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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Induction of Drug Metabolism Enzymes and MDR1 Using a Novel Human Hepatocyte Cell Line

Jessica B. Mills, Kelly A. Rose, Nalini Sadagopan, Jasminder Sahi and Sonia M. F. de Morais
Journal of Pharmacology and Experimental Therapeutics April 2004, 309 (1) 303-309; DOI: https://doi.org/10.1124/jpet.103.061713
Jessica B. Mills
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Kelly A. Rose
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Nalini Sadagopan
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Jasminder Sahi
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Sonia M. F. de Morais
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Abstract

Induction of drug-metabolizing enzymes and transporters can cause drug-drug interactions and loss of efficacy. In vitro induction studies traditionally use primary hepatocyte cultures and enzyme activity with selected marker compounds. We investigated the use of a novel human hepatocyte clone, the Fa2N-4 cell line, as an alternative reagent, which is readily available and provides a consistent, reproducible system. We used the Invader assay to monitor gene expression in these cells. This assay is a robust, yet simple, high-throughput system for quantification of mRNA transcripts. CYP1A2, CYP3A4, CYP2C9, UGT1A, and MDR1 transcripts were quantified from total RNA extracts from Fa2N-4 cells treated with a panel of known inducers and compared with vehicle controls. In addition, we used enzyme activity assays to monitor the induction of CYP1A2, CYP2C9, and CYP3A4. The Fa2N-4 cells responded in a similar manner as primary human hepatocytes. Treatment with 10 μM rifampin resulted in increases in CYP3A4 mRNA (17-fold) and activity (6-β-hydroxytestoterone formation, 9-fold); and in CYP2C9 mRNA (4-fold) and activity (4′-hydroxydiclofenac formation, 2-fold). Treatment with 50 μM β-naphthoflavone resulted in increases in CYP1A2 mRNA (15-fold) and activity (7-ethoxyresorufin O-dealkylation, 27-fold). UGT1A mRNA was induced by β-naphthoflavone (2-fold), and MDR1 (P-glycoprotein) mRNA was induced by rifampin (3-fold). These preliminary data using a few prototypical inducers show that Fa2N-4 cells can be a reliable surrogate for primary human hepatocytes, and, when used in conjunction with the Invader technology, could provide a reliable assay for assessment of induction of drug-metabolizing enzymes and transporters.

Footnotes

  • DOI: 10.1124/jpet.103.061713.

  • ABBREVIATIONS: P450, cytochrome P450; MDR1, multidrug resistance 1; HPLC, high-performance liquid chromatography; LC/MS/MS, liquid chromatography/tandem mass spectrometry; DMSO, dimethyl sulfoxide.

    • Received October 15, 2003.
    • Accepted December 5, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 1
1 Apr 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Induction of Drug Metabolism Enzymes and MDR1 Using a Novel Human Hepatocyte Cell Line

Jessica B. Mills, Kelly A. Rose, Nalini Sadagopan, Jasminder Sahi and Sonia M. F. de Morais
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 303-309; DOI: https://doi.org/10.1124/jpet.103.061713

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Induction of Drug Metabolism Enzymes and MDR1 Using a Novel Human Hepatocyte Cell Line

Jessica B. Mills, Kelly A. Rose, Nalini Sadagopan, Jasminder Sahi and Sonia M. F. de Morais
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 303-309; DOI: https://doi.org/10.1124/jpet.103.061713
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