Cited by 1,758Histone Deacetylase Inhibitors ResearchPharmacological Effects and Toxicity StudiesEpigenetics and DNA Methylation

Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

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Phiel, Christopher J., Zhang, Fang, Huang, Eric Y., Guenther, Matthew G., Lazar, Mitchell A., Klein, Peter S.·2001·Journal of Biological Chemistry

Abstract

Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC(50) for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.

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  • Phiel et al. (174), using cell lines, showed that valproate at therapeutic concentrations inhibits histone deacetylases; this inhibition correlates with increased expression of multiple genes.

    “Phiel et al. (174), using cell lines, showed that valproate at therapeutic concentrations inhibits histone deacetylases; this inhibition correlates with increased expression of multiple genes.”
  • Valproic acid is known as a reactivator of silenced genes and appeared to be a weak reactivator of full mutation.

    “The third tested compound is valproic acid (101), which is already known as a reactivator of silenced genes (102) that appeared to be a weak reactivator of FM (103).”

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  1. Dixon, J. F., and Hokin, L. E. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4757-4760
  2. Nonaka, S., Hough, C. J., and Chuang, D. M. (1998) Proc. Natl. Acad. Sci.
  3. York, J. D., Ponder, J. W., and Majerus, P. W. (1995) Proc. Natl. Acad. Sci.
  4. Klein, P. S., and Melton, D. A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 8455-8459
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Authors
Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A., & Klein, P. S.
Affiliations
Howard Hughes Medical Institute (US)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2001-09
Volume
276
Issue
39
Pages
36734-36741
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2098249941
Cited by
1,758
References
67
Citations by year
2026: 32 · 2025: 50 · 2024: 39 · 2023: 46 · 2022: 65 · 2021: 78 · 2020: 77 · 2019: 53 · 2018: 56 · 2017: 66 · 2016: 93 · 2015: 90 · 2014: 102 · 2013: 110 · 2012: 93
FWCI
13.57
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (DK43806)
  • National Institute of Mental Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK43806, R01DK045586, DK 45586)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
valproic acid, histone deacetylase inhibition, HDAC1, trichostatin A, histone hyperacetylation, lithium, bipolar disorder, epilepsy, teratogenicity, congenital malformations, antiepileptic drugs, mood stabilizers, transcriptional activation
MeSH terms
Acetylation, Animals, Anticonvulsants, Cell Line, Dose-Response Relationship, Drug, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Lithium, Luminescent Proteins, Plasmids, Promoter Regions, Genetic, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Teratogens, Time Factors, Transcription, Genetic, Transfection, Valproic Acid, Xenopus, Signal Transduction, Calcium-Calmodulin-Dependent Protein Kinases, Antimanic Agents, Inhibitory Concentration 50, Zebrafish Proteins, Glycogen Synthase Kinase 3, Green Fluorescent Proteins, Wnt Proteins, Histone Deacetylase 1, Histone Deacetylase Inhibitors

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