Elmazar M M, Thiel R, Nau H
Institute of Toxicology and Embryopharmacology, Free University Berlin, Germany.
Fundam Appl Toxicol. 1992 Apr;18(3):389-94. doi: 10.1016/0272-0590(92)90137-7.
The effect of administration of folinic acid, vitamin B6 + vitamin B12, and their combination on valproic acid (VPA)-induced teratogenesis was studied in NMRI mice. VPA (500 mg/kg, sc) was injected on Day 8 of gestation and the vitamins (two dose levels) were injected ip 1 hr before, immediately before, and 1 hr after VPA administration. Folinic acid significantly reduced VPA-induced resorptions (21-24%), and palate, rib, and sternebral malformations. Exencephaly and spina bifida occulta were also reduced (14 and 40%, respectively), but the difference was not statistically significant. On the other hand, vitamin B6 + vitamin B12 significantly reduced VPA-induced exencephaly (23%), spina bifida occulta (80%), palate and rib malformations, kidney abnormalities, and fetal weight retardation. A combination of the three vitamins was effective in reducing VPA-induced exencephaly (23-30%), spina bifida occulta (60%), and palate and rib malformations. The protection against VPA-induced malformations was not complete and was not always dose related, and the reduction in exencephaly rate was only significant in the absence of a reduction in resorption rate. Full-length cleft palate, sternebral malformations, and retarded sternebral and caudal ossification were, however, increased by the high dose of combined vitamin administration. The present study supports the view that VPA-induced teratogenesis may be mediated via an interaction with folate metabolism. Although folinic acid and vitamin B6 + vitamin B12 can effectively reduce VPA malformations, the protection was not complete, which may suggest the involvement of other factors. Furthermore, the dose levels should be carefully chosen since high doses of the combined vitamins can actually increase the incidence of certain defects.
在NMRI小鼠中研究了亚叶酸、维生素B6加维生素B12及其组合对丙戊酸（VPA）诱导的致畸作用。在妊娠第8天皮下注射VPA（500mg/kg），并在VPA给药前1小时、给药前即刻和给药后1小时腹腔注射维生素（两种剂量水平）。亚叶酸显著降低了VPA诱导的吸收（21%-24%）以及腭、肋骨和胸骨畸形。无脑儿和隐性脊柱裂也有所减少（分别为14%和40%），但差异无统计学意义。另一方面，维生素B6加维生素B12显著降低了VPA诱导的无脑儿（23%）、隐性脊柱裂（80%）、腭和肋骨畸形、肾脏异常以及胎儿体重发育迟缓。三种维生素的组合有效降低了VPA诱导的无脑儿（23%-30%）、隐性脊柱裂（60%）以及腭和肋骨畸形。对VPA诱导畸形的保护并不完全，且并不总是与剂量相关，无脑儿发生率的降低仅在吸收发生率未降低的情况下才具有显著意义。然而，高剂量联合维生素给药会增加全腭裂、胸骨畸形以及胸骨和尾骨骨化迟缓的发生率。本研究支持这样的观点，即VPA诱导的致畸作用可能通过与叶酸代谢的相互作用介导。尽管亚叶酸和维生素B6加维生素B12可有效降低VPA畸形，但保护并不完全，这可能提示其他因素的参与。此外，应谨慎选择剂量水平，因为高剂量联合维生素实际上可能增加某些缺陷的发生率。
