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Received for publication July 29, 2005.
Revised September 30, 2005.
Accepted for publication September 30, 2005.
Most human hepatocyte cell lines lack a substantial set of liver-specific functions, especially
major cytochrome P450 (CYP)-related enzyme activities, making them unrepresentative of in
vivo hepatocytes. We have used the HepaRG cells derived from a human hepatocellular
carcinoma, that exhibit a high differentiation pattern after 2 weeks at confluency to determine
whether they could mimic human hepatocytes for drug metabolism and toxicity studies. We
show that when passaged at low density these cells reversed to an undifferentiated
morphology, actively divided and after having reached confluency formed typical hepatocytelike
colonies surrounded by biliary epithelial-like cells. By contrast, when seeded at high
density, hepatocyte-like clusters retained their typical differentiated morphology. Transcripts
of various nuclear receptors (AhR, PXR, CAR, PPAR
), CYPs (1A2, 2C9, 2D6, 2E1, 3A4),
phase 2 enzymes (UGT1A1, GSTA1, GSTA4, GSTM1) and other liver-specific functions
were estimated by RT-qPCR and found to be expressed for most of them at comparable levels
in both confluent differentiated and high density differentiated HepaRG cells and in cultured
primary human hepatocytes. For several transcripts the levels were strongly increased in
presence of 2% dimethylsulfoxide. Measurement of basal activities of several CYPs and their
response to prototypical inducers as well as analysis of metabolic profiles and cytotoxicity of
several compounds confirmed the functional resemblance of HepaRG cells to primary
cultured human hepatocytes. In conclusion, HepaRG cells constitute the first human hepatoma
cell line expressing high levels of the major CYPs involved in xenobiotic metabolism and
represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies.
Key words:
CAR, cytochrome P450, enzyme induction, glutathione transferases, hepatocytes, in vitro toxicity assays, PXR
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