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

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 B[6]+B[12] without and with folinic acid, serine with folinic acid, and carnitine was found to reduce valproate- induced exencephaly rate. Vitamin B[6]+B[12] 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 advise 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 antiepileptic agents with low teratogenic potency

Mutagenic potentials of certain herbal extracts in mutant strains of salmonella typhimurium

Damage to DNA appears to be the major cause of most cancer and genetic birth defects and may contribute to aging heart diseases. The genetical damage can be caused by many substances used in medicine, industry, pest control and food preservatives. The present study investigated the mutagenic potentials of certain medicinal plants commonly used in traditional medicine, using five mutant strains of salmonella typhimurium/mammalian microsome in-vitro test [Ames test]. The histidine-dependent strains [TA 98, TA 100, TA 1535, TA 1537, and TA 1538] were used to detect DNA frame shifts and base-pair substitutions, which were recommended for preliminary screening of potential mutagens and carcinogens. Three different concentrations of each extract were used in the presence and absence of activated rat liver microsomal enzymes [S9 mix] to detect whether they produce direct or indirect genotoxic activity. Positive controls using diagnostic mutagens were also used to confirm the reversion properties and specificity of each strain and efficacy of the S9 mix. The results showed that extracts of the 16 herbs investigated did not induce mutations in the Salmonella mammalian microsome general mutagenicity test of Ames in concentrations up to 10 mg/plate