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Research ArticleArticle

Application of HC-AFW1 Hepatocarcinoma Cells for Mechanistic Studies: Regulation of Cytochrome P450 2B6 Expression by Dimethyl Sulfoxide and Early Growth Response 1

Barbara Petzuch, Nicola Groll, Michael Schwarz and Albert Braeuning
Drug Metabolism and Disposition November 2015, 43 (11) 1727-1733; DOI: https://doi.org/10.1124/dmd.115.064659
Barbara Petzuch
University of Tübingen, Department of Toxicology, Tübingen (B.P., M.S., A.B.), Natural and Medical Sciences Institute, Reutlingen (N.G.), and Federal Institute for Risk Assessment, Department of Food Safety, Berlin (A.B.), Germany
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Nicola Groll
University of Tübingen, Department of Toxicology, Tübingen (B.P., M.S., A.B.), Natural and Medical Sciences Institute, Reutlingen (N.G.), and Federal Institute for Risk Assessment, Department of Food Safety, Berlin (A.B.), Germany
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Michael Schwarz
University of Tübingen, Department of Toxicology, Tübingen (B.P., M.S., A.B.), Natural and Medical Sciences Institute, Reutlingen (N.G.), and Federal Institute for Risk Assessment, Department of Food Safety, Berlin (A.B.), Germany
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Albert Braeuning
University of Tübingen, Department of Toxicology, Tübingen (B.P., M.S., A.B.), Natural and Medical Sciences Institute, Reutlingen (N.G.), and Federal Institute for Risk Assessment, Department of Food Safety, Berlin (A.B.), Germany
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Abstract

Various exogenous compounds, for example, the drugs bupropione and propofol, but also various cytostatics, are metabolized in the liver by the enzyme cytochrome P450 (P450) CYP2B6. Transcription from the CYP2B6 gene is regulated mainly via the transcription factors constitutive androstane receptor (CAR) and pregnane-X-receptor (PXR). Most hepatic cell lines express no or only low levels of CYP2B6 because of loss of these two regulators. Dimethyl sulfoxide (DMSO) is frequently used in liver cell cultivation and is thought to affect the expression of various P450 isoforms by inducing or preserving cellular differentiation. We studied the effects of up to 1.5% of DMSO as cell culture medium supplement on P450 expression in hepatocarcinoma cells from line HC-AFW1. DMSO did not induce differentiation of the HC-AFW1 cell line, as demonstrated by unaltered levels of selected mRNA markers important for hepatocyte differentiation, and also by the lack of a DMSO effect on a broader spectrum of P450s. By contrast, CYP2B6 mRNA was strongly induced by DMSO. This process was independent of CAR or PXR activation. Interestingly, elevated transcription of CYP2B6 was accompanied by a simultaneous induction of early growth response 1 (EGR1), a transcription factor known to influence the expression of CYP2B6. Expression of wild-type EGR1 or of a truncated, dominant-negative EGR1 mutant was able to mimic or attenuate the DMSO effect, respectively. These findings demonstrate that EGR1 is involved in the regulation of CYP2B6 by DMSO in HC-AFW1 cells.

Footnotes

    • Received May 9, 2015.
    • Accepted August 24, 2015.
  • This work was supported by the European Union [Grant IMI- MARCAR].

  • dx.doi.org/10.1124/dmd.115.064659.

  • 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

CYP2B6 Regulation by DMSO and EGR1

Barbara Petzuch, Nicola Groll, Michael Schwarz and Albert Braeuning
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1727-1733; DOI: https://doi.org/10.1124/dmd.115.064659

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Research ArticleArticle

CYP2B6 Regulation by DMSO and EGR1

Barbara Petzuch, Nicola Groll, Michael Schwarz and Albert Braeuning
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1727-1733; DOI: https://doi.org/10.1124/dmd.115.064659
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