Inhibitory Effect of Dimethyl Sulforxide on Phenytoin-induced Fetal Cleft Palate and Maternal Corticosterone Level

Phenytoin의 태아 구개열 유발과 모체 혈청 Corticosterone 증가에 대한 Dimethyl Sulfoxide 억제 작용

It is well known that phenytoin (PHT), a commonly prescribed anticonvulsant, has teratogenicity in experimental animals and human. The major malformation induced by PHT in mouse is cleft palate. The mechanisms of the embryotoxic effects of PHT are unknown. However, PHT and synthetic glucocorticoids share several features with respect to their teratogenicity, and it was known that PHT increased maternal corticosterone level. Therefore PHT-induced cleft palate may be mediated indirectly by elevated maternal corticosterone. Recently it was reported that secalonic acid Dinduced cleft palate and elevated endogenous corticosterone level, and that such effects were antagonized by DMSO. The purpose of this work was to investigate whether the elevated maternal corticosterone is associated with the teratogenicity of PHT in the ICR mouse fetuses by treatment with PHT or PHT plus DMSO. PHT (74mg/kg, BW) was daily administered intraperitoneally on day 10~12 of gestation with and without DMSO(2ml/kg, BW), and the fetal malformation was observed on day 18. Maternal serum corticosterone and fetal PHT levels were determined by HPLC. The results are summarized as follows. 1)The percentage of cleft palate incidense in fetuses following treatment with PHT on day 10~12 of gestation was 51.7%. 2)There was a significant decrement in the cleft palate incidence in fetuses to 30.8% in the group treated with PHT plus DMSO compared with 51.7% in that with PHT alone. 3) Maternal serum corticosterone levels following treatment with PHT on day 10~12 of gestation increased by 116~343% compared with that of vehicle control. Such effect was antagonized by DMSO. 4)PHT concentration in the fetuses was not affected by DMSO. These results suggest that PHT-induced cleft-palate in fetuses seems to be closely associated with the elevation of maternal corticosterone level.