Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 7 May 2013
Vol. 6, Issue 274, p. ra31
[DOI: 10.1126/scisignal.2003705]

RESEARCH ARTICLES

Editor's Summary

Antagonistic Activation
Phenobarbital stimulates the transcription of genes in the liver that encode drug metabolism enzymes by indirectly stimulating the constitutive active androstane receptor (CAR). Mutoh et al. identified epidermal growth factor receptor (EGFR) as a cell surface binding target of phenobarbital. Phenobarbital bound to EGFR and blocked the binding of the ligand EGF, thereby preventing the activation of EGFR. This inhibition of EGFR promoted the activation of CAR. Molecular simulation predicted that phenobarbital and EGF share binding sites on EGFR. Together, the findings indicate that phenobarbital stimulates the nuclear activity of CAR by inhibiting the activity of EGFR at the cell surface.

Citation: S. Mutoh, M. Sobhany, R. Moore, L. Perera, L. Pedersen, T. Sueyoshi, M. Negishi, Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling. Sci. Signal. 6, ra31 (2013).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors.
R. Luisier, H. Lempiainen, N. Scherbichler, A. Braeuning, M. Geissler, V. Dubost, A. Muller, N. Scheer, S.-D. Chibout, H. Hara, et al. (2014)
Toxicol. Sci.
   Abstract »    Full Text »    PDF »
Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion.
R. Luisier, E. B. Unterberger, J. I. Goodman, M. Schwarz, J. Moggs, R. Terranova, and E. van Nimwegen (2014)
Nucleic Acids Res. 42, 4180-4195
   Abstract »    Full Text »    PDF »
Dose-Response Modeling of Early Molecular and Cellular Key Events in the CAR-Mediated Hepatocarcinogenesis Pathway.
D. R. Geter, V. S. Bhat, B. B. Gollapudi, R. Sura, and S. D. Hester (2014)
Toxicol. Sci. 138, 425-445
   Abstract »    Full Text »    PDF »
Utility of B-13 Progenitor-Derived Hepatocytes in Hepatotoxicity and Genotoxicity Studies.
P. M. E. Probert, G. W. Chung, S. J. Cockell, L. Agius, P. Mosesso, S. A. White, F. Oakley, C. D. A. Brown, and M. C. Wright (2014)
Toxicol. Sci. 137, 350-370
   Abstract »    Full Text »    PDF »
Flame Retardant BDE-47 Effectively Activates Nuclear Receptor CAR in Human Primary Hepatocytes.
T. Sueyoshi, L. Li, H. Wang, R. Moore, P. R. S. Kodavanti, H.-J. Lehmler, M. Negishi, and L. S. Birnbaum (2014)
Toxicol. Sci. 137, 292-302
   Abstract »    Full Text »    PDF »
Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling.
H. Yang, B. Garzel, S. Heyward, T. Moeller, P. Shapiro, and H. Wang (2014)
Mol. Pharmacol. 85, 249-260
   Abstract »    Full Text »    PDF »
Old Dance with a New Partner: EGF Receptor as the Phenobarbital Receptor Mediating Cyp2B Expression.
S. A. Meyer and R. L. Jirtle (2013)
Science Signaling 6, pe16
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882