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

By C. Phiel, Fang Zhang, E. Huang, M. Guenther, Mitchell A. Lazar, P. S. Klein. Journal of Biological Chemistry, 2001

1,768 citations recorded by the source corpus.

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 (IC50 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.

Subfields: Cellular and Molecular Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e5706c4d5cf09609a8f3afe4efa65fac6439bab0

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Citations in the corpus

Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells (2001, background): “While this manuscript was in preparation, inhibition of HDAC activity by VPA has also been reported by another group (Phiel et al., 2001).”
Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents (2015, background): “Comparing clinically important three drugs, vorinostat, entinostat and valproic acid that contain a hydroxamate, benzamide and a carboxylate metal binding moiety, respectively, a drastic change in the IC50 value was observed, when the hydroxamate (110–370 nM) [157,158] was changed to a benzamide (2 ”
Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline (2007, background): “Recently, VPA has been shown to directly inhibit histone deacetylases (HDACs) (Gottlicher et al., 2001; Phiel et al., 2001).”
Phenotypic plasticity and the epigenetics of human disease (2007, background): “For example, valproic acid is used to treat various disorders, including seizures, bipolar disorder and cancer, and valproic acid was recently found to be a potent histone deacetylase inhibito”
Histone-deacetylase inhibitors: novel drugs for the treatment of cancer (2002, background): “asp?DrugCode=1%2D1882&DrugName=VALPROIC+ACID+ORAL&DrugType=1">valproic acid , inhibit HDAC activity and affect the expression of numerous genes with disparate cellular function”
Combination therapy in combating cancer (2017, background): “com/oncotarget lymphoma but have also shown anti-cancer effects in solid tumours [103, 104].”