Abstract
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-3β-ol-20-one-16α-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.
Footnotes
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This research in entirety is a portion of the dissertation research in progress by Jonathan P. Jackson and was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences. This work was previously presented at Experimental Biology 2006 meeting, April 1–5, 2006, San Francisco, CA.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012005.
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ABBREVIATIONS: P450, cytochrome P450; hRXR, human retinoid X receptor; PXR, pregnane X receptor; DR-n, direct repeat spaced by n nucleotides; PHREM, phenytoin responsive module; CAR, constitutive androstane receptor; CAR-RE, CAR responsive element; PCN, 5-pregnen-3β-ol-20-one-16α-carbonitrile; TCPOBOP, 1,4-bis-[2-(3, 5-dichloropyridyloxy)]benzene; DMSO, dimethyl sulfoxide; C3H, C3H/HeNCrlBR; EMSA, electrophoretic mobility shift assay; bp, base pair(s); mCAR, murine CAR; kb, kilobase(s); RT-PCR, reverse transcription-polymerase chain reaction; HSD, honestly significant difference.
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↵1 Current affiliation: CellzDirect, Inc., Austin, TX.
- Received July 14, 2006.
- Accepted August 23, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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Phenytoin Induction of the Cyp2c37 Gene Is Mediated by the Constitutive Androstane Receptor
