Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems.
Primary human hepatocytes (hHEP), human HepaRG and HepG2 cell lines are the most used human liver-based in vitro models for hepatotoxicity testing, including screening of drug-induced liver injury (DILI)-inducing compounds. hHEP are the reference hepatic in vitro system, but their availability is limited and the cells available for toxicology studies are often of poor quality. Hepatic cell lines on the other hand are highly proliferative and represent an inexhaustible hepatic cell source. However, these hepatoma-derived cells do not represent the population diversity and display reduced hepatic metabolism. Alternatively, stem cell-derived hepatic cells, which can be produced in high numbers and can differentiate into multiple cell lineages, are also being evaluated as a cell source for in vitro hepatotoxicity studies. Human skin-derived precursors (hSKP) are post-natal stem cells that, after conversion towards hepatic cells (hSKP-HPC), respond to hepatotoxic compounds in a comparable way as hHEP. In the current study, four different human hepatic cell systems (hSKP-HPC, hHEP, HepaRG and HepG2) are evaluated for their capacity to predict hepatic toxicity. Their hepatotoxic response to acetaminophen (APAP) exposure is compared to data obtained from patients suffering from APAP-induced acute liver failure (ALF). The results indicate that hHEP, HepaRG and hSKP-HPC identify comparable APAP-induced hepatotoxic functions and that HepG2 cells show the slightest hepatotoxic response. Pathway analyses further points out that HepaRG cells show the highest predicted activation of the functional genes related to 'damage of liver', followed by hSKP-HPC and hHEP cells that generated similar results. HepG2 did not show any activation of this function.
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: robim.marcelino.rodrigues@vub.ac.be.
Robim M
RM
Rodrigues
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Anja
A
Heymans
Department of Urology, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
Veerle
V
De Boe
Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 21, 50931 Cologne, Germany.
Agapios
A
Sachinidis
Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 21, 50931 Cologne, Germany.
Umesh
U
Chaudhari
Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, Katholieke Universiteit Leuven (KUL), Minderbroedersstraat 12, 3000 Leuven, Belgium.
Olivier
O
Govaere
Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, Katholieke Universiteit Leuven (KUL), Minderbroedersstraat 12, 3000 Leuven, Belgium.
Tania
T
Roskams
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Tamara
T
Vanhaecke
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Vera
V
Rogiers
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Joery
J
De Kock
D000082:Acetaminophen / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D043922:Toxicogenetics / Q000379:methods*
D000082:Acetaminophen
Acetaminophen (APAP); Acute liver failure; Adult stem cells; Alternative methods; DILI; HepG2; HepaRG; Human primary hepatocytes; In vitro toxicity testing