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J. Biol. Chem., Vol. 280, Issue 6, 4367-4373, February 11, 2005

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AMP-activated Protein Kinase Mediates Phenobarbital Induction of CYP2B Gene Expression in Hepatocytes and a Newly Derived Human Hepatoma Cell Line^*

Franck Rencurel¶, Alasdair Stenhouse, Simon A. Hawley||, Thomas Friedberg, D. Grahame Hardie||, Calum Sutherland**, and C. Roland Wolf

From the Biomedical Research Centre and Cancer Research UK Molecular Pharmacology Unit, Level 5, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom, Division of Molecular Physiology, School of Life Sciences and Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom, and ^**Pharmacology and Neuroscience, Ninewells Hospital, Dundee University, Dundee DD1 9SY, Scotland, United Kingdom

Phenobarbital (PB) administration is known to trigger pleiotropic responses, including liver hypertrophy, tumor promotion, and induction of genes encoding drug-metabolizing enzymes. The induction of human CYP2B6 and the rat (CYP2B1) and mouse (Cyp2b10) homologues by PB is mediated by the nuclear receptor constitutive androstane receptor (CAR). The study of CYP2B gene regulation and CAR activity by PB 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 PB. 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 (AMPK) functions as an energy sensor and is activated when cells experience energy-depleting stresses. In this report, we show that addition of 5-amino-imidazole carboxamide riboside, an AMPK activator, to WGA and human hepatocytes induces CYP2B6 gene expression. Expression of a constitutively active form of AMPK mimics the PB induction of CYP2B6 and CYP2B1 gene expression. Conversely, the expression of a dominant negative form of AMPK inhibits the induction of these genes by PB. Finally, we demonstrate, for the first time, that AMPK activity increases in cells cultured with PB. Our data strongly support a role for AMPK in the PB induction of CYP2B gene expression and provide new insights into the regulation of gene expression by barbiturate drugs.

Received for publication, November 10, 2004

^* This work was supported in part by AstraAlderly, AstraCharnwood, Aventis, Boehringer-Ingelheim, GlaxoSmithkline, Hoffmann-La Roche, Janssen Pharmaceutical, Novartis, Novo Nordisk, and Pfizer Wyeth-Ayerst. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: Biozentrum, University of Basel, Pharmacology/Neuroscience, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.

^|| Supported by a program grant from the Wellcome Trust.

The recipient of the Diabetes UK Senior Fellowship 02/0002473.

To whom correspondence should be addressed. Tel.: 44-1382-632621; Fax: 44-1382-669993; E-mail: roland.wolf{at}cancer.org.uk.

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