16α-Bromoepiandrosterone, an Antimalarial Analogue of the Hormone Dehydroepiandrosterone, Enhances Phagocytosis of Ring Stage Parasitized Erythrocytes: a Novel Mechanism for Antimalarial Activity

Abstract

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 M, as well as their analogue, 16␣-bromoepiandrosterone (EPI), exerted antimalarial activities against two chloroquine-sensitive Plasmodium falciparum strains (Palo Alto, 50% inhibitory concentration [IC 50 ] of EPI, 4.8 ؎ 0.68 M; T996/86, IC 50 of EPI, 7.5 ؎ 0.91 M, and IC 50 of DHEA-S, 19 ؎ 2.6 M) and one mildly chloroquine-resistant strain (FCR-3, IC 50 of EPI, 6.5 ؎ 1.01 M). Both EPI and DHEA/DHEA-S are potent inhibitors of glucose-6-phosphate dehydrogenase (G6PD), 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. Plasmacompatible, 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.Recently, it has been shown that 16␣-bromoepiandrosterone (EPI), an analogue of the human adrenal steroid hormones dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), was endowed with antimalarial activity against several strains of Plasmodium falciparum in vitro and against Plasmodium berghei in a mouse model (7). Interestingly, another study (16) has indicated that age-related decreases in the frequency and density of P. falciparum parasitemia were greater during puberty and that the blood level of DHEA-S was a significant predictor of resistance. Both EPI and DHEA/DHEA-S inhibit glucose-6-phosphate dehydrogenase (G6PD) (10) and cell proliferation (13, 24). G6PD deficiency is known to afford antimalaria protection (12), possibly mediated by enhanced phagocytosis of rings, the early parasite stage within the erythrocytes (RBC) (3). Therefore, we explored whether the antimalarial activity of EPI could be related to inhibition of erythrocytic G6PD. The present results confirm the antimalarial activities of EPI and DHEA-S and indicate that sub-and low-micromolar EPI concentrations remarkably stimulated ring phagocytosis. EPI did not inhibit G6PD activity and did not enhance deposition of phagocytic opsonins, but enhanced exposure on the ring surface of phosphatidylserine (PS), a signal for phagocytic removal independent of opsonization (30). We propose that enhanced ring stage phagocytosis due to exposure of negatively charged membrane phospholipids may explain the antimalarial activity of EPI. MATERIALS AND METHODS Materials.Buffers, culture media, substrates, enzymes and coenzymes, adenine, heparin, gentamicin, mannitol, dehydroepiandrosterone sulfate (5-androsten-...

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