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.

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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.