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Drug Metabolism and Disposition Fast Forward
First published on August 25, 2006; DOI: 10.1124/dmd.106.012005

0090-9556/06/3412-2003-2010$20.00
DMD 34:2003-2010, 2006

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Phenytoin Induction of the Cyp2c37 Gene Is Mediated by the Constitutive Androstane Receptor

Jonathan P. Jackson, Stephen S. Ferguson1, Masahiko Negishi, and Joyce A. Goldstein

Laboratory of Pharmacology and Chemistry (J.P.J., S.S.F., J.A.G.) and Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology (M.N.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; and Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina (J.P.J.)

The CYP2C subfamily of cytochrome P450 monooxygenases is responsible for the metabolism of approximately 20% of therapeutic drugs and many endogenous compounds in humans. These enzymes can be induced by prior treatment with drugs, resulting in changes in drug efficacy. Induction of human CYP2C enzymes by xenobiotics occurs at the transcriptional level and is reported to involve the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). In the present study, we report that murine CYP2C37 mRNA is induced by phenobarbital and phenytoin. In contrast, the mouse PXR agonist 5-pregnen-3ß-ol-20-one-16{alpha}-carbonitrile did not induce CYP2C37 mRNA, suggesting that PXR does not regulate this gene. The induction of CYP2C37 mRNA by phenobarbital and phenytoin is essentially abolished in CAR-null mice; thus, induction of Cyp2c37 by these xenobiotics is CAR-dependent. A functional CAR response element (CAR-RE) was identified at –2791 base pairs from the translation start site of the Cyp2c37 gene. Mutation of this CAR-RE abolished mouse CAR transactivation of a Cyp2c37 –2.9-kilobase pair luciferase reporter construct in HepG2 cells.

Address correspondence to: Dr. Masahiko Negishi, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. E-mail: negishi{at}niehs.nih.gov




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