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Papers In Press, published online ahead of print November 29, 2004
Biomedical Research Centre, University of Dundee, Dundee, Tayside DD1 9SY
Corresponding Author: margaret.rooney{at}cancer.org.uk
Phenobarbital administration is known to trigger pleiotropic responses, including liver hypertrophy, tumor promotion and induction of genes encoding drug metabolising enzymes. The induction of human CYP2B6, and the rat (CYP2B1) and the mouse (Cyp2b10) homologues, by phenobarbital is mediated by the nuclear receptor CAR. The study of CYP2B gene regulation and CAR activity by phenobarbital has been difficult due to the lack of a cellular model. In this study we describe a novel differentiated human hepatoma cell line (WGA), derived from HepG2, which expresses CYP2B6 and CAR. WGA cells represent a powerful system to study the regulation of CYP2B6 gene expression by phenobarbital. There is evidence that CAR activity is regulated by phosphorylation, and that regulation of some CYP genes depends on the nutritional status of cells. The AMP-activated protein kinase functions as an energy sensor and is activated when cells experience energy depleting stresses. In this report we show that addition of AICAR, an AMPK activator, to WGA and human hepatocytes induces CYP2B6 gene expression. Expression of a constitutively active form of AMPK mimics the phenobarbital induction of CYP2B6 and CYP2B1 gene expression. Conversely, the expression of a dominant negative form of AMPK inhibits the induction of these genes by phenobarbital. Finally, we demonstrate, for the first time, that AMPK activity increases in cells cultured with phenobarbital. Our data strongly support a role for AMPK in the phenobarbital induction of CYP2B gene expression and provides new insights into the regulation of gene expression by barbiturate drugs.
J. Biol. Chem, 10.1074/jbc.M412711200
Submitted on November 10, 2004
Revised on November 29, 2004
Accepted on November 24, 2004
AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line
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