16α-bromoepiandrosterone, an antimalarial analogue of the hormone dehydroepiandrosterone, enhances phagocytosis of ring stage parasitized erythrocytes:: a novel mechanism for antimalarial activity
16α-bromoepiandrosterone, an antimalarial analogue of the hormone dehydroepiandrosterone, enhances phagocytosis of ring stage parasitized erythrocytes:: a novel mechanism for antimalarial activity
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DOI：
10.1128/aac.46.10.3180-3184.2002
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发表时间：
2002-10-01
影响因子：
4.9
通讯作者：
Arese, P
中科院分区：
文献类型：
--
作者：
Ayi, K;Giribaldi, G;Arese, P
脱氢表雄酮(DHEA)和硫酸脱氢表雄酮(DHEA-S)是肾上腺皮质分泌的最丰富的激素，存在于血浆中约6um，及其类似物16α-溴表雄酮(EPI)对两株氯喹敏感的恶性疟原虫具有抗疟疾活性(Palo Alto，EPI的50%抑制浓度[IC50]，4.8+/-0.68um；T996/86，对EPI的IC_(50)为7.5+/-0.91um，对脱氢表雄酮-S的IC_(50)为19+/-2.6um)；EPI和DHEA/DHEA-S都是葡萄糖-6-磷酸脱氢酶(GOD)的有效抑制剂，G6PD缺乏已知通过增强调理和环的吞噬作用来发挥抗疟疾保护作用，环是寄生虫的早期形式。血浆相容的抗疟疾EPI浓度不会抑制G6PD活性，也不会像G6PD缺乏症那样引起免疫球蛋白G和补体片段的环调理作用，但仍显著刺激环吞噬作用。血浆相容，低微摩尔浓度的EPI导致磷脂酰丝氨酸环表面暴露，这是一个不依赖于调理的吞噬细胞去除的信号。我们认为，暴露于带负电荷的膜磷脂导致的环状吞噬功能增强可能解释了EPI的抗疟疾活性。
Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), which are the most abundant hormones secreted by the adrenal cortex and are present in plasma at approximately 6 muM, as well as their analogue, 16alpha-bromoepiandrosterone (EPI), exerted antimalarial activities against two chloroquine-sensitive Plasmodium falciparum strains (Palo Alto, 50% inhibitory concentration [IC50] of EPI, 4.8 +/- 0.68 muM; T996/86, IC50 of EPI, 7.5 +/- 0.91 muM, and IC50 of DHEA-S, 19 +/- 2.6 muM) and one mildly chloroquine-resistant strain (FCR-3, IC50 of EPI, 6.5 +/- 1.01 muM). Both EPI and DHEA/DHEA-S are potent inhibitors of glucose-6-phosphate dehydrogenase (GOD), and G6PD deficiency is known to exert antimalaria protection via enhanced opsonization and phagocytosis of rings, the early forms of the parasite. Plasma-compatible antimalarial EPI concentrations did not inhibit G6PD activity and did not induce ring opsonization by immunoglobulin G and complement fragments, as observed in G6PD deficiency, but nevertheless remarkably stimulated ring phagocytosis. Plasma-compatible, low-micromolar concentrations of EPI induced exposure on the ring surface of phosphatidylserine, a signal for phagocytic removal independent of opsonization. We propose that enhanced ring phagocytosis due to exposure of negatively charged membrane phospholipids may explain the antimalarial activity of EPI.