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Research ArticleArticle

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

Marcus Klein, Maria Thomas, Ute Hofmann, Daniel Seehofer, Georg Damm and Ulrich M. Zanger
Drug Metabolism and Disposition February 2015, 43 (2) 273-283; DOI: https://doi.org/10.1124/dmd.114.060962
Marcus Klein
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.)
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Maria Thomas
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.)
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Ute Hofmann
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.)
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Daniel Seehofer
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.)
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Georg Damm
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.)
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Ulrich M. Zanger
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.)
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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.

Footnotes

    • Received September 8, 2014.
    • Accepted December 5, 2014.
  • This work was supported by the German Federal Ministry of Education and Research [Grants 0315755 and 0315741] and by the Robert Bosch Foundation, Stuttgart, Germany.

  • dx.doi.org/10.1124/dmd.114.060962.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (2)
Drug Metabolism and Disposition
Vol. 43, Issue 2
1 Feb 2015
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Research ArticleArticle

Drug Metabolism during Inflammation in PHH and HepaRG

Marcus Klein, Maria Thomas, Ute Hofmann, Daniel Seehofer, Georg Damm and Ulrich M. Zanger
Drug Metabolism and Disposition February 1, 2015, 43 (2) 273-283; DOI: https://doi.org/10.1124/dmd.114.060962

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Research ArticleArticle

Drug Metabolism during Inflammation in PHH and HepaRG

Marcus Klein, Maria Thomas, Ute Hofmann, Daniel Seehofer, Georg Damm and Ulrich M. Zanger
Drug Metabolism and Disposition February 1, 2015, 43 (2) 273-283; DOI: https://doi.org/10.1124/dmd.114.060962
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