Comparison of human hepatoma HepaRG cells with human and rat hepatocytes in uptake transport assays in order to predict a risk of drug induced hepatotoxicity

PLoS One. 2013;8(3):e59432. doi: 10.1371/journal.pone.0059432. Epub 2013 Mar 14.


Human hepatocytes are the gold standard for toxicological studies but they have several drawbacks, like scarce availability, high inter-individual variability, a short lifetime, which limits their applicability. The aim of our investigations was to determine, whether HepaRG cells could replace human hepatocytes in uptake experiments for toxicity studies. HepaRG is a hepatoma cell line with most hepatic functions, including a considerable expression of uptake transporters in contrast to other hepatic immortalized cell lines. We compared the effect of cholestatic drugs (bosentan, cyclosporinA, troglitazone,) and bromosulfophthalein on the uptake of taurocholate and estrone-3-sulfate in human and rat hepatocytes and HepaRG cells. The substrate uptake was significantly slower in HepaRG cells than in human hepatocytes, still, in the presence of drugs we observed a concentration dependent decrease in uptake. In all cell types, the culture time had a significant impact not only on the uptake process but on the inhibitory effect of drugs too. The most significant drug effect was measured at 4 h after seeding. Our report is among the first concerning interactions of the uptake transporters in the HepaRG, at the functional level. Results of the present study clearly show that concerning the inhibition of taurocholate uptake by cholestatic drugs, HepaRG cells are closer to human hepatocytes than rat hepatocytes. In conclusion, we demonstrated that HepaRG cells may provide a suitable tool for hepatic uptake studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Bosentan
  • Carcinoma, Hepatocellular
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chromans / pharmacology
  • Cyclosporine / pharmacology
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism*
  • Humans
  • Rats
  • Sulfobromophthalein / pharmacology
  • Sulfonamides / pharmacology
  • Taurocholic Acid / metabolism*
  • Thiazolidinediones / pharmacology
  • Troglitazone


  • Chromans
  • Sulfonamides
  • Thiazolidinediones
  • Sulfobromophthalein
  • Taurocholic Acid
  • Cyclosporine
  • Troglitazone
  • Bosentan

Grant support

This study was supported by KMOP-1.1.2-07/1-2008-0002, GOP-1.1.1-09/1-2009-0054 and ETT 2009-2011 grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.