Membrane heme as a host factor in reducing effectiveness of dihydroartemisinin Vattanaviboon P, Siritanaratkul N, Ketpirune J, Wilairat P, Yuthavong Y 1. Mahidol Univ, Siriraj Hosp, Fac Med Technol, Dept Clin Microscopy, Bangkok 10700, Thailand 2. Siriraj Hosp, Fac Med, Dept Med, Div Hematol, Bangkok 10400, Thailand 3. Mahidol Univ, Fac Sci, Dept Biochem, Bangkok 10400, Thailand 4. Natl Sci & Technol Dev Agcy, Bangkok 10700, Thailand Abstract: Plasmodium falciparum infecting alpha-thalassemic erythrocytes are resistant to artemisinin and its derivatives. Binding of the drug to hemoglobin H resulting in drug inactivation was previously demonstrated. We now show that an additional host factor, membrane heme, significantly accounted for decreased antimalarial activity of artemisinin. The antimalarial activity of dihydroartemisinin in the presence of normal and thalassemic erythrocyte membranes showed a correlation with the heme content of the membrane (r(2) = 0.466, P < 0.01). The correlation was more clearly seen when the drug effectiveness was correlated with the heme content of &alpha;-thalassemic membrane (r(2) = 0.636, P < 0.01). However, the drug effectiveness showed no correlation to ferrozine-reactive (free or non-heme) iron content (r(2) = 0.0001, P > 0.05). alpha-Thalassemic erythrocytes contained higher amounts of membrane heme (11.04 +/- 8.96 nmol/mg membrane protein) than those from normal and beta- thalassemia/HbE erythrocytes (2.68 +/- 1.28 and 3.98 +/- 3.98 nmol/mg membrane protein, respectively, P < 0.01). Loss of drug effectiveness was also correlated with increment of heme content in membrane prepared from normal erythrocytes treated with phenylhydrazine. It is concluded that heme in both normal and thalassemic erythrocyte membranes is an important factor in drug inactivation. Keywords: artemisinin; heme; thalassemia; malaria BIOCHEMICAL PHARMACOLOGY. 2002; 64(1) : 91-98