Grupo de Química Medicinal, Universidad de la República, Iguá, Montevideo, Uruguay.
Future Microbiol. 2011 Aug;6(8):847-50. doi: 10.2217/fmb.11.74.
Hall BS, Bot C, Wilkinson SR. Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites. J. Biol. Chem. 286, 13088-13095 (2011). The prodrug nifurtimox has been one of the pharmacologic alternatives to treat Chagas disease and currently forms part of a combinational therapy to treat West African trypanosomiasis. Despite this, nifurtimox's mechanism of action is only partially understood and has been related to induction of oxidative stress in the target cell. An alternative mechanism involving reductive activation by a eukaryotic type I nitroreductase has been described. Bloodstream form Trypanosoma brucei overexpressing enzymes, proposed to metabolize nifurtimox, were generated and only cells with elevated levels of the nitroreductase displayed altered susceptibility to the drug, implying that it has a key role in drug action. Reduction of nifurtimox by trypanosomal type I nitroreductases was shown to be insensitive to oxygen and yielded a product characterized by liquid chromatography/mass spectrometry as an unsaturated open chain nitrile. This nitrile inhibited both parasite and mammalian cell growth at equivalent concentrations, in marked contrast to the parental prodrug. These studies indicated that nifurtimox selectivity against T. brucei could be the result of the expression of a parasite-encoded type I nitroreductase.
霍尔 BS、博特 C、威尔金森 SR。利什曼原虫 I 型硝基还原酶激活硝呋替莫产生细胞毒性腈代谢物。J. 生物化学。286, 13088-13095 (2011)。前药硝呋替莫是治疗恰加斯病的药物之一，目前是治疗西非锥虫病联合治疗的一部分。尽管如此，硝呋替莫的作用机制仍不完全清楚，与靶细胞中氧化应激的诱导有关。已描述了涉及通过真核 I 型硝基还原酶还原激活的替代机制。生成了过表达用于代谢硝呋替莫的酶的血液期布氏锥虫，并仅显示出硝基还原酶水平升高的细胞对药物的敏感性发生改变，这表明它在药物作用中起关键作用。利什曼原虫 I 型硝基还原酶还原硝呋替莫对氧气不敏感，并生成通过液相色谱/质谱法表征为不饱和开链腈的产物。该腈以与母体前药相当的浓度抑制寄生虫和哺乳动物细胞的生长，形成鲜明对比。这些研究表明，硝呋替莫对 T. brucei 的选择性可能是寄生虫编码的 I 型硝基还原酶表达的结果。
