gms | German Medical Science

122. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

05. bis 08.04.2005, München

Augmenter of liver regeneration ALR modulates hepatic metabolism by reduction of cytochrom P450 activity in human hepatocytes in vitro

Meeting Abstract

  • corresponding author W.E. Thasler - Chirurgische Klinik und Poliklinik Klinikum Großhadern, LMU München
  • M. Lichtenauer - Zentrum für Leberzellforschung, Klinikum der Universität Regensburg
  • C. Hellerbrand - Zentrum für Leberzellforschung, Klinikum der Universität Regensburg
  • M. Mühlbauer - Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg
  • A. Gräbe - Zentrum für Leberzellforschung, Klinikum der Universität Regensburg
  • K.-W. Jauch - Chirurgische Klinik und Poliklinik Klinikum Großhadern, LMU München
  • H.-J. Schlitt - Zentrum für Leberzellforschung, Klinikum der Universität Regensburg
  • T.S. Weiss - Zentrum für Leberzellforschung, Klinikum der Universität Regensburg

Deutsche Gesellschaft für Chirurgie. 122. Kongress der Deutschen Gesellschaft für Chirurgie. München, 05.-08.04.2005. Düsseldorf, Köln: German Medical Science; 2005. Doc05dgch3728

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgch2005/05dgch400.shtml

Veröffentlicht: 15. Juni 2005

© 2005 Thasler et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Einleitung

Pathological disorders of the liver were shown to be associated with an impairment of hepatic drug metabolism, particularly that mediated by cytochrome P450s (CYP). Cytokines and growth factors, regulators of liver regeneration, were identified to modulate CYP expression. Recently, a novel liver specific hepatotrophic growth factor ALR, augmenter of liver regeneration, were found to have beneficial effects on liver growth, whereas its action on CYP metabolism is fully unknown.

Material und Methoden

Primary human hepatocytes in vitro were treated with recombinant human ALR followed by determination of proliferation rate (thymidine incorporation, polyamine metabolism), specific CYP isoenzyme activity, protein expression using western blotting and mRNA quantification using RT-PCR technique.

Ergebnisse

Application of ALR enhanced proliferation associated processes of human hepatocytes like thymidine incorporation and putrescine synthesis. Further, culture time-course analysis of effects on CYP 1A2 activity and dose response investigations of effects on CYP 1A2 and 2A6 activity revealed, that maximal inhibition was reached at 48 – 72 h of exposure with 50 nM ALR. The impact of ALR on basal activities of CYP isoenzymes demonstrated an overall reduction for CYP 1A2 of 34.5 ± 16.0% (n=19), CYP 2A6 of 55.5 ± 21.1% (n=19), CYP 2B6 of 18.1 ± 7.2% (n=4) and CYP 2E1 of 44.9 ± 26.4% (n=9). Additional an inhibitory effect of ALR after induction of CYP isoenzymes with methylcholantherene (CYP 1A2, 40.6 ± 10.1%, n=12) and phenobarbital (CYP 2B6, 34.7 ± 7.1%, n=3) were observed. Investigations of protein and mRNA expression of basal and induced CYP 1A2 and 3A4 isoenzymes after ALR treatment suggest a regulation on pretranscriptional level. Influence of ALR on phase II reactions (GSH/GSSG ratio, UGT conjugation) was not detected.

Schlussfolgerung

Here we demonstrate that ALR, as a member of hepatotrophic factors, not only function as augmenter of hepatocyte proliferation but also as an effective agent to down-regulate basal and induced CYP in human liver. This further implies a possible role of ALR in drug interactions of impaired hepatic function while tissue regeneration is triggered