期刊
JOURNAL OF TOXICOLOGICAL SCIENCES
卷 35, 期 4, 页码 571-576出版社
JAPANESE SOC TOXICOLOGICAL SCIENCES
DOI: 10.2131/jts.35.571
关键词
Constitutive androstane receptor; Phenobarbital; AMP-activated protein kinase
类别
资金
- Ministry of Education, Science, Sports and Culture (MESSC)
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.
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