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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
Author(s) -
Gotfryd Kamil,
Hansen Maria,
Kawa Anna,
Ellerbeck Ursula,
Nau Heinz,
Berezin Vladimir,
Bock Elisabeth,
Walmod Peter S.
Publication year - 2011
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2011.00702.x
Subject(s) - acetylation , histone deacetylase , phosphorylation , histone deacetylase inhibitor , valproic acid , chemistry , pharmacology , biochemistry , cell growth , histone , biology , epilepsy , neuroscience , gene
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.