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Research ArticleArticle

HepaRG Cells as Human-Relevant In Vitro Model to Study the Effects of Inflammatory Stimuli on Cytochrome P450 Isoenzymes

Katarina Rubin, Annika Janefeldt, Linda Andersson, Zsofia Berke, Ken Grime and Tommy B. Andersson
Drug Metabolism and Disposition January 2015, 43 (1) 119-125; DOI: https://doi.org/10.1124/dmd.114.059246
Katarina Rubin
AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Annika Janefeldt
AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Linda Andersson
AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Zsofia Berke
AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Ken Grime
AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Tommy B. Andersson
AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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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 proinflammatory 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 CYP1A2, CYP2B6, and CYP3A4 mRNA levels as well as their 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 proinflammatory 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.

Footnotes

    • Received May 27, 2014.
    • Accepted October 31, 2014.
  • dx.doi.org/10.1124/dmd.114.059246.

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

HepaRG Cells and Effects of IL-6, IL-18, and LPS on P450

Katarina Rubin, Annika Janefeldt, Linda Andersson, Zsofia Berke, Ken Grime and Tommy B. Andersson
Drug Metabolism and Disposition January 1, 2015, 43 (1) 119-125; DOI: https://doi.org/10.1124/dmd.114.059246

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Research ArticleArticle

HepaRG Cells and Effects of IL-6, IL-18, and LPS on P450

Katarina Rubin, Annika Janefeldt, Linda Andersson, Zsofia Berke, Ken Grime and Tommy B. Andersson
Drug Metabolism and Disposition January 1, 2015, 43 (1) 119-125; DOI: https://doi.org/10.1124/dmd.114.059246
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