Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite

作     者：Pandey, AV Tekwani, BL Singh, RL Chauhan, VS 

作者机构：Int Ctr Genet Engn & Biotechnol Malaria Res Grp New Delhi 110067 India Cent Drug Res Inst Div Biochem Lucknow 226001 Uttar Pradesh India RML Avadh Univ Dept Biochem Faizabad 224001 Uttar Pradesh India 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：1999年第274卷第27期

页      面：19383-19388页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：抗疟药/药理学 青蒿素类 中草药/药理学 电泳 聚丙烯酰氨凝胶 血红素/代谢 血红素蛋白类/代谢 血红蛋白类/代谢 恶性疟原虫/药物作用 恶性疟原虫/代谢 约氏疟原虫/药物作用 约氏疟原虫/代谢 前列腺素内过氧化物/代谢 倍半萜类/药理学 动物 男(雄)性 小鼠 

摘      要：Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin, These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.