Research ArticlePharmacology

Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling

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Science Signaling  07 May 2013:
Vol. 6, Issue 274, pp. ra31
DOI: 10.1126/scisignal.2003705

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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.