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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Wolfgang E. Thasler, Rania Dayoub, Marcus Mühlbauer, Claus Hellerbrand, Thomas Singer, Anja Gräbe, Karl-Walter Jauch, Hans-Jürgen Schlitt and Thomas S. Weiss
Journal of Pharmacology and Experimental Therapeutics February 2006, 316 (2) 822-829; DOI: https://doi.org/10.1124/jpet.105.094201
Wolfgang E. Thasler
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Rania Dayoub
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Marcus Mühlbauer
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Claus Hellerbrand
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Thomas Singer
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Anja Gräbe
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Karl-Walter Jauch
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Hans-Jürgen Schlitt
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Thomas S. Weiss
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Abstract

Pathological disorders of the liver were shown to be associated with an impairment of hepatic drug metabolism mediated in part by growth factors. Augmenter of liver regeneration (ALR) is a novel liver-specific hepatotrophic growth factor, whereas its action on cytochrome P450 (P450) metabolism is completely unknown. Application of ALR to primary human hepatocytes in vitro reduced P450 isoenzyme activities (1A2 and 2A6) in a dose-dependent manner. Time-course analysis revealed that the maximal inhibitory effect was reached after 24 to 72 h of exposure with 50 nM ALR. The reduction of basal activities upon ALR treatment was 35% for CYP1A2, 56% for CYP2A6, 18% for CYP2B6, and 45% for CYP2E1. Additionally, after induction of P450 with specific inducers, ALR revealed an inhibitory effect on the isoenzyme activities (CYP1A2, 41%; CYP2B6, 35%). Investigations of protein and mRNA expression of basal and induced CYP1A2 and CYP3A4 after ALR treatment by Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively, suggest a regulation on the transcriptional level. Furthermore, ALR treatment increased nuclear factor kB activity and reduced constitutive androstane receptor but not pregnane X receptor or aryl hydrocarbon receptor expression. In contrast, ALR revealed no effects on phase II reactions (glutathione/oxidized glutathione, UDP-glucuronyltransferase conjugation). Our results indicate that ALR, as a member of hepatotrophic factors, down-regulates basal and induced P450 in human liver and therefore cross-links growth signals to regulation of hepatic metabolism. These findings further imply a possible role of ALR in drug interactions during impaired hepatic function, whereas liver regeneration is triggered.

Footnotes

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

  • ↵1 Current affiliation: Department of Surgery, LM University Munich, Hospital Grosshadem, Munich, Germany.

  • doi:10.1124/jpet.105.094201.

  • ABBREVIATIONS: P450, cytochrome(s) P450; IL, interleukin; TNF, tumor necrosis factor; HGF, hepatocyte growth factor; EGF, epidermal growth factor; ALR, augmenter of liver regeneration; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kB; MC, 3-methylcholanthrene; Rif, rifampicin; rhALR, recombinant human ALR; EROD, 7-ethoxyresorufin O-deethylase; BROD, 7-benzoxyresorufin O-debenzylase; CH, coumarin 7-hydroxylase; PNP, p-nitrophenol hydroxylase; UGT, UDP-glucuronyltransferase; GSH, glutathione; GSSG, oxidized glutathione; PCR, polymerase chain reaction; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay.

    • Received August 14, 2005.
    • Accepted October 5, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 316 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 2
1 Feb 2006
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Wolfgang E. Thasler, Rania Dayoub, Marcus Mühlbauer, Claus Hellerbrand, Thomas Singer, Anja Gräbe, Karl-Walter Jauch, Hans-Jürgen Schlitt and Thomas S. Weiss
Journal of Pharmacology and Experimental Therapeutics February 1, 2006, 316 (2) 822-829; DOI: https://doi.org/10.1124/jpet.105.094201

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Wolfgang E. Thasler, Rania Dayoub, Marcus Mühlbauer, Claus Hellerbrand, Thomas Singer, Anja Gräbe, Karl-Walter Jauch, Hans-Jürgen Schlitt and Thomas S. Weiss
Journal of Pharmacology and Experimental Therapeutics February 1, 2006, 316 (2) 822-829; DOI: https://doi.org/10.1124/jpet.105.094201
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