Resolving studies on mechanism of developmental toxicity induced by chemical substances in culture system

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To investigate clearly the mechanism of developmental toxicity induced by chemical substances, the whole embryo culture system using day 10.5 to 12.5 rat embryos of gestation was confirmed. Aspirin, salicylic acid and aminopyrine produced malformations in cultured rat embryos at day 11.5 of gestation. Caffeine caused malformation in cultured 12.5 day old rat embryo. Similar effect of caffeine was observed with 11.5 day old embryos, but in lower quantity. The embryotoxicity of cyclophosphamide and DMSO were evaluated in cultured 10.5 day old rat embryos. The whole embryo culture system was utilized in order to avoid potentially confounding meternal factors. Phenobarbital pretreated rat lever S-9 fraction singificantly increased the embryotoxicity and malformations of aminopyrine. And then teratological potency of 4-aminoantipyrine or 4-acetoamidoantipyrine was less than that of aminopyrine on cultured rat embryos. These results suggest that intrinsic teratogenicity, true active compound, of aminopyrine would be 3-position hydroxy metabolites rather than aminopyrine itself or 4-position N-demethyl metabolites. The increase of gamma-glutamyltranspeptidase activity in rat liver during perinatal period was observed in agreement with the elevation of cysteine consunption in fetus and the reduction of conversion from methionine to cysteine in this period. Sex and species differences of hepatic glutathione S-transferase and cytochrome P-450 in experimantal animals including monkey were investigated.