Toward the mechanism of valproate teratogenesis: Structural basis and interactions with agents that alter folate metabolism

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The hypothesis that valproate-induced neural tube defects (NTDs) may be due to interference with folate metabolic pathways was investigated by studying the possible interactions of valproate and a number of agents that modulate folate metabolism. Valproate (VPA)-induced exencephaly (an anterior NTDs) in NMRI mice was used as an animal model. A single dose of valproic acid sodium salt (300-500 mg/kg, s.c.) on day 8 of gestation produced a dose related increase in exencephaly rate, embryolethality, and fetal weight retardation. Supplementation with vitamin B6 + B12 without and with folinic acid, serine with folinic acid, and carnitine was found to reduce valproate-induced exencephaly rate. Vitamin B6 + B12 and methionine reduced VPA-induced fetal weight retardation and embryotoxicity, respectively. The protection was not complete and was not always dose related, and in case of carnitine, higher doses were devoid of such effects and even increased valproate-induced exencephaly. On the other hand, coadministration of valproate with low (threshold) doses of methotrexate, trimethoprim, nitrous oxide and ethanol was found to increase the incidence of exencephaly rate. Embryotoxicity was also increased as a result of such combinations except with trimethoprim. The observed effects were not due to altered valproate toxicokinetics in case of methotrexate and trimethoprim but was probably due to decreased valproate elimination by ethanol and advice against the use of these agents in valproate-treated epileptics during pregnancy. The previous results support the view that valproate-induced NTDs may be mediated via an interaction with folate metabolism. Study of the structural-activity relationships of several valproate analogues revealed a strict structural requirement for high teratogenic potency. In contrast, the anticonvulsant activity and neurotoxicity showed broader structural specificity. Furthermore, the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid and 2-n-propyl-4-pentynoic acid showed different teratogenic activity (S-enantiomers were more teratogenic than R-enantiomers) in contrast to anticonvulsant potency in the absence of pharmacokinetic differences. These findings opens the possibility for development of novel antiepileptics agents with low teratogenic potency.

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