Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period

Abstract

Previous works have shown that differentiated human HepaRG cells can exhibit drug metabolism activities close to those of primary human hepatocytes for several weeks at confluence. The present study was designed to evaluate their long-term functional stability and their response to repeated daily drug treatments over a 14-day period, using a transcriptomic approach. Our data show that less than 1% of the expressed genes were markedly deregulated over this two weeks period and mainly included down-regulation of genes related to the cell cycle and from 3 days, overexpression of genes involved in xenobiotic and lipid metabolism. After daily treatment with the three PPAR agonists, fenofibrate, troglitazone and rosiglitazone qualitative and/or quantitative changes in gene profiling were observed depending on the compound and duration of treatment. The highest increase in the number of deregulated genes as a function of drug treatment was seen with rosiglitazone. The most up-regulated genes common across the three compounds were mainly related to lipid and xenobiotic metabolisms. All the data support the conclusion that human HepaRG cells have an exceptional functional stability at confluence and that they are suitable for investigations on chronic effects of drugs and other chemicals.

Biokinetics in repeated-dosing in vitro drug toxicity studies

“…The cells express most CYPs, phase II enzymes and transporters at levels comparable to cultured primary human hepatocytes and in vivo, making them ideally suited for long-term in vitro clearance and hepatotoxicity studies. Within Predict-IV, Savary et al (2015) evaluated the long-term functional stability of the cell line and their response to drugs after repeated dosing using a transcriptomic approach. The authors found less than 1% of the expressed genes to be markedly altered over the 14-day period.…”

Transcriptional and Epigenetic Consequences of DMSO Treatment on HepaRG Cells

“…In this context, we performed a large-scale analysis to determine the global role of DMSO exposure during the differentiation process. As evaluations of drug toxicity are usually performed with a lower level of DMSO or after DMSO removal [ 53 , 54 , 55 ] we also assessed the effect of DMSO removal after differentiation.…”