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Research ArticleArticle

Phase 1 and Phase 2 Drug Metabolism and Bile Acid Production of HepaRG Cells in a Bioartificial Liver in Absence of Dimethyl Sulfoxide

Ruurdtje Hoekstra, Geert A.A. Nibourg, Tessa V. van der Hoeven, Gabrielle Plomer, Jurgen Seppen, Mariëtte T. Ackermans, Sandrine Camus, Wim Kulik, Thomas M. van Gulik, Ronald P. Oude Elferink and Robert A.F.M. Chamuleau
Drug Metabolism and Disposition March 2013, 41 (3) 562-567; DOI: https://doi.org/10.1124/dmd.112.049098
Ruurdtje Hoekstra
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Geert A.A. Nibourg
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Tessa V. van der Hoeven
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Gabrielle Plomer
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Jurgen Seppen
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Mariëtte T. Ackermans
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Sandrine Camus
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Wim Kulik
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Thomas M. van Gulik
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Ronald P. Oude Elferink
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Robert A.F.M. Chamuleau
Tytgat Institute for Liver and Intestinal Research (R.H., G.A.A.N., T.V.v.d.H., G.P., J.S., R.P.O.E., R.A.F.M.C), Surgical Laboratory (R.H., G.A.A.N., T.V.v.d.H., G.P., T.M.v.G.) Department of Clinical Chemistry, Laboratory of Endocrinology (M.T.A.), Department of Genetic Metabolic Diseases (W.K.) Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; and Biopredic International, Rennes, France (S.C.)
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Abstract

The human liver cell line HepaRG has been recognized as a promising source for in vitro testing of metabolism and toxicity of compounds. However, currently the hepatic differentiation of these cells relies on exposure to dimethylsulfoxide (DMSO), which, as a side effect, has a cytotoxic effect and represses an all-round hepatic functionality. The AMC-bioartificial liver (AMC-BAL) is a three-dimensional bioreactor that has previously been shown to upregulate various liver functions of cultured cells. We therefore cultured HepaRG cells in the AMC-BAL without DMSO and characterized the drug metabolism. Within 14 days of culture, the HepaRG-AMC-BALs contained highly polarized viable liver-like tissue with heterogeneous expression of CYP3A4. We found a substantial metabolism of the tested substrates, ranging from 26% (UDP-glucuronosyltransferase 1A1), 47% (CYP3A4), to 240% (CYP2C9) of primary human hepatocytes. The CYP3A4 activity could be induced 2-fold by rifampicin, whereas CYP2C9 activity remained equally high. The HepaRG-AMC-BAL secreted bile acids at 43% the rate of primary human hepatocytes and demonstrated hydroxylation, conjugation, and transport of bile salts. Concluding, culturing HepaRG cells in the AMC-BAL yields substantial phase 1 and phase 2 drug metabolism, while maintaining high viability, rendering DMSO addition superfluous for the promotion of drug metabolism. Therefore, AMC-BAL culturing makes the HepaRG cells more suitable for testing metabolism and toxicity of drugs.

Footnotes

  • This work was supported by Subsidy Regulation Knowledge Exploitation (SKE-fund) of the Academic Medical College and Hep-Art Medical Devices B.V.

  • dx.doi.org/10.1124/dmd.112.049098.

  • Received October 12, 2012.
  • Accepted December 10, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

Drug Metabolism and Bile acid Formation of HepaRG Bioreactor

Ruurdtje Hoekstra, Geert A.A. Nibourg, Tessa V. van der Hoeven, Gabrielle Plomer, Jurgen Seppen, Mariëtte T. Ackermans, Sandrine Camus, Wim Kulik, Thomas M. van Gulik, Ronald P. Oude Elferink and Robert A.F.M. Chamuleau
Drug Metabolism and Disposition March 1, 2013, 41 (3) 562-567; DOI: https://doi.org/10.1124/dmd.112.049098

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Research ArticleArticle

Drug Metabolism and Bile acid Formation of HepaRG Bioreactor

Ruurdtje Hoekstra, Geert A.A. Nibourg, Tessa V. van der Hoeven, Gabrielle Plomer, Jurgen Seppen, Mariëtte T. Ackermans, Sandrine Camus, Wim Kulik, Thomas M. van Gulik, Ronald P. Oude Elferink and Robert A.F.M. Chamuleau
Drug Metabolism and Disposition March 1, 2013, 41 (3) 562-567; DOI: https://doi.org/10.1124/dmd.112.049098
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