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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 7, 2005; DOI: 10.1124/jpet.105.094201

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Received for publication August 15, 2005.
Revised October 5, 2005.
Accepted for publication October 5, 2005.

Repression of cytochrome P450 activity in human hepatocytes in vitro by a novel hepatotrophic factor Augmenter of Liver Regeneration

Wolfgang E Thasler 1, Rania Dayoub 2, Marcus Muehlbauer 3, Claus Hellerbrand 3, Thomas Singer 4, Anja Graebe 2, Karl-Walter Jauch 1, Hans-Jurgen Schlitt 5, Thomas S. Weiss 2*

1 Department of Surgery, LM University Munich, Hospital Grosshadern, Germany 2 Center for Liver Cell Research, University of Regensburg Hospital, Germany 3 Department of Internal Medicine I, University of Regensburg Hospital, Germany 4 Hoffmann-LaRoche, Ltd, Non Clinical Safety, Basel, Switzerland 5 Department of Surgery, University of Regensburg Hospital, Germany

* Address correspondence to: E-mail: thomas.weiss{at}klinik.uni-regensburg.de

Abstract

Pathological disorders of the liver were shown to be associated with an impairment of hepatic drug metabolism mediated in part by growth factors. ALR (Augmenter of Liver Regeneration) is a novel liver specific hepatotrophic growth factor, whereas its action on cytochrome P450 (CYP) metabolism is completely unknown. Application of ALR to primary human hepatocytes in vitro reduced CYP isoenzyme activities (1A2 and 2A6) in a dose dependent manner. Time-course analysis revealed that the maximal inhibitory effect was reached after 24-72 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 CYPs 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 RT- PCR, respectively, suggest a regulation on the transcriptional level. Further, ALR treatment increased NFkB activity and reduced CAR (constitutive androstane receptor) but not PXR (pregnane X receptor) or AhR (aryl hydrocarbon receptor) expression. In contrast, ALR revealed no effects on phase II reactions (GSH/GSSG, UGT conjugation). Our results indicate that ALR, as a member of hepatotrophic factors, down-regulates basal and induced CYPs in human liver and therefore cross-linkes growth signals to regulation of hepatic metabolism. These findings further imply a possible role of ALR in drug interactions during impaired hepatic function while liver regeneration is triggered.


Key words: Nuclear factor k B, augmente of liver regenertion, cytochrome P450, hepatotrophic factor, human hepatocyte, metabolic capacity


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