Valproic acid-induced neural tube defects.
Valproic acid-induced neural tube defects.
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丙戊酸引起的神经管缺陷。
DOI：
10.1002/9780470514559.ch9
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
H. Nau
中科院分区：
文献类型：
--
作者：
H. Nau
妊娠早期使用丙戊酸 (VPA) 进行抗癫痫药物治疗可导致 1-2% 的脊柱裂（人类后神经管闭合缺陷）发生率。 VPA 在小鼠中产生的主要缺陷是无脑畸形，即前神经管的闭合缺陷。适当的给药方案（妊娠第 9 天连续服用 VPA）也可以降低小鼠的开放性脊柱裂发生率和高隐性脊柱裂发生率。最接近的致畸剂很可能是母体药物而不是代谢物。结构-活性关系显示出高致畸效力的严格结构要求：该分子必须包含一个α-氢原子、一个羧基官能团并在C-2上分支，具有两条链，每条链包含三个碳原子，以获得最大活性。如果这两条碳链不同，则存在对映体。合成了成对的对映异构体，结果显示它们在致畸效力方面存在显着差异。每种化合物的两种对映体到达胚胎的程度相同，因此，对映体的内在致畸活性不同。这表明药物和胚胎内的手性结构之间发生立体选择性相互作用。 VPA致畸的分子机制尚不清楚；一种假设是 VPA 与胚胎叶酸代谢相互作用。
Antiepileptic drug therapy with valproic acid (VPA) during early pregnancy can result in a 1-2% incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. An appropriate dosing regimen (consecutive doses of VPA on Day 9 of gestation) can also result in a low incidence of spina bifida aperta and a high incidence of spina bifida occulta in the mouse. It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function and branching on C-2 with two chains containing three carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present. Pairs of enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Both enantiomers of each compound reach the embryo to the same degree, therefore, the intrinsic teratogenic activity of the enantiomers differs. This suggests that stereoselective interaction occurs between the drugs and a chiral structure within the embryo. The molecular mechanism of the teratogenicity of VPA is not known; one hypothesis is that VPA interacts with embryonic folate metabolism.
丝氨酸羟甲基转移酶将 5,10-次甲基四氢蝶酰谷氨酸水解为 5-甲酰四氢蝶酰谷氨酸的酶机制。
影响因子：
2.9
作者：
Stover,P;Schirch,V
通讯作者：
Schirch,V
胚胎细胞内 pH 值降低：乙酰唑胺诱导肢体畸形的潜在机制。
影响因子：
3.8
作者：
Scott,WJ;Duggan,CA;Schreiner,CM;Collins,MD
通讯作者：
Collins,MD