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Toxicol In Vitro. 2017 Dec;45(Pt 2):222-232. doi: 10.1016/j.tiv.2017.09.009. Epub 2017 Sep 11.

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

Author information

1
European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, EURL ECVAM, Ispra, Italy.
2
European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, EURL ECVAM, Ispra, Italy. Electronic address: alicia.paini@ec.europa.eu.

Abstract

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.

KEYWORDS:

HepaRG; ICell cardiomyocyte; In silico; In vitro; Mitochondrial membrane potential; VCBA

PMID:
28911986
PMCID:
PMC5745147
DOI:
10.1016/j.tiv.2017.09.009
[Indexed for MEDLINE]
Free PMC Article

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