Artemisinin and heme.

A recent Letter to the Editor (R. K. Haynes, D. Monti, D. Taramelli, N. Basilico, S. Parapini, and P. Olliaro, Letter, Antimicrob. Agents Chemother. 47:1175, 2003) presented cogent evidence that artemisinin and its derivatives do not inhibit hemozoin formation in vitro. However, the authors misinterpret these data to conclude that “binding of artemisinins with Fe(III)PPIX is not necessary for antimalarial activity.” The authors show that heme [Fe(III)PPIX] may not be the important alkylation target; however, their data do not shed light on the role of heme as the drug activator. The authors cite an article published by my group (1) and state that we “proposed that artemisinins kill the parasite through inhibition of hemozoin formation.” In fact we found (and stated) exactly the opposite. In whole living parasites, artemisinin did not cause a reduction in hemozoin content. Since other studies showed that the artemisinin was activated by Fe(III)PPIX to become a potent alkylating agent which reacted with both Fe(III)PPIX and proteins (2, 3, 5, 6), we concluded that proteins were more important alkylation targets than Fe(III)PPIX. Work by 19 other research groups in 11 countries (summarized in reference 4) has corroborated the importance of heme in the activation of artemisinin and its derivatives. The results from this paper are consistent with the current hypothesis that heme is only the activator of artemisinin, not its target.