The activity of antiepileptic drugs as histone deacetylase inhibitors
The activity of antiepileptic drugs as histone deacetylase inhibitors
复制标题
DOI：
10.1111/j.0013-9580.2004.00104.x
复制
发表时间：
2004-07-01
期刊：
影响因子：
5.6
通讯作者：
Bialer, M
中科院分区：
文献类型：
--
作者：
Eyal, S;Yagen, B;Bialer, M
目的：丙戊酸（Valproic acid，VPA）是一种广泛应用的抗癫痫药物，近年来发现其对组蛋白脱乙酰酶（Histone deacetylases，HDACs）有抑制作用。多种结构的HDAC抑制剂，例如异羟肟酸、羧酸和环四肽，对转化和非转化细胞具有各种作用，包括神经调节和神经保护。本研究的目的是评估比较传统和较新的抗癫痫药物作为HDAC inhibitors.Methods的活动：培养后的HeLa细胞与测试的抗癫痫药物，组蛋白乙酰化进行了评估，通过免疫印迹与乙酰化组蛋白H4的抗体。通过使用HeLa细胞核提取物作为HDAC来源和乙酰化赖氨酸底物来估计AED对HDAC的直接抑制。我们发现，除了VPA，托吡酯（TPM）抑制HDAC的表观Ki值为2.22 +/- 0.67 mM。虽然左乙拉西坦（LEV）对HDAC没有直接影响，但其在人体内的主要羧酸代谢物2-吡咯烷酮丁酸（PBA），抑制HDAC，Ki值为2.25 +/- 0.78 mM。AED LEV、苯巴比妥、苯妥英、卡马西平、乙琥胺、加巴喷丁和氨己烯酸不抑制HDAC。直接抑制HDAC的化合物也诱导乙酰化组蛋白H4在HeLa细胞中的积累。TPM和PBA对组蛋白乙酰化的影响是显着的，在0.25 mM和1 mM，force.Conclusions：我们发现，除了VPA，较新的AED TPM和LEV的主要代谢产物，PBA，能够诱导组蛋白超乙酰化在人类细胞中，虽然具有较低的效力比VPA。
Purpose: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors.Methods: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate.Results: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent K-i values of 2.22 +/- 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinonen-butyric acid (PBA), inhibited HDACs with Ki values of 2.25 +/- 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively.Conclusions: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.