In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase.
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 PB 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.
Blättler
Sharon M
SM
Division of Pharmacology/Neurobiology of the Biozentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Rencurel
Franck
F
Kaufmann
Michel R
MR
Meyer
Urs A
UA
D000818:Animals; D002460:Cell Line; D002645:Chickens; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D008564:Membrane Potentials / Q000187:drug effects; D008797:Metyrapone / Q000494:pharmacology; D051336:Mitochondrial Membranes / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D021122:Protein Subunits; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C516138:dorsomorphin; D010768:Phosphoserine; D003577:Cytochrome P-450 Enzyme System; D011494:Protein Kinases; D010634:Phenobarbital; D008797:Metyrapone