title: The teratogenic potencies of valproic acid derivatives and their effects on biological end-points are related to changes in histone deacetylase and Erk1/2 activities.
abstract: Valproic acid (VPA) is a known teratogen. In the present study, the effects of VPA and seven VPA derivatives with different teratogenic potencies (isobutyl-, 5-methyl-, ethyl-, propyl-, butyl-, pentyl- and hexyl-4-yn-VPA) were investigated in L929 cells in vitro. Evaluated end-points included changes in cell proliferation, growth, cell cycle distribution, morphology, speed, glycogen synthase kinase-3β (GSK-3β) and Erk1/2 phosphorylation, and histone H3 acetylation. Changes in proliferation, growth, speed, Erk1/2 and GSK-3β-Tyr216 phosphorylation, and H3 acetylation were significantly associated with the teratogenic potencies of the VPA derivatives. However, in contrast to changes in Erk1/2 phosphorylation and H3 acetylation, significant changes in GSK-3β phosphorylation could only be obtained in response to prolonged incubation at high drug concentration. There was an association between changes in H3 acetylation and GSK-3β-Tyr216 phosphorylation, whereas none of these end-points were associated with changes in Erk1/2 phosphorylation. These results suggest that the teratogenic potencies of VPA and VPA derivatives are related to effects on both Erk1/2 and histone deacetylase activities, whereas changes in GSK-3β activity are possibly a secondary effect.
authors: Protein Laboratory, Institute of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors: Kamil
authors: K
authors: Gotfryd
authors: Maria
authors: M
authors: Hansen
authors: Anna
authors: A
authors: Kawa
authors: Ursula
authors: U
authors: Ellerbeck
authors: Heinz
authors: H
authors: Nau
authors: Vladimir
authors: V
authors: Berezin
authors: Elisabeth
authors: E
authors: Bock
authors: Peter S
authors: PS
authors: Walmod
mesh_terms: D000107:Acetylation; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D023381:Endpoint Determination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D013723:Teratogens / Q000633:toxicity*; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000633:toxicity*
chemical_list: D006657:Histones; D013723:Teratogens; D014635:Valproic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases