de Koning H P, Jarvis S M
Institute of Biomedical and Life Sciences, Division of Infection and Immunity, University of Glasgow, Glasgow G12 8QQ, UK.
Acta Trop. 2001 Dec 21;80(3):245-50. doi: 10.1016/s0001-706x(01)00177-2.
Diamidine drugs such as pentamidine and berenil (diminazene aceturate) are vital drugs for the treatment of early stage human African trypanosomiasis and the corresponding veterinary condition, respectively. The action of diamidines on trypanosomes is critically dependent on their efficient uptake by the parasite. We have therefore investigated the mode of uptake of pentamidine by Trypanosoma brucei brucei, using [(125)I]iodopentamidine as a permeant. [(125)I]Iodopentamidine uptake was linear for up to 15 min and inhibited by adenosine with a K(i) value of 0.64+/-0.03 microM to a maximum of 50-70%. The adenosine-sensitive flux was also inhibited by adenine with a K(i) value of 0.44+/-0.04 microM. Iodopentamidine uptake was saturable, with the adenosine-insensitive flux displaying a K(m) of 22+/-2 microM and a V(max) of 2.2+/-0.9 pmol(10(7) cells)(-1)s(-1), whereas the adenosine-sensitive flux was inhibited by much lower iodopentamidine concentrations. These results clearly demonstrate that iodopentamidine is taken up by at least two different T. b. brucei transporters, an adenosine-sensitive pentamidine transporter (ASPT1) and a low-affinity pentamidine transporter (LAPT1). The identity of these transporters was investigated, and their significance for drug uptake and resistance in African trypanosomes is discussed.
双脒类药物如喷他脒和贝尼尔（二脒那嗪）分别是治疗人类非洲锥虫病早期阶段和相应兽医疾病的重要药物。双脒类药物对锥虫的作用严重依赖于寄生虫对它们的有效摄取。因此，我们使用[（125）I]碘喷他脒作为渗透剂，研究了布氏布氏锥虫摄取喷他脒的方式。[（125）I]碘喷他脒的摄取在长达15分钟内呈线性，并且被腺苷抑制，K（i）值为0.64±0.03微摩尔，最大抑制率为50 - 70%。腺嘌呤也抑制腺苷敏感通量，K（i）值为0.44±0.04微摩尔。碘喷他脒的摄取是可饱和的，腺苷不敏感通量的K（m）为22±2微摩尔，V（max）为2.2±0.9皮摩尔（10（7）个细胞）（-1）秒（-1），而腺苷敏感通量被低得多的碘喷他脒浓度所抑制。这些结果清楚地表明，碘喷他脒至少通过两种不同的布氏布氏锥虫转运蛋白摄取，一种是腺苷敏感的喷他脒转运蛋白（ASPT1）和一种低亲和力的喷他脒转运蛋白（LAPT1）。研究了这些转运蛋白的特性，并讨论了它们在非洲锥虫药物摄取和耐药性方面的意义。
