title: Artemisinin effectiveness in erythrocytes is reduced by heme and heme-containing proteins.
abstract: Artemisinin loses its antimalarial activity on prolonged exposure to erythrocytes, especially alpha-thalassemic erythrocytes. In this report, we show that the major artemisinin-inactivating factor in cytosol of normal erythrocytes was heat-labile but a heat-stable factor from alpha-thalassemic cells also played a significant role in reducing artemisinin effectiveness, which was shown to be heme released from hemoglobin (Hb). Studies of fractionated lysate from genetically normal erythrocytes revealed that the protein fraction with molecular weight greater than 100 kDa was capable of reducing artemisinin effectiveness more readily than lower molecular weight fraction. Catalase and Hb A, but not selenoprotein glutathione peroxidase, were capable of reducing artemisinin effectiveness. Hemin (ferriprotoporphyrin IX) also reduced artemisinin effectiveness in a concentration- and time-dependent manner. It is concluded that heme and heme-containing proteins in erythrocyte are largely responsible for reducing artemisinin effectiveness and may contribute to resistance of Plasmodium falciparum infecting alpha-thalassemic erythrocytes observed in vitro.
authors.affiliation: National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, 113 Thailand Science Park, Klong Luang, Pathumthani 12120, Thailand.
authors.forename: Napawan
authors.initials: N
authors.lastname: Ponmee
authors.forename: Tatsanee
authors.initials: T
authors.lastname: Chuchue
authors.forename: Prapon
authors.initials: P
authors.lastname: Wilairat
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D037621:Artemisinins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D005591:Chemical Fractionation; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004336:Drug Antagonism; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism* / Q000494:pharmacology; D006441:Hemoglobin A / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D013789:Thalassemia / Q000097:blood / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D006427:Hemin; D006441:Hemoglobin A; C031327:artemisinin; D002374:Catalase