GABA(A)/central benzodiazepine receptor and peripheral benzodiazepine receptor ligands as inducers of phenobarbital-inducible CYP2B and CYP3A

Biochemical Pharmacology
Christian RobergeA Anderson

Abstract

A sequence critical for phenobarbital (PB) induction, the PB response unit (PBRU), situated upstream of the rat CYP2B1 and CYP2B2 genes, includes two nuclear receptor binding sites, NR1 and NR2. When NR1 and NR2 are mutated PB responsiveness is abolished. While no nuclear receptor for which PB is an agonist ligand has yet been identified, PB is a ligand of GABA(A) receptors and it can displace [(3)H] 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195) from its binding site on the peripheral benzodiazepine receptor (PBR). We assessed CYP2B levels in primary rat hepatocytes following treatment with 10 ligands of either or both of these receptors. All compounds tested were found to be CYP2B1/CYP2B2 inducers and most were CYP3A inducers. Five had not previously been described as CYP2B1/CYP2B2 inducers: bicuculline, flunitrazepam, 4'-chlorodiazepam (Ro5-4864), N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN 1-27) and 7-(dimethylcarbamoyloxy)-6-phenylpyrrolo-[2,1-d][1,5]benzothiazepine (DCPPBT). Reporter gene analysis demonstrated that CYP2B induction by these agents and other PBR or GABA(A) receptor ligands is mediated through the PBRU and the NR1/NR2 sites, suggesting a molecular mechanism sim...Continue Reading

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Citations

Nov 7, 2007·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ashu JohriDevendra Parmar
Sep 8, 2009·Expert Opinion on Drug Metabolism & Toxicology·Etienne Audet-WalshAlan Anderson
Jan 13, 2015·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Shikha SrivastavaDevendra Parmar
Dec 3, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Etienne Audet-Walsh, Alan Anderson
Oct 26, 2016·Psychiatry and Clinical Neurosciences·Jui-Kang TsaiCheng-Fang Yen
May 21, 2011·Congenital Anomalies·Yumei LiYukiharu Matsumoto
Sep 11, 2008·Biochemical Pharmacology·Etienne Audet-WalshAlan Anderson

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