell lines are Fa2N-4, HepG2, Hep3B, PLc/PRFs Huh7, HBG, and HepaRG, most of which do not possess phenotypic characteristics of the liver tissue.
Primary Hepatocyte Suspensions
Hepatocyte suspensions are an easy to use method for moderately high-throughput toxicity studies. The suspension retains a high level of functionality making it more accurately associated with in vivo toxicity than cultured cells. However, it is well known that most isolation protocols result in damage to cell junctions, cell surface receptors and antigens, cell membranes, and cytosolic contents.
Primary Hepatocyte Cultures
Cultures of primary hepatocytes have been the gold standard for in vitro testing because they can maintain functional activities for 24-72 hours, can be used for enzyme induction and inhibition studies, allow for medium-throughput screening of compounds, and are ideal for determining interspecies and inter-individual differences in metabolism.
Primary Hepatocyte Cultures Combined with Inflammatory Mediators
The combination of in vitro drug/inflammatory cytokine/inflammatory mediator is used to replicate clinical drug hepatotoxicity characteristics, especially for idiosyncratic drugs, in cultured primary human and rat hepatocytes, as well as HepG2 cells. Using this method, drug-cytokine hepatotoxicity synergies are shown to be detectable for multiple idiosyncratic hepatotoxicants, but not for non-toxic.
Three-dimensional Culture Systems
The highly polarized morphology of the hepatocytes is lost when cells are cultured under non-physiological conditions. Hepatocytes cultured in a three-dimensional environment using bioreactors, hanging drop methods, collagen sandwich cultures, micro-space cultures, collagen and matrigel cultures, and other synthetic biomaterials have been shown to be tissue-specific and possess many hallmarks of in vivo epithelial cells.
Bioartificial Livers
Bioartificial livers (BALs) are a promising approach for patients with liver disease or failure. If properly designed and manufactured, the devices can also be used for toxicological studies. The most common designs for BALs are hollow-fiber systems and flat-plate systems, using aggregates or single layers of hepatocytes respectively. In these systems, plasma can either be in direct contact to, or separated from, the hepatocytes.
Co-culture Systems
Hepatocyte co-cultures are usually comprised of hepatocytes with one other cell type, often other liver cells, non-liver epi- or endo-thelial cells, fibroblasts or cell lines. Co-cultures have also been prepared using hepatocytes and more than one additional cell type, such as hepatocyte-non-parenchymal cell (NPC) cultures. Co-culture system is one of the most successful techniques for maintaining hepatocyte function under in vitro conditions.
Stem Cells
A toxicity model containing a relatively unlimited supply of human hepatocytes with defined phenotypes will allow for a better prediction of drug treatment response. Theoretically, stem cells would represent a renewable source of cells and would potentially provide large numbers of functionally equivalent cells that could be stored for later use.
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