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A Systematic Comparison of the Impact of Inflammatory Signaling on ADME 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 (IL-6). The HepaRG 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 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 activity measurements. Exposure of PHH and HepaRG cells to IL-6 resulted in highly similar coordinated reduction of DMET mRNA, including major ABCs, CYPs, GSTs, UGTs, and 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, while 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.

25480923

Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes, Showcase LPS and Inflammation, Showcase Steatosis

Drug Metab. Dispos.
Drug Metab. Dispos. :
7th Dec 2014

Marcus Klein, Maria Thomas, Ute Hofmann, Daniel Seehofer, Georg Damm, Ulrich M Zanger

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[Marcus Klein] [Maria Thomas] [Ute Hofmann] [Georg Damm] [Ulrich Zanger]

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Views: 1285
  • Created: 7th Dec 2014 at 10:17

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