Our previous studies have suggested a role for AMP-activated protein kinase (AMPK) in the induction of CYP2B6 by phenobarbital (PB) in hepatoma-derived cells (Rencurel et al., 2005). In this study, we showed in primary human hepatocytes that: 1) 5'-phosphoribosyl-5-aminoimidazol-4-carboxamide 1-beta-d-ribofuranoside and the biguanide metformin, known activators of AMPK, dose-dependently increase the expression of CYP2B6 and CYP3A4 to an extent similar to that of PB. 2) PB, but not the human nuclear receptor constitutive active/androstane receptor (CAR) ligand 6-(4-chlorophenyl)imidazol[2,1-6][1,3]thiazole-5-carbaldehyde, dose-dependently increase AMPK activity. 3) Pharmacological inhibition of AMPK activity with compound C or dominant-negative forms of AMPK blunt the inductive response to phenobarbital. Furthermore, in transgenic mice with a liver-specific deletion of both the alpha1 and alpha2 AMPK catalytic subunits, basal levels of Cyp2b10 and Cyp3a11 mRNA were increased but not in primary culture of mouse hepatocytes. However, phenobarbital or 1,4 bis[2-(3,5-dichloropyridyloxy)]benzene, a mouse CAR ligand, failed to induce the expression of these genes in the liver or cultured hepatocytes from mice lacking hepatic expression of the alpha1 and alpha2 subunits of AMPK. The distribution of CAR between the nucleus and cytosol was not altered in hepatocytes from mice lacking both AMPK catalytic subunits. These data highlight the essential role of AMPK in the CAR-mediated signal transduction pathway.

译文

我们先前的研究表明,AMP激活的蛋白激酶 (AMPK) 在苯巴比妥 (PB) 在肝癌衍生细胞中诱导CYP2B6中的作用 (rencorel等人,2005)。在这项研究中,我们在原代人类肝细胞中显示: 1) 5 '-phosphoribosyl-5-aminoimidazol-4-carboxamide 1-β-d-呋喃核苷和双胍二甲双胍 (已知的AMPK激活剂) 剂量依赖性地增加CYP2B6和CYP3A4的表达与PB相似的程度。2) PB,但不是人核受体组成型活性/雄甾烷受体 (CAR) 配体6-(4-氯苯基) 咪唑 [2,1-6][1,3]thiazole-5-carbaldehyde,剂量依赖性地增加AMPK活性。3) 用化合物C或AMPK的显性阴性形式对AMPK活性的药理抑制钝化对苯巴比妥的诱导反应。此外,在具有肝脏特异性的 α1和 α2 AMPK催化亚基缺失的转基因小鼠中,Cyp2b10和Cyp3a11 mRNA的基础水平增加,但在小鼠肝细胞的原代培养中却没有。然而,苯巴比妥或1,4双 [2-(3,5-二氯吡啶基氧基)] 苯 (一种小鼠CAR配体) 未能诱导这些基因在肝脏或培养的肝细胞中的表达,这些基因来自缺乏AMPK的 α1和 α2亚基的肝表达的小鼠。缺乏两个AMPK催化亚基的小鼠的肝细胞中,核与胞质之间的CAR分布没有改变。这些数据强调了AMPK在CAR介导的信号转导途径中的重要作用。

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