16alpha-bromoepiandrosterone, an antimalarial analogue of the hormone dehydroepiandrosterone, enhances phagocytosis of ring stage parasitized erythrocytes: a novel mechanism for antimalarial activity

Antimicrob Agents Chemother. 2002 Oct;46(10):3180-4. doi: 10.1128/AAC.46.10.3180-3184.2002.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Androsterone / analogs & derivatives*
  • Androsterone / pharmacology*
  • Animals
  • Antimalarials / pharmacology*
  • Cell Membrane / chemistry
  • Dehydroepiandrosterone / analogs & derivatives*
  • Dehydroepiandrosterone / pharmacology
  • Dehydroepiandrosterone Sulfate / chemistry
  • Dehydroepiandrosterone Sulfate / pharmacology
  • Erythrocytes / immunology
  • Erythrocytes / parasitology*
  • Female
  • Humans
  • Malaria, Falciparum / parasitology
  • Male
  • Parasitic Sensitivity Tests
  • Phagocytosis / drug effects*
  • Phosphatidylserines / metabolism
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / growth & development


  • Antimalarials
  • Phosphatidylserines
  • 16-bromoepiandrosterone
  • Dehydroepiandrosterone
  • Dehydroepiandrosterone Sulfate
  • Androsterone