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

TY - JOUR

T1 - 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

AU - Gotfryd, Kamil

AU - Hansen, Maria

AU - Kawa, Anna

AU - Ellerbeck, Ursula

AU - Nau, Heinz

AU - Berezin, Vladimir

AU - Bock, Elisabeth

AU - Walmod, Peter S

N1 - © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

U2 - 10.1111/j.1742-7843.2011.00702.x

DO - 10.1111/j.1742-7843.2011.00702.x

M3 - Journal article

C2 - 21439023

SN - 1742-7843

VL - 109

SP - 164

EP - 174

JO - Basic & Clinical Pharmacology & Toxicology Online

JF - Basic & Clinical Pharmacology & Toxicology Online

IS - 3

ER -