New molecular bioassays for the estimation of the teratogenic potency of valproic acid derivatives in vitro:: Activation of the peroxisomal proliferator-activated receptor (PPARδ)
New molecular bioassays for the estimation of the teratogenic potency of valproic acid derivatives in vitro:: Activation of the peroxisomal proliferator-activated receptor (PPARδ)
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DOI：
10.1006/taap.1999.8770
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发表时间：
1999-11-01
影响因子：
3.8
通讯作者：
Nau, H
中科院分区：
文献类型：
--
作者：
Lampen, A;Siehler, S;Nau, H
在怀孕早期使用抗癫痫药物丙戊酸(2-丙基戊酸，VPA)治疗可能会导致人类和小鼠的畸形效应(神经管缺陷)。VPA和一种致畸衍生物特异性地诱导F9畸胎癌细胞分化并激活PPAR Delta。我们现在已经通过定量比较它们的致畸效力和它们在两个新的体外系统中的作用来研究11个VPA相关化合物的构效关系。基于Rous肉瘤病毒(RSV)启动子驱动的与F9细胞分化相关的报告基因的诱导，建立了一种适合于高通量和定量筛选的系统。结构活性研究表明，只有致畸的VPA衍生物才能在F9细胞中诱导应答，并在中国仓鼠卵巢(CHO)细胞中激活PPAR Delta依赖的报告系统。VPA相关的2-烷基-戊烯酸侧链长度的增加在基于细胞培养的检测中产生更强的诱导剂，这也显示出更高的致畸率和胚胎致死率。PPAR Delta的激活与F9细胞试验的效果和体内的致畸能力有很好的相关性(p<；0.007)。对所提出的一组化合物的效果的评估允许得出结论，体外系统真实地反映了VPA相关化合物的致畸作用。PPAR Delta的激活是否与胚胎正常发育的中断有因果关系，或者它是否反映了其他尚不清楚的VPA诱导事件，仍有待确定。(C)1999年学术出版社。
Therapy with the antiepileptic drug valproic acid (2-propylpentanoic acid, VPA) during early pregnancy can cause teratogenic effects (neural tube defects) in humans and in mice. VPA and a teratogenic derivative specifically induce differentiation of F9 teratocarcinoma cells and activate PPAR delta. We have now studied structure-activity relationships of 11 VPA-related compounds by quantitatively comparing their teratogenic potency with their effects in the two novel in vitro systems. Based on the induction of a Rous sarcoma virus (RSV) promoter-driven reporter gene, which is associated with the differentiation of F9 cells, a system suitable for high-throughput and quantitative screening was established, Structure-activity investigations showed that only teratogenic derivatives of VPA induced the response in F9 cells as well as activated the PPAR delta-dependent reporter system in Chinese hamster ovary (CHO) cells. Increases in the length of the side chain in the VPA-related 2-alkyl-pentynoic acid generate more potent inducers in the cell-culture-based assays, which also show higher teratogenicity and embryonic lethality rates. Activation of PPAR delta correlated well with the effects in the F9 cell assay and with teratogenic potency in vivo (p < 0.007). Evaluation of the effects of the presented set of compounds allows the conclusion that the in vitro systems faithfully reflect teratogenicity of VPA-related compounds. Whether the activation of PPAR delta is causally related to the disruption of proper embryonic development or whether it reflects other yet unknown VPA-induced events remains to be established. (C) 1999 Academic Press.