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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes.
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Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes.

机译：Miltefosine（十六烷基磷酸胆碱）抑制利什曼原虫前鞭毛体中的细胞色素c氧化酶。

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摘要

Miltefosine (hexadecylphosphocholine [HePC]) is currently on trial as a first-choice, orally active drug for the treatment of visceral leishmaniasis when resistance to organic pentavalent antimonials becomes epidemic. However, data on the targets involved in its leishmanicidal mechanism have, until now, been only fragmentary. We have carried out a systematic study of the alterations induced on the bioenergetic metabolism of Leishmania donovani promastigotes by HePC. Overnight incubation with HePC caused a significant decline in the intracellular ATP levels of the parasites, together with a reduction in the oxygen consumption rate and mitochondrial depolarization, while the integrity of the plasma membrane remained undamaged. In a further step, the effects of HePC on the respiratory chain were addressed in digitonized parasites. The inhibition of the oxygen consumption rate caused by HePC was not reverted either with the uncoupling agent carbonyl cyanide p-trifluoromethoxyphenylhydrazone or with tetramethyl-p-phenylenediamine plus ascorbate, which feeds the electron transport chain at the level of cytochrome c. These results suggest that cytochrome c oxidase is a likely target in the complex leishmanicidal mechanism of HePC. This was further confirmed from the finding that this enzyme was specifically inhibited in a dose-dependent manner by HePC, but not the cytochrome c reductase, ruling out an unspecific effect of HePC on the respiratory chain.
机译：Miltefosine（十六烷基磷酸胆碱[HePC]）目前正在作为一种口服的活性药物进行试验，当对有机五价锑的耐药性流行时，该药物可治疗内脏利什曼病。但是，到目前为止，有关其杀人机理的目标的数据还很少。我们已经对HePC对Leishmania donovani前鞭毛体的生物能代谢引起的改变进行了系统的研究。与HePC一起过夜孵育会导致寄生虫的细胞内ATP水平显着下降，以及耗氧率和线粒体去极化的降低，而质膜的完整性仍未受到损害。在进一步的步骤中，在数字化寄生虫中解决了HePC对呼吸链的影响。用解偶联剂羰基氰化物对三氟甲氧基苯基hydr或四甲基对苯二胺加抗坏血酸盐不能恢复由HePC引起的耗氧率的抑制作用，后者使电子传输链达到细胞色素c的水平。这些结果表明，细胞色素C氧化酶可能是HePC的复杂杀人机理的靶标。从发现中进一步证实，该酶被HePC特异性抑制，但呈剂量依赖性，但不受细胞色素C还原酶抑制，排除了HePC对呼吸链的非特异性作用。

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