|Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.|
|PMID: 11473107 Owner: NLM Status: MEDLINE|
|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.|
|C J Phiel; F Zhang; E Y Huang; M G Guenther; M A Lazar; P S Klein|
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|Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2001-07-25|
|Title: The Journal of biological chemistry Volume: 276 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2001 Sep|
|Created Date: 2001-09-24 Completed Date: 2001-11-01 Revised Date: 2009-11-19|
Medline Journal Info:
|Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States|
|Languages: eng Pagination: 36734-41 Citation Subset: IM|
|Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148, USA.|
|APA/MLA Format Download EndNote Download BibTex|
Anticonvulsants / pharmacology*
Antimanic Agents / pharmacology*
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Dose-Response Relationship, Drug
Glycogen Synthase Kinase 3
Green Fluorescent Proteins
Histone Deacetylase 1
Histone Deacetylase Inhibitors*
Histone Deacetylases / metabolism*
Histones / metabolism
Hydroxamic Acids / pharmacology
Inhibitory Concentration 50
Lithium / pharmacology
Luminescent Proteins / metabolism
Plasmids / metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins / metabolism
Recombinant Fusion Proteins / metabolism
Valproic Acid / pharmacology*
|DK43806/DK/NIDDK NIH HHS; DK45586/DK/NIDDK NIH HHS|
|0/Anticonvulsants; 0/Antimanic Agents; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/Hydroxamic Acids; 0/Luminescent Proteins; 0/Proto-Oncogene Proteins; 0/Recombinant Fusion Proteins; 0/Teratogens; 0/Wnt Proteins; 0/Zebrafish Proteins; 147336-22-9/Green Fluorescent Proteins; 58880-19-6/trichostatin A; 7439-93-2/Lithium; 99-66-1/Valproic Acid; EC 184.108.40.206/Calcium-Calmodulin-Dependent Protein Kinases; EC 220.127.116.11/Glycogen Synthase Kinase 3; EC 18.104.22.168/HDAC1 protein, human; EC 22.214.171.124/Histone Deacetylase 1; EC 126.96.36.199/Histone Deacetylases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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