QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jackson, J. P. Articles by Goldstein, J. A. Search for Related Content PubMed PubMed Citation Articles by Jackson, J. P. Articles by Goldstein, J. A.

The Constitutive Active/Androstane Receptor Regulates Phenytoin Induction of Cyp2c29

Laboratory of Pharmacology and Chemistry (J.P.J., S.S.F., J.A.G.) and Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology (R.M., 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.)

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 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.

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

This article has been cited by other articles:

				R. A. B. van Waterschoot, R. W. Rooswinkel, E. Wagenaar, C. M. M. van der Kruijssen, A. E. van Herwaarden, and A. H. Schinkel Intestinal cytochrome P450 3A plays an important role in the regulation of detoxifying systems in the liver FASEB J, January 1, 2009; 23(1): 224 - 231. [Abstract] [Full Text] [PDF]

				D. Masson, M. Qatanani, A. L. Sberna, R. Xiao, J. P. Pais de Barros, J. Grober, V. Deckert, A. Athias, P. Gambert, L. Lagrost, et al. Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice J. Lipid Res., August 1, 2008; 49(8): 1682 - 1691. [Abstract] [Full Text] [PDF]

				M. D. Merrell, J. P. Jackson, L. M. Augustine, C. D. Fisher, A. L. Slitt, J. M. Maher, W. Huang, D. D. Moore, Y. Zhang, C. D. Klaassen, et al. The Nrf2 Activator Oltipraz Also Activates the Constitutive Androstane Receptor Drug Metab. Dispos., August 1, 2008; 36(8): 1716 - 1721. [Abstract] [Full Text] [PDF]

				Y. Yamamoto and M. Negishi The Antiapoptotic Factor Growth Arrest and DNA-Damage-Inducible 45 {beta} Regulates the Nuclear Receptor Constitutive Active/Androstane Receptor-Mediated Transcription Drug Metab. Dispos., July 1, 2008; 36(7): 1189 - 1193. [Abstract] [Full Text] [PDF]

				T. Sueyoshi, R. Moore, J. Sugatani, Y. Matsumura, and M. Negishi PPP1R16A, The Membrane Subunit of Protein Phosphatase 1{beta}, Signals Nuclear Translocation of the Nuclear Receptor Constitutive Active/Androstane Receptor Mol. Pharmacol., April 1, 2008; 73(4): 1113 - 1121. [Abstract] [Full Text] [PDF]

				R. A. B. van Waterschoot, A. E. van Herwaarden, J. S. Lagas, R. W. Sparidans, E. Wagenaar, C. M. M. van der Kruijssen, J. A. Goldstein, D. C. Zeldin, J. H. Beijnen, and A. H. Schinkel Midazolam Metabolism in Cytochrome P450 3A Knockout Mice Can Be Attributed to Up-Regulated CYP2C Enzymes Mol. Pharmacol., March 1, 2008; 73(3): 1029 - 1036. [Abstract] [Full Text] [PDF]

				J. P. Jackson, S. S. Ferguson, M. Negishi, and J. A. Goldstein Phenytoin Induction of the Cyp2c37 Gene Is Mediated by the Constitutive Androstane Receptor Drug Metab. Dispos., December 1, 2006; 34(12): 2003 - 2010. [Abstract] [Full Text] [PDF]

				P A Sinclair, W J Gilmore, Z Lin, Y Lou, and E J Squires Molecular cloning and regulation of porcine SULT2A1: relationship between SULT2A1 expression and sulfoconjugation of androstenone. J. Mol. Endocrinol., April 1, 2006; 36(2): 301 - 311. [Abstract] [Full Text] [PDF]

				M. Tsutsui, S. Ogawa, Y. Inada, E. Tomioka, A. Kamiyoshi, S. Tanaka, T. Kishida, M. Nishiyama, M. Murakami, J. Kuroda, et al. CHARACTERIZATION OF CYTOCHROME P450 EXPRESSION IN MURINE EMBRYONIC STEM CELL-DERIVED HEPATIC TISSUE SYSTEM Drug Metab. Dispos., April 1, 2006; 34(4): 696 - 701. [Abstract] [Full Text] [PDF]

				S. S. Ferguson, Y. Chen, E. L. LeCluyse, M. Negishi, and J. A. Goldstein Human CYP2C8 Is Transcriptionally Regulated by the Nuclear Receptors Constitutive Androstane Receptor, Pregnane X Receptor, Glucocorticoid Receptor, and Hepatic Nuclear Factor 4{alpha} Mol. Pharmacol., September 1, 2005; 68(3): 747 - 757. [Abstract] [Full Text] [PDF]

				M. Qatanani, J. Zhang, and D. D. Moore Role of the Constitutive Androstane Receptor in Xenobiotic-Induced Thyroid Hormone Metabolism Endocrinology, March 1, 2005; 146(3): 995 - 1002. [Abstract] [Full Text] [PDF]