Abstract
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.
Highlights
Drug-induced liver injury is one of the major reasons for the withdrawal of an approved drug from the market [1], [2]
Effect of culture time on TC and E3S uptake The effect of culture time on the uptake of TC and E3S was studied in conventional monolayer cultures of human and rat hepatocytes and HepaRG cells
The uptake of TC and E3S was significantly slower in HepaRG cells compared to that in the primary hepatocytes, and was linear over a 5-min time period
Summary
Drug-induced liver injury is one of the major reasons for the withdrawal of an approved drug from the market [1], [2]. Only the HepaRG cells maintain several key hepatic functions, including metabolic enzymes, drug transporters and nuclear receptors at levels comparable with those found in primary human hepatocytes [9], [14], [7].
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