Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen
Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen
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DOI：
10.1074/jbc.m101287200
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发表时间：
2001-09-28
影响因子：
4.8
通讯作者：
Klein, PS
中科院分区：
文献类型：
--
作者：
Phiel, CJ;Zhang, F;Klein, PS
丙戊酸被广泛用于治疗癫痫和双相情感障碍，也是一种强效致畸剂，但其在任何这些情况下的作用机制尚不清楚。我们报告，丙戊酸激活Wnt依赖的基因表达，类似于锂，治疗双相情感障碍的支柱。然而，丙戊酸通过一种不同的途径起作用，该途径涉及直接抑制组蛋白脱乙酰酶（HDAC 1的IC50 = 0.4 mM）。在治疗水平下，丙戊酸模拟组蛋白脱乙酰酶抑制剂阿司他丁A，导致培养细胞中组蛋白的过度乙酰化。丙戊酸，如阿司他丁A，也激活不同的外源和内源启动子的转录。此外，在脊椎动物胚胎中，丙戊酸和阿司他丁A具有非常相似的致畸作用，而丙戊酸的非致畸类似物不抑制组蛋白脱乙酰酶，也不激活转录。基于这些观察结果，我们认为组蛋白去乙酰化酶的抑制为丙戊酸诱导的出生缺陷提供了一种机制，也可以解释丙戊酸治疗双相情感障碍的疗效。
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 Wnt-dependent 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 (IC50 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.