Fantel A G, Person R E, Tracy J W, Juchau M R
Department of Pediatrics, University of Washington, Seattle 98195.
Teratology. 1988 Mar;37(3):213-21. doi: 10.1002/tera.1420370306.
We report the results of studies on the reductive activation of the schistosomicidal agent, niridazole (NDZ). Intact rat embryos in vitro reduced this compound, generating a stable metabolite in the presence of 5% O2. By contrast, embryo and yolk sac homogenates or liver microsomes appeared to require anaerobiasis. Malformation incidence--specifically, axial asymmetry--showed a strong correlation with nitroreductase activity rates when the latter were modulated by oxygen tension. Data presented here suggest that when embryos are exposed to NDZ under conditions of low oxygen in vitro, redox cycling ensues with molecular oxygen serving to oxidize early reduction products. This process continues, regenerating the parent compound until oxygen is depleted locally. The basis of this localized depletion is unknown, but inability of the immature supply system to replete oxygen or demand by precociously aerobic tissues may be involved. Once local anaerobiasis is attained, further reduction could generate toxic metabolites capable of covalently binding cellular macromolecules. Localized hypoxia represents another potential mechanism of dysmorphogenesis.
我们报告了关于杀血吸虫剂硝唑咪（NDZ）还原激活的研究结果。体外完整的大鼠胚胎可还原该化合物，在5%氧气存在的情况下生成一种稳定的代谢物。相比之下，胚胎和卵黄囊匀浆或肝微粒体似乎需要无氧环境。当通过氧张力调节硝基还原酶活性速率时，畸形发生率——特别是轴向不对称——与该活性速率呈现出强烈的相关性。此处呈现的数据表明，当胚胎在体外低氧条件下暴露于NDZ时，会发生氧化还原循环，分子氧用于氧化早期还原产物。这个过程持续进行，使母体化合物再生，直到局部氧气耗尽。这种局部耗尽的基础尚不清楚，但可能涉及未成熟供应系统无法补充氧气或早熟需氧组织的需求。一旦达到局部无氧状态，进一步的还原可能会产生能够与细胞大分子共价结合的有毒代谢物。局部缺氧代表了致畸的另一种潜在机制。
