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Research ArticleArticle

Comparative Analysis and Functional Characterization of HC-AFW1 Hepatocarcinoma Cells: Cytochrome P450 Expression and Induction by Nuclear Receptor Agonists

Albert Braeuning, Maria Thomas, Ute Hofmann, Silvia Vetter, Eva Zeller, Barbara Petzuch, Janina Johänning, Werner Schroth, Thomas S. Weiss, Ulrich M. Zanger and Michael Schwarz
Drug Metabolism and Disposition November 2015, 43 (11) 1781-1787; DOI: https://doi.org/10.1124/dmd.115.064667
Albert Braeuning
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Maria Thomas
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Ute Hofmann
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Silvia Vetter
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Eva Zeller
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Barbara Petzuch
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Janina Johänning
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Werner Schroth
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Thomas S. Weiss
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Ulrich M. Zanger
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Michael Schwarz
Department of Food Safety, Federal Institute for Risk Assessment, Berlin, Germany (A.B.); Dr.-Margarethe-Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (M.T., U.H., J.J., W.S., U.M.Z.); Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany (A.B., S.V., E.Z., B.P., M.S.); Regensburg University Hospital, Regensburg, Germany (T.S.W.)
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Abstract

Enzymatic conversion of most xenobiotic compounds is accomplished by hepatocytes in the liver, which are also an important target for the manifestation of the toxic effects of foreign compounds. Most cell lines derived from hepatocytes lack important toxifying or detoxifying enzymes or are defective in signaling pathways that regulate expression and activity of these enzymes. On the other hand, the use of primary human hepatocytes is complicated by scarce availability of cells and high interdonor variability. Thus, analyses of drug metabolism and hepatotoxicity in vitro are a difficult task. The cell line HC-AFW1 was isolated from a pediatric hepatocellular carcinoma and so far has been used for tumorigenicity and chemotherapy resistance studies. Here, a comprehensive characterization of xenobiotic metabolism in HC-AFW1 cells is presented along with studies on the functionality of the most important transcriptional regulators of drug-metabolizing enzymes. Results from HC-AFW1 cells were compared with commercially available HepaRG cells and cultured primary human hepatocytes. Data show that the nuclear receptors and xenosensors AHR (aryl hydrocarbon receptor), CAR (constitutive androstane receptor), PXR (pregnane-X-receptor), NRF2 [nuclear factor (erythroid-derived 2)–like 2], and PPARα (peroxisome proliferator–activated receptor α) are functional in HC-AFW1 cells, comparable to HepaRG and primary cells. HC-AFW1 cells possess considerable activities of different cytochrome P450 enzymes, which, however, are lower than corresponding enzyme activities in HepaRG cells or primary hepatocytes. In summary, HC-AFW1 are a new promising tool for studying the mechanisms of the regulation of drug metabolism in human liver cells in vitro.

Footnotes

    • Received May 19, 2015.
    • Accepted August 24, 2015.
  • This study was supported by the Deutsche Forschungsgemeinschaft [Grants SCHR 1323/2-1 and MU 1727/2-1], by the German Federal Ministry of Education and Research [Virtual Liver Network Grant 0315755], and by the Robert Bosch Foundation, Stuttgart.

  • dx.doi.org/10.1124/dmd.115.064667.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Induction of Drug Metabolism in HC-AFW1 Cells

Albert Braeuning, Maria Thomas, Ute Hofmann, Silvia Vetter, Eva Zeller, Barbara Petzuch, Janina Johänning, Werner Schroth, Thomas S. Weiss, Ulrich M. Zanger and Michael Schwarz
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1781-1787; DOI: https://doi.org/10.1124/dmd.115.064667

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Research ArticleArticle

Induction of Drug Metabolism in HC-AFW1 Cells

Albert Braeuning, Maria Thomas, Ute Hofmann, Silvia Vetter, Eva Zeller, Barbara Petzuch, Janina Johänning, Werner Schroth, Thomas S. Weiss, Ulrich M. Zanger and Michael Schwarz
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1781-1787; DOI: https://doi.org/10.1124/dmd.115.064667
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