Functional expression, inhibition and induction of CYP enzymes in HepaRG cells.

Practically all human hepatocyte cell lines are deficient in major cytochrome P450 (CYP)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the recently developed HepaRG cell line to determine the spectrum of most important CYP enzyme activities involved in xenobiotic metabolism (CYP1A1/2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) and the effect of the prototypical CYP-inducer phenobarbital and a panel of known CYP-selective inhibitors on these activities. Comparison of these activities was carried out with two human primary hepatocyte populations. We show that excluding CYP2A6 and CYP2E1, HepaRG cells express high functional levels of most of the major xenobiotic metabolising CYPs. These activities were found to be selectively inhibited and induced by prototypical CYP-selective inhibitors and inducer at comparable levels to primary hepatocytes. In conclusion, HepaRG cells may be a promising cell line for various applications, which currently employ hepatic subcellular preparations or cultured primary hepatocytes.