Meshnick S R, Blobstein S H, Grady R W, Cerami A
J Exp Med. 1978 Aug 1;148(2):569-79. doi: 10.1084/jem.148.2.569.
The inability of the bloodstream form of Trypanosoma brucei brucei to decompose hydrogen peroxide forms the basis of our attempt to develop new pharmacological agents to kill these organisms. Approximately 1-3% of the oxygen consumed by these parasites appears in the form of hydrogen peroxide. Our previous observation that free radical initiators such as heme and hematoporphyrin D proved to be trypanocidal in vitro and in vivo, respectively, prompted this investigation into the mechanism of action of this class of compounds to enhance their therapeutic efficacy. The locus of H2O2 production within the trypanosome was examined using cell-free homogenates. Experiments described herein suggest that H2O2 is formed by the alpha-glycerol phosphate dehydrogenase in an adventitious manner, and that no enzymatic means of disposing of this potentially toxic compound are present with the organisms. Naphthoquinones were found to substantially increase the rate of both oxygen consumption and H2O2 production by trypanosomal mitochondrial preparations. Presumably, the naphthoquinones are acting as coenzyme Q analogues. The addition of sublytic concentrations of both naphthoquinones and heme leads to a synergistic lysis of the organisms in vitro. Another approach to increasing the susceptibility of T. b. brucei to free radical damage involved reduction of the intracellular concentration of glutathione. This was accomplished through the use of trypanocidal arsenicals. Melarsenoxide and heme acted synergistically in vitro, an effect which was further enhanced via addition of a naphthoquinone. Moreover, hematoporphyrin D and tryparsamide were shown to have a synergistic effect in T. b. brucei-infected mice.
布氏布氏锥虫血液形式无法分解过氧化氢，这构成了我们研发新型药理剂以杀灭这些生物体的尝试的基础。这些寄生虫消耗的氧气中约有1 - 3%以过氧化氢的形式出现。我们之前观察到，诸如血红素和血卟啉D等自由基引发剂分别在体外和体内被证明具有杀锥虫作用，这促使我们对这类化合物的作用机制进行研究，以提高它们的治疗效果。使用无细胞匀浆研究了锥虫体内过氧化氢的产生位点。本文所述实验表明，α - 甘油磷酸脱氢酶以偶然方式形成过氧化氢，并且这些生物体不存在处理这种潜在有毒化合物的酶促手段。发现萘醌可显著提高锥虫线粒体制剂的耗氧率和过氧化氢产生率。推测萘醌起辅酶Q类似物的作用。添加亚裂解浓度的萘醌和血红素会导致体外生物体的协同裂解。另一种提高布氏布氏锥虫对自由基损伤敏感性的方法涉及降低细胞内谷胱甘肽浓度。这是通过使用杀锥虫砷剂来实现的。美拉胂醇氧化物和血红素在体外具有协同作用，通过添加萘醌可进一步增强这种作用。此外，血卟啉D和锥虫胂胺在感染布氏布氏锥虫的小鼠中显示出协同作用。
