In vivo model to predict human fetal toxicity of xenobiotics : Establishment and evaluation of humanized mice carrying multiple forms of human fetal drug metabolizing enzymes.

大多数外源药物对人类胎儿的毒性是不可预测的，因为药物代谢酶，如细胞色素P450 (CYP)，存在于人类胎儿中，不存在于啮齿动物胎儿中。为了建立预测人类胎儿毒性的动物模型，我们通过转基因技术将多种形式的人类胎儿药物代谢酶引入小鼠体内。建立了四种携带人胎酶的转基因小鼠系。在小鼠36p系中，在小鼠胎儿中检测到人CYP1A1、CYP1B1、CYP3A7、环氧化酶(COX)-1和COX-2 mRNA水平的表达。在妊娠第9天用单剂量沙利度胺（100 mg/kg / wt.）治疗36p雌性小鼠，导致死亡或胚胎吸收增加。沙利度胺是一种众所周知的人类致畸物。因此，这些人源化小鼠可能成为预测化学物质对人类胎儿毒性的合适模型。

Most of the human fetal toxicities of xenobiotics are unpredictable, since drug metabolizing enzymes such as cytochrome P450 (CYP), which are present in human fetuses, do not exist in rodent fetuses. In order to establish and animal model to predict human fetal toxicities, we introduced multiple forms of human fetal drug metabolizing enzymes into mice by transgenic technique. Four transgenic lines of mice carrying human fetal enzymes were established. In the 36p line of mice, the expression of human CYP1A1, CYP1B1, CYP3A7, cyclooxygenase (COX)-1 and COX-2 at mRNA levels were detected in the mouse fetuses. Treatment of the 36p female mice with a single dose of thalidomide (100 mg/kg b wt.), a well-known teratogen in humans, on gestational day 9 resulted in the increased deaths or the resorptions of embryos. Thus, these humanized mice may become a suitable model to predict human fetal toxicities of chemicals.