In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase
In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase
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DOI：
10.1073/pnas.0610216104
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发表时间：
2007-01-16
影响因子：
11.1
通讯作者：
Meyer, Urs A.
中科院分区：
文献类型：
--
作者：
Blaettler, Sharon M.;Rencurel, Franck;Meyer, Urs A.
细胞色素P450（CYP）基因和各种药物代谢酶的转录激活由原型诱导剂苯巴比妥（PB）和许多其他药物和化学品是生物体暴露于外源性物质的适应性反应。对PS的反应由核受体组成型雄烷受体（CAR）介导，而鸡异生素受体（CXR）已被表征为鸡肝细胞中的PB介质。我们以前的研究结果表明，在PB诱导的分子机制的AMP激活的蛋白激酶（AMPK）的参与。在这里，我们发现AMPK激活的机制与PB型诱导剂对线粒体功能的影响有关，从而形成活性氧（ROS）和上游激酶LKB 1对AMPK的磷酸化。获得和丧失功能的实验表明，LKB1激活的AMPK是必要的药物诱导机制，这是一个进化保守的途径解毒的外源性和内源性化学物质。LKB1的激活为PB和其他药物诱导多个基因转录的事件序列增加了一个近端靶点。
Transcriptional activation of cytochrome P450 (CYP) genes and various drug metabolizing enzymes by the prototypical inducer phenobarbital (PB) and many other drugs and chemicals is an adaptive response of the organism to exposure to xenobiotics. The response to PS is mediated by the nuclear receptor constitutive androstane receptor (CAR), whereas the chicken xenobiotic receptor (CXR) has been characterized as the PB mediator in chicken hepatocytes. Our previous results suggested an involvement of AMP-activated protein kinase (AMPK) in the molecular mechanism of PB induction. Here, we show that the mechanism of AMPK activation is related to an effect of PB-type inducers on mitochondrial function with consequent formation of reactive oxygen species (ROS) and phosphorylation of AMPK by the upstream kinase LKB1. Gain- and loss-of-function experiments demonstrate that LKB1-activated AMPK is necessary in the mechanism of drug induction and that this is an evolutionary conserved pathway for detoxification of exogenous and endogenous chemicals. The activation of LKB1 adds a proximal target to the so far elusive sequence of events by which PB and other drugs induce the transcription of multiple genes.