16alpha-bromoepiandrosterone, an antimalarial analogue of the hormone dehydroepiandrosterone, enhances phagocytosis of ring stage parasitized erythrocytes: a novel mechanism for antimalarial activity.
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 micro M, as well as their analogue, 16alpha-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 micro M; T996/86, IC(50) of EPI, 7.5 +/- 0.91 micro M, and IC(50) of DHEA-S, 19 +/- 2.6 micro M) and one mildly chloroquine-resistant strain (FCR-3, IC(50) of EPI, 6.5 +/- 1.01 micro 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. 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.
Ayi
Kodjo
K
Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Torino, Italy.
Giribaldi
Giuliana
G
Skorokhod
Aleksei
A
Schwarzer
Evelin
E
Prendergast
Patrick T
PT
Arese
Paolo
P
D000328:Adult; D000738:Androsterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology*; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D008297:Male; D021261:Parasitic Sensitivity Tests; D010587:Phagocytosis / Q000187:drug effects*; D010718:Phosphatidylserines / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
D000962:Antimalarials; D010718:Phosphatidylserines; C032020:16-bromoepiandrosterone; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D000738:Androsterone