title: A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells.
abstract: Inflammatory processes are associated with compromised metabolism and elimination of drugs in the liver, largely mediated by proinflammatory cytokines, such as interleukin-6. The Hepa-RG cell line is an established surrogate for primary human hepatocytes (PHH) in drug metabolism and toxicity studies. However, the impact of inflammatory signaling on HepaRG cells has not been well characterized. In this study, the response of primary human hepatocytes and HepaRG cells to interleukin (IL)-6 was comparatively analyzed. For this purpose, broad-spectrum gene expression profiling, including acute-phase response genes and a large panel of drug-metabolizing enzyme and transporter (DMET) genes as well as their modifiers and regulators, was conducted in combination with cytochrome P450 (P450) activity measurements. Exposure of PHH and HepaRG cells to IL-6 resulted in highly similar coordinated reduction of DMET mRNA, including major ATP-binding cassette transporters (ABCs), P450s, glutathione S-transferases (GSTs), uridine diphosphate glucuronosyltransferases (UGTs), and solute carriers (SLCs). Enzyme activities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 were reduced upon 48-72 hours exposure to IL-6 in PHH and HepaRG. However, although these effects were not significant in PHH due to large interindividual donor variability, the impact on HepaRG was more pronounced and highly significant, thus emphasizing the advantage of HepaRG as a more reproducible model system. Exposure of HepaRG cells to interleukin-1β and tumor necrosis factor α resulted in similar effects on gene expression and enzyme activities. The present study emphasizes the role of proinflammatory cytokines in the regulation of drug metabolism and supports the use of HepaRG in lieu of PHH to minimize subject variability.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany (M.K., M.T., U.H., U.M.Z.); and Department of General, Visceral, and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany (D.S., G.D.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Klein
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany (M.K., M.T., U.H., U.M.Z.); and Department of General, Visceral, and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany (D.S., G.D.).
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany (M.K., M.T., U.H., U.M.Z.); and Department of General, Visceral, and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany (D.S., G.D.).
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany (M.K., M.T., U.H., U.M.Z.); and Department of General, Visceral, and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany (D.S., G.D.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany (M.K., M.T., U.H., U.M.Z.); and Department of General, Visceral, and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany (D.S., G.D.).
authors.forename: Georg
authors.initials: G
authors.lastname: Damm
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany (M.K., M.T., U.H., U.M.Z.); and Department of General, Visceral, and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany (D.S., G.D.) uli.zanger@ikp-stuttgart.de.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D017920:Antiporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D005260:Female; D020869:Gene Expression Profiling; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D018528:ATP-Binding Cassette Transporters; D017920:Antiporters; C508600:IL6 protein, human; D015850:Interleukin-6; D020033:Protein Isoforms; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase