Essodaïgui M, Frézard F, Moreira E S, Dagger F, Garnier-Suillerot A
Laboratoire de Physicochimie Biomolëculaire et Cellulaire (UPRES-A 7033), Université Paris Nord, Bobigny, France.
Mol Biochem Parasitol. 1999 May 15;100(1):73-84. doi: 10.1016/s0166-6851(99)00036-5.
We demonstrated the existence of three transport activities in promastigotes of Leishmania braziliensis, Leishmania guyanensis, and Leishmania mexicana. The first activity, an energy-dependent efflux of pirarubicin, was observed in all Leishmania species and inhibited by verapamil, by 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1, 3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-py ridinecarboxylate P oxide (PAK104P) and by the phenothiazine derivatives: thioridazine, prochlorperazine, trifluoperazine, chlorpromazine and trifluoropromazine. The second activity, an energy-dependent efflux of calcein acetoxymethylester, was observed in all Leishmania species and inhibited by PAK104P and the same phenothiazine derivatives, but not by verapamil. The third activity, an energy-dependent efflux of calcein, was clearly detected in L. braziliensis and guyanensis and inhibited only by prochlorperazine and trifluoperazine. The fact that prochlorperazine and trifluoperazine inhibited the energy-dependent efflux of the three substrates suggests that these activities are mediated by the same transport system. It is noteworthy that the transport system identified in this study shares several properties with the mammalian multidrug resistance pump, MRP1. Pirarubicin, calcein acetoxymethylester and calcein are well known substrates of the MRP. Furthermore, the three types of inhibitors are also inhibitors of the MRP function.
我们证明了在巴西利什曼原虫、圭亚那利什曼原虫和墨西哥利什曼原虫的前鞭毛体中存在三种转运活性。第一种活性是吡柔比星的能量依赖性外排，在所有利什曼原虫物种中均有观察到，并被维拉帕米、2-[4-(二苯甲基)-1-哌嗪基]乙基-5-(反式-4,6-二甲基-1,3,2-二氧磷杂环己烷-2-基)-2,6-二甲基-4-(3-硝基苯基)-3-吡啶羧酸P氧化物(PAK104P)以及吩噻嗪衍生物：硫利达嗪、丙氯拉嗪、三氟拉嗪、氯丙嗪和三氟丙嗪所抑制。第二种活性是钙黄绿素乙酰氧基甲酯的能量依赖性外排，在所有利什曼原虫物种中均有观察到，并被PAK104P和相同的吩噻嗪衍生物所抑制，但不受维拉帕米抑制。第三种活性是钙黄绿素的能量依赖性外排，在巴西利什曼原虫和圭亚那利什曼原虫中可明显检测到，且仅被丙氯拉嗪和三氟拉嗪所抑制。丙氯拉嗪和三氟拉嗪抑制三种底物的能量依赖性外排这一事实表明，这些活性是由同一转运系统介导的。值得注意的是，本研究中鉴定的转运系统与哺乳动物多药耐药泵MRP1具有若干共同特性。吡柔比星、钙黄绿素乙酰氧基甲酯和钙黄绿素是MRP的众所周知的底物。此外，这三种类型的抑制剂也是MRP功能的抑制剂。
