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

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Received for publication July 17, 2006.
Revised August 22, 2006.
Accepted for publication August 23, 2006.

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

Jonathan P Jackson 1, Stephen S. Ferguson 1, Masahiko Negishi 1*, Joyce A. Goldstein 1

1 NIEHS

* Address correspondence to: E-mail: negishi{at}niehs.nih.gov

Abstract

The CYP2C subfamily of cytochrome P450 monoxygenases 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 (mPXR) agonist PCN 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 bp from the translation start site of the Cyp2c37 gene. Mutation of this CAR-RE abolished mouse CAR (mCAR) transactivation of a Cyp2c37 -2.9 kb luciferase reporter construct in HepG2 cells.


Key words: CAR, CYP induction, CYP2C, enzyme induction, PXR, transcriptional regulation, transgenic models


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