Fantel A G, Greenaway J C, Walker E, Juchau M R
Teratology. 1986 Feb;33(1):105-12. doi: 10.1002/tera.1420330113.
The antischistosomal drug niridazole (NDZ) was found to be teratogenic in a concentration-dependent manner from 10 to 50 micrograms/ml (47-233 microM) in rat embryos cultured from day 10 to day 11. A striking malformation consisting of axial asymmetry in which the right side of the embryo showed severe necrosis was the predominant malformation. The drug showed significantly greater dysmorphogenic activity at low (5%) compared to high (20%) oxygen tensions in cultures. Coincubation of embryos and NDZ with an exogenous source of metabolic enzymes and cofactors (NADPH) failed to modify teratogenicity. Inclusion of CO in the culture atmosphere significantly reduced the malformation incidence as did preincubation of the drug with S-9 and cofactors in medium with low O2 tension. Treatment of gravida with NDZ up to and including the maternal-lethal dose failed to result in observable malformations despite the use of several routes of exposure. These data lead us to hypothesize that rat embryos are capable of performing the reductive activation of NDZ in a fashion analogous to the schistosome but that reductive extraembryonic metabolism may result in teratogenic bioinactivation.
抗血吸虫药物硝唑咪（NDZ）在第10天至第11天培养的大鼠胚胎中，在10至50微克/毫升（47 - 233微摩尔）的浓度范围内呈浓度依赖性致畸。一种由轴向不对称组成的显著畸形是主要畸形，其中胚胎右侧显示严重坏死。与高（20%）氧张力培养相比，该药物在低（5%）氧张力培养中显示出显著更高的致畸活性。胚胎和NDZ与代谢酶和辅因子（NADPH）的外源来源共同孵育未能改变致畸性。在培养气氛中加入一氧化碳显著降低了畸形发生率，在低氧张力培养基中用S - 9和辅因子对药物进行预孵育也有同样效果。尽管使用了几种给药途径，但用NDZ治疗妊娠大鼠直至包括母体致死剂量，均未导致可观察到的畸形。这些数据使我们推测，大鼠胚胎能够以类似于血吸虫的方式进行NDZ的还原激活，但胚胎外的还原代谢可能导致致畸性生物失活。
