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

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