Virtual Cell Based Assay simulations of intra-mitochondrial concentrations in hepatocytes and cardiomyocytes

• Published in: Toxicology in vitro 2017-12, Vol.45 (Pt 2), p.222-232
• Main Authors: Worth, Andrew P., Louisse, Jochem, Macko, Peter, Sala Benito, J.V., Paini, Alicia
• Format: Article
• Language: English
• Subjects: Amiodarone - toxicity; Animal Testing Alternatives; Biocompatibility; Caffeine - toxicity; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - toxicity; Cardiomyocytes; Cell culture; Cell Line; Cell Survival - drug effects; Cells, Cultured; Chemicals; Computer Simulation; HepaRG; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatology; Humans; ICell cardiomyocyte; In silico; In vitro; In vitro methods and tests; In vivo methods and tests; Liver; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria - metabolism; Mitochondrial membrane potential; Models, Biological; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Organic chemistry; Toxicity; Toxicity testing; VCBA
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2017.09.009

In order to replace the use of animals in toxicity testing, there is a need to predict human in vivo toxic doses from concentrations that cause adverse effects in in vitro test systems. The virtual cell based assay (VCBA) has been developed to simulate intracellular concentrations as a function of time, and can be used to interpret in vitro concentration-response curves. In this study we refine and extend the VCBA model by including additional target-organ cell models and by simulating the fate and effects of chemicals at the organelle level. In particular, we describe the extension of the original VCBA to simulate chemical fate in liver (HepaRG) cells and cardiomyocytes (ICell cardiomyocytes), and we explore the effects of chemicals at the mitochondrial level. This includes a comparison of: a) in vitro results on cell viability and mitochondrial membrane potential (mmp) from two cell models (HepaRG cells and ICell cardiomyocytes); and b) VCBA simulations, including the cell and mitochondrial compartment, simulating the mmp for both cell types. This proof of concept study illustrates how the relationship between intra cellular, intra mitochondrial concentration, mmp and cell toxicity can be obtained by using the VCBA. •The VCBA has been developed to simulate intracellular concentrations.•The VCBA was extended to predict intra-mitochondrial concentrations in cardiomyocytes and HepaRG cells.•The VCBA has potential in supporting in vitro to in vivo extrapolation.