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

为了明确化学物质诱导发育毒性的机制，确认了使用妊娠10.5 - 12.5天大鼠胚胎的全胚胎培养系统。阿司匹林，水杨酸和氨基比林在培养的大鼠胚胎在妊娠第11.5天产生畸形。咖啡因可引起培养12.5天的大鼠胚胎畸形。在11.5天龄的胚胎中观察到咖啡因的类似作用，但数量较低。在培养的10.5日龄大鼠胚胎中评价了环磷酰胺和DMSO的胚胎毒性。使用整个胚胎培养系统，以避免潜在的混淆母体因素。苯巴比妥预处理大鼠肝S-9组份可显著增加氨基比林的胚胎毒性和畸形率。4-氨基安替比林和4-乙酰氨基安替比林对体外培养大鼠胚胎的致畸作用均小于氨基比林。这些结果表明，氨基比林的内在致畸性，真正的活性化合物，将是3位羟基代谢产物，而不是氨基比林本身或4位N-去甲基代谢产物。围产期大鼠肝脏γ-谷氨酰转肽酶活性增高，与胎鼠半胱氨酸消耗增高和蛋氨酸向半胱氨酸转化减少相一致。本文研究了包括猴在内的实验动物肝脏谷胱甘肽S-转移酶和细胞色素P-450的性别和种属差异。

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.