@article{jackson_ferguson_negishi_goldstein_2006, title={Phenytoin induction of the Cyp2c37 gene is mediated by the constitutive androstane receptor}, volume={34}, ISSN={["0090-9556"]}, DOI={10.1124/dmd.106.012005}, abstractNote={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.}, number={12}, journal={DRUG METABOLISM AND DISPOSITION}, author={Jackson, Jonathan P. and Ferguson, Stephen S. and Negishi, Masahiko and Goldstein, Joyce A.}, year={2006}, month={Dec}, pages={2003–2010} }
 @article{jackson_ferguson_moore_negishi_goldstein_2004, title={The constitutive active/androstane receptor regulates phenytoin induction of Cyp2c29}, volume={65}, ISSN={["1521-0111"]}, DOI={10.1124/mol.65.6.1397}, abstractNote={Many cytochrome P450 isoforms are known to be drug-inducible. The anticonvulsant phenytoin has been reported to be an inducer of human CYP2B6, CYP3A4, and murine CYP2C29. However, the molecular mechanism mediating phenytoin induction remains unclear. Herein, we used in vivo and in vitro gene reporter assays of the Cyp2c29 promoter to delineate the phenytoin-response activity to a phenytoin-responsive module located at -1371 kb upstream of the Cyp2c29 translation start site. The phenytoin-responsive module, consisting of two motifs of two imperfect direct repeat hexamers spaced by four nucleotides and a putative CCAAT/enhancer-binding protein-binding site, mediated luciferase reporter induction by phenytoin in mouse livers in vivo and was activated by CAR in HepG2 cells. Hepatic CYP2C29 mRNA was induced by phenytoin in wild-type but not in CAR-null mice, indicating that constitutive active or androstane receptor (CAR) regulates phenytoin-induced transcription of the Cyp2c29 gene. Furthermore, the constitutive levels of CYP2C29 mRNA were reduced approximately 77-fold in CAR-null mice compared with those in the wild-type mice, suggesting that CAR may also regulate the constitutive expression of the Cyp2c29 gene either directly or indirectly.}, number={6}, journal={MOLECULAR PHARMACOLOGY}, author={Jackson, JP and Ferguson, SS and Moore, R and Negishi, M and Goldstein, JA}, year={2004}, month={Jun}, pages={1397–1404} }