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Research ArticleArticle

Evaluation of HepaRG Cells as an in Vitro Model for Human Drug Metabolism Studies

Kajsa P. Kanebratt and Tommy B. Andersson
Drug Metabolism and Disposition July 2008, 36 (7) 1444-1452; DOI: https://doi.org/10.1124/dmd.107.020016
Kajsa P. Kanebratt
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Abstract

HepaRG cells, a newly developed human hepatoma cell line, differentiate into hepatocyte-like morphology by treatment with dimethyl sulfoxide (DMSO). The expression of cytochrome P450 (P450) enzymes, transporter proteins, and transcription factors was stable in differentiated HepaRG cells over a period of 6 weeks when cultured with DMSO. Compared with human hepatocytes, expression of P450 in HepaRG cells was in general lower with the exception for a considerably higher expression of CYP3A4 and CYP7A1. The expression of P450s generally decreased when DMSO was removed from the medium, whereas transporters and liver-specific factors were unaffected. The relative mRNA content of drug-metabolizing P450s displayed the highest resemblance between human hepatocytes and differentiated HepaRG cells 1 day after removal of DMSO from the medium. The metabolism of midazolam, naloxone, and clozapine in HepaRG cells was similar to human hepatocytes, indicating the function of CYP3A4, CYP1A2, and UDP-glucuronosyltransferase enzymes. However, the metabolism of 7-ethoxycoumarin and dextromethorphan was low, confirming low levels of CYP2E1 and CYP2D6 in HepaRG cells. The P450 probe substrates indicate a decrease in CYP1A2, CYP2B6, CYP2C9, and CYP3A4 activities in HepaRG cells 1 day after removal of DMSO from the medium. The activities were then relatively stable in DMSO-free medium for up to 14 days. Based on the stable expression of liver-specific functions over a long period in culture, the relative mRNA content of drug-metabolizing P450s, and metabolic properties, HepaRG cells provide a valuable in vitro model for human drug metabolism studies.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.020016.

  • ABBREVIATIONS: DMSO, dimethyl sulfoxide; P450, cytochrome P450; PCR, polymerase chain reaction; AoD, Assay-on-Demand Gene Expression assay(s); PXR, pregnane X receptor; HSM, hepatocyte suspension media; CLint, intrinsic clearance; LC/MS, liquid chromatography/mass spectrometry; MDR, multidrug resistance; UGT, UDP-glucuronosyltransferase; SULT, sulfotransferase; OATP, organic anion transporting polypeptide; MRP, multidrug resistance-associated protein; CAR, constitutive androstane receptor; AhR, aryl hydrocarbon receptor; CEBP, CCAAT/enhancer binding protein.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received December 6, 2007.
    • Accepted April 1, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (7)
Drug Metabolism and Disposition
Vol. 36, Issue 7
1 Jul 2008
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Research ArticleArticle

Evaluation of HepaRG Cells as an in Vitro Model for Human Drug Metabolism Studies

Kajsa P. Kanebratt and Tommy B. Andersson
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1444-1452; DOI: https://doi.org/10.1124/dmd.107.020016

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Research ArticleArticle

Evaluation of HepaRG Cells as an in Vitro Model for Human Drug Metabolism Studies

Kajsa P. Kanebratt and Tommy B. Andersson
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1444-1452; DOI: https://doi.org/10.1124/dmd.107.020016
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