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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Center for Liver Cell Research (W.E.T., R.D., A.G., H.-J.S., T.S.W.) and Departments of Surgery (H.-J.S., T.S.W.) and Internal Medicine I (M.M., C.H.), University of Regensburg Hospital, Regensburg, Germany; Department of Surgery, LM University Munich, Hospital Grosshadern, Munich, Germany (K.-W.J.); and Hoffmann-LaRoche, Ltd., Nonclinical Safety, Basel, Switzerland (T.S.)

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.

Address correspondence to: Dr. Thomas S. Weiss, Center for Liver Cell Research, University of Regensburg Hospital, F.-J.-S.-Allee 11, 93042 Regensburg, Germany. E-mail: thomas.weiss{at}klinik.uni-regensburg.de

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