5-aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) prevents nuclear translocation of constitutive androstane receptor by AMP-activated protein kinase (AMPK) independent manner.
The nuclear receptor superfamily consists of ligand-dependent transcription factors. Among them, constitutive androstane receptor (CAR) plays a key role in the detoxification of xenobiotics, inducing various drug-metabolizing enzymes including human CYP2B6 and its homologues of other species. AMP-activated protein kinase (AMPK) acts as an important energy sensor, being activated by an increased AMP/ATP ratio. CAR is activated by phenobarbital (PB) treatment. It has been recently reported that AMPK is involved in PB-mediated CYP2B induction both in vitro and in vivo. We investigated the relationship between the functions of AMPK and CAR in rat primary hepatocyte. The AMPK-activator 5-aminoimidazole-4-Carboxamide-1-beta-Ribofuranoside (AICAR) unexpectedly repressed PB-induced CYP2B mRNA expression as well as AMPK-inhibitor compound C. In contrast, both the AMPK-activator metformin and the constitutive active form of AMPK enhanced PB-induced PB-responsive enhancer module-driven reporter gene expression. We demonstrated that AICAR prevented nuclear translocation of CAR in an AMPK-independent manner in rat primary hepatocytes. AICAR might be a convenient probe for studying the mechanisms of PB-induced activation, especially nuclear translocation, of CAR in rat primary hepatocytes.
Kanno
Yuichiro
Y
Inoue
Yoshimi
Y
Inouye
Yoshio
Y
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D010634:Phenobarbital / Q000494:pharmacology; D021381:Protein Transport; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*
D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D010634:Phenobarbital