Inactivation of artemisinin by thalassemic erythrocytes

Plasmodium falciparum infecting alpha-thalassemic erythrocytes (Hb H or Hb H/Hb Constant Spring) is resistant to artemisinin derivatives. Similar resi stance, albeit at a much lower level, is shown by the parasite infecting be ta-thalassemia/Hb E erythrocytes. The resistance is due to host-specific fa ctors, one of which is the higher uptake of the drugs by thalassemic erythr ocytes than normal erythrocytes, due to binding with Hb H. In addition to h igher drug binding, incubation of artemisinin with a-thalassemic erythrocyt es resulted in preferential inactivation of the drug. Both thalassemic and normal erythrocytes have the capability to inactivate the drug. Addition of serum can protect against inactivation by normal erythrocytes, but not by thalassemic erythrocytes. Incubation with either the hemolysate or the memb rane fraction from these erythrocytes also resulted in preferential inactiv ation of the drug. The drug was also inactivated by purified Hb H. It is co ncluded that the ineffectiveness of artemisinin derivatives against P. falc iparum infecting thalassemic erythrocytes is due partly to competition of t he host cell components for binding with the drugs, and partly to inactivat ion of the drugs by the cell components. BIOCHEM PHARMACOL 59;11:1337-1344, 2000. (C) 2000 Elsevier Science Inc.