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Cytochrome P450 1A1/2, 2B6 and 3A4 HepaRG Cell-Based Biosensors to Monitor Hepatocyte Differentiation, Drug Metabolism and Toxicity

1
Inserm, INRA, Univ Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR-A 1341, UMR-S 1241, Plateforme BiogenOuest SynNanoVect, F-35000 Rennes, France
2
Université de Lorraine, CNRS, CRAN, F-54000 Nancy, France
*
Author to whom correspondence should be addressed.
The authors have contributed to this work equally.
Deceased.
Sensors 2019, 19(10), 2245; https://doi.org/10.3390/s19102245
Received: 14 March 2019 / Revised: 10 May 2019 / Accepted: 13 May 2019 / Published: 15 May 2019
(This article belongs to the Section Biosensors)
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Abstract

Human hepatoma HepaRG cells express most drug metabolizing enzymes and constitute a pertinent in vitro alternative cell system to primary cultures of human hepatocytes in order to determine drug metabolism and evaluate the toxicity of xenobiotics. In this work, we established novel transgenic HepaRG cells transduced with lentiviruses encoding the reporter green fluorescent protein (GFP) transcriptionally regulated by promoter sequences of cytochromes P450 (CYP) 1A1/2, 2B6 and 3A4 genes. Here, we demonstrated that GFP-biosensor transgenes shared similar expression patterns with the corresponding endogenous CYP genes during proliferation and differentiation in HepaRG cells. Interestingly, differentiated hepatocyte-like HepaRG cells expressed GFP at higher levels than cholangiocyte-like cells. Despite weaker inductions of GFP expression compared to the strong increases in mRNA levels of endogenous genes, we also demonstrated that the biosensor transgenes were induced by prototypical drug inducers benzo(a)pyrene and phenobarbital. In addition, we used the differentiated biosensor HepaRG cells to evidence that pesticide mancozeb triggered selective cytotoxicity of hepatocyte-like cells. Our data demonstrate that these new biosensor HepaRG cells have potential applications in the field of chemicals safety evaluation and the assessment of drug hepatotoxicity. View Full-Text
Keywords: HepaRG cells; cell-based biosensors; cytochromes P450; drug screening; hepatotoxicity HepaRG cells; cell-based biosensors; cytochromes P450; drug screening; hepatotoxicity
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Vlach, M.; Quesnot, N.; Dubois-Pot-Schneider, H.; Ribault, C.; Verres, Y.; Petitjean, K.; Rauch, C.; Morel, F.; Robin, M.-A.; Corlu, A.; Loyer, P. Cytochrome P450 1A1/2, 2B6 and 3A4 HepaRG Cell-Based Biosensors to Monitor Hepatocyte Differentiation, Drug Metabolism and Toxicity. Sensors 2019, 19, 2245.

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