Carbamazepine is an inhibitor of histone deacetylases

Andreas S Beutler, SiDe Li, Rebekka Nicol, Martin J. Walsh

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Carbamazepine (CBZ) is a common antiepileptic drug (AED) that acts through multiple mechanisms including blockade and potentiation of cation channels and modulation of neurotransmitter levels. Whether it affects any component of the gene transcription machinery is unknown. Histone deacetylases (HDAC) are important in the regulation of gene expression and are currently considered a potential target for drug development. Using a high-throughput screening assay based on acetylation-dependent gene expression, we identified CBZ as a candidate and proceeded to characterize its effects on HDAC. CBZ induced acetylation of histone H4 in the HepG2 liver carcinoma cell line. CBZ inhibited HDAC 3 and HDAC 7, which are representatives of HDAC class I and II respectively. Quantitative testing in an in vitro assay demonstrated HDAC inhibition with an IC 50 of 2 μM. The major active metabolite of CBZ, CBZ-10,11-epoxide, was found to have the same HDAC inhibitory activity. The IC50 is considerably lower than therapeutic plasma levels that are typically achieved in patients (25-51 μM). CBZ shares important clinical characteristics (teratogenicity, activity as a mood stabilizer) with valproic acid, another AED that was recently identified as an inhibitor of HDAC. These observations raise the possibility that HDAC inhibition may contribute to the pharmacological profile of CBZ.

Original languageEnglish (US)
Pages (from-to)3107-3115
Number of pages9
JournalLife Sciences
Volume76
Issue number26
DOIs
StatePublished - May 13 2005
Externally publishedYes

Fingerprint

Histone Deacetylases
Carbamazepine
Acetylation
Gene expression
Anticonvulsants
Assays
High-Throughput Screening Assays
Gene Components
Valproic Acid
Gene Expression Regulation
Transcription
Metabolites
Liver
Histones
Inhibitory Concentration 50
Machinery
Neurotransmitter Agents
Cations
Screening
Genes

Keywords

  • Carbamazepine
  • Chromatin
  • Histone deacetylase inhibitor

ASJC Scopus subject areas

  • Pharmacology

Cite this

Carbamazepine is an inhibitor of histone deacetylases. / Beutler, Andreas S; Li, SiDe; Nicol, Rebekka; Walsh, Martin J.

In: Life Sciences, Vol. 76, No. 26, 13.05.2005, p. 3107-3115.

Research output: Contribution to journalArticle

Beutler, Andreas S ; Li, SiDe ; Nicol, Rebekka ; Walsh, Martin J. / Carbamazepine is an inhibitor of histone deacetylases. In: Life Sciences. 2005 ; Vol. 76, No. 26. pp. 3107-3115.
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