Thasler, Wolfgang E. and Dayoub, Rania and Muehlbauer, Marcus and Hellerbrand, Claus and Singer, Thomas and Graebe, Anja and Jauch, Karl-Walter and Schlitt, Hans-Juergen and Weiss, Thomas S. (2006) Repression of cytochrome P450 activity in human hepatocytes in vitro by a novel hepatotrophic factor, augmenter of liver regeneration. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 316 (2). pp. 822-829. ISSN 0022-3565,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EPIDERMAL GROWTH-FACTOR; HEPATIC STIMULATOR SUBSTANCE; RAT HEPATOCYTES; PRIMARY CULTURE; INDUCIBLE EXPRESSION; SIGNAL-TRANSDUCTION; NUCLEAR RECEPTORS; DRUG-METABOLISM; DOWN-REGULATION; MESSENGER-RNA; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Innere Medizin I Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Feb 2021 09:24 |
| Last Modified: | 24 Feb 2021 09:24 |
| URI: | https://pred.uni-regensburg.de/id/eprint/35000 |
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