TY - JOUR T1 - Heparg Cells as Human Relevant In Vitro Model to Study the Effects of Inflammatory Stimuli on Cytochrome P450 Isoenzymes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.114.059246 SP - dmd.114.059246 AU - Katarina A. L Rubin AU - Annika Janefeldt AU - Linda C Andersson AU - Zsofia Berke AU - Ken Grime AU - Tommy B Andersson Y1 - 2014/01/01 UR - http://dmd.aspetjournals.org/content/early/2014/11/04/dmd.114.059246.abstract N2 - Abstract The suppression of hepatic Cytochrome P450 (P450) expression during inflammatory and infectious diseases and the relief of this suppression by successful disease treatment have been previously demonstrated to impact drug disposition. To address this clinically relevant phenomenon preclinically, the effect of pro-inflammatory cytokines on P450 isoenzymes in human hepatocytes has been examined by several researchers. In the present study we used the human hepatoma cell line HepaRG and cryopreserved primary human hepatocytes to investigate the effects of various inflammatory stimuli on P450 levels with the aim of further characterizing HepaRG cells as a useful surrogate for primary hepatocytes. In this study, HepaRG cells were exposed to bacterial lipopolysaccharide (LPS), interleukin-6 (IL-6) and interleukin-18 (IL-18) for 48 or 72 hours. The effects on CYP1A2, CYP2B6 and CYP3A4 mRNA and catalytic activity (phenacetin-O-deethylase, bupropion-hydroxylase and midazolam-1'-hydroxylase) were measured. Cryopreserved pooled plateable hepatocytes were also exposed to IL-6 or IL-18 for 48 hours and the effects on CYP1A2, CYP2B6 and CYP3A4 mRNA levels were measured. The exposure of HepaRG cells to IL-6 and LPS resulted in suppression of and CYP1A2, CYP2B6 and CYP3A4 mRNA levels as well catalytic activities. However, no suppression of P450 activities or mRNA levels was observed after exposure to IL-18. Similar results on CYP1A2, CYP2B6 and CYP3A4 mRNA levels were observed with primary hepatocytes. The present study indicates that different pro-inflammatory mediators influence the expression of P450 differentially and that HepaRG cells may be used as an alternative to human hepatocytes for studies on cytokine-mediated suppression of drug-metabolizing enzymes. ER -