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|Title:||Binding of dihydroartemisinin to hemoglobin H: Role in drug accumulation and host-induced antimalarial ineffectiveness α-thalassemic erythrocytes|
Thailand National Science and Technology Development Agency
|Keywords:||Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics|
|Citation:||Molecular Pharmacology. Vol.53, No.3 (1998), 492-496|
|Abstract:||Dihydroartemisinin and other artemisinin derivatives are relatively ineffective against Plasmodium falciparum infecting α-thalassemic erythrocytes, namely hemoglobin (hb) H or HbH-Hb Constant Spring erythrocytes, as compared with those infecting genetically normal erythrocytes. The variant erythrocytes accumulate radiolabeled dihydroartemisinin to a much higher extent than the normal ones, and the accumulated drug was retained after extensive washing, in contrast to the drug in normal erythrocytes which was mostly removed. At initial drug concentration of 1 mM, most (82-88%) of the drug was found in the cytosol fraction of both variant and normal erythrocytes. Binding of the drug to hemoglobins accounted for 40-70% of the total uptake. Hb H accounted for 10.9 ± 2.7% and 12.4 ± 6.2% of total protein in HbH and HbH/Hb Constant Spring erythrocytes. HbH bound with 28.7 ± 6.7% of the drug, whereas HbH/Hb Constant Spring erythrocytes bound with 21.8 ± 8.3% of the drug. Binding experiments showed that Hb H had 5-7 times the drug-binding capacity of Hb A. For Hb H, the maximum binding capacity (B(max)) = 1.67 ± 0.17 mol/mol Hb, and the dissociation constant (K(d)) = 66 ± 17 μm, and for Hb A, B(max) = 0.74 ± 0.18 mol/mol Hb and K(d) = 224 ± 15 μm. It is concluded that preferential binding of dihydroartemisinin to Hb H over Hb A accounts partly for the higher accumulation capacity of the α-thalassemic erythrocytes, which leads to its antimalarial ineffectiveness.|
|Appears in Collections:||Scopus 1991-2000|
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