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Antimicrobial Agents and Chemotherapy, October 2002, p. 3180-3184, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3180-3184.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Kodjo Ayi,1 Giuliana Giribaldi,1 Aleksei Skorokhod,1 Evelin Schwarzer,1 Patrick T. Prendergast,2 and Paolo Arese1*

Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Torino, Italy,1 Edenland, Inc., Straffan, Ireland2

Received 12 November 2001/ Returned for modification 20 December 2001/ Accepted 16 July 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 µM, as well as their analogue, 16{alpha}-bromoepiandrosterone (EPI), exerted antimalarial activities against two chloroquine-sensitive Plasmodium falciparum strains (Palo Alto, 50% inhibitory concentration [IC50] of EPI, 4.8 ± 0.68 µM; T996/86, IC50 of EPI, 7.5 ± 0.91 µM, and IC50 of DHEA-S, 19 ± 2.6 µM) and one mildly chloroquine-resistant strain (FCR-3, IC50 of EPI, 6.5 ± 1.01 µM). 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.

* Corresponding author. Mailing address: Dipartimento di Genetica, Biologia e Biochimica, University of Torino Medical School, Torino, Italy. Phone: 39 011 6706686. Fax: 30 011 6706590. E-mail: paolo.arese{at}unito.it.

Antimicrobial Agents and Chemotherapy, October 2002, p. 3180-3184, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3180-3184.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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