HEMOGLOBIN CATABOLISM AND THE KILLING OF INTRAERYTHROCYTIC PLASMODIUM-FALCIPARUM BY CHLOROQUINE
HEMOGLOBIN CATABOLISM AND THE KILLING OF INTRAERYTHROCYTIC PLASMODIUM-FALCIPARUM BY CHLOROQUINE
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DOI：
10.1007/bf01992046
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发表时间：
1994-01-15
期刊：
影响因子：
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通讯作者：
FITCH, CD
中科院分区：
文献类型：
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作者：
ORJIH, AU;RYERSE, JS;FITCH, CD
为了评估氯喹如何杀死疟疾寄生虫，研究了红细胞内寄生虫发育的各个阶段的血红蛋白分解代谢。我们发现，当恶性疟原虫成熟到滋养体晚期或分裂体早期时，血红蛋白分解代谢被关闭，并在环期再次开启。当血红蛋白分解代谢被关闭时，寄生虫对氯喹的形态影响具有抵抗力。尽管环期寄生虫在氯喹的存在下无法成熟，但其中一些寄生虫开启了血红蛋白的摄取，并充满了充满血红蛋白的囊泡，这表明分解代谢的远端受阻。事实上，我们证明了同步环型22小时孵育期间血色素蛋白产生的高度阻滞；铁原卟啉IX （FP）与血色素β -血红素的结合从900 pmol/10降低到50 pmol/10(6)。我们提出氯喹对血红蛋白分解代谢的主要作用是阻止FP聚合到-血红素。其次，有毒的FP和FP-氯喹复合物积聚并可发挥其几种毒性，包括抑制血红蛋白降解蛋白酶和膜损伤。因此，成熟被阻止，最终寄生虫死亡并腐烂。
To evaluate how chloroquine kills malaria parasites, hemoglobin catabolism was studied at the various stages of intraerythrocytic parasite development. We found that hemoglobin catabolism is switched off when Plasmodium falciparum parasites mature to the late trophozoite or early schizont stages and is switched on again during the ring stage. When hemoglobin catabolism is switched off, the parasites are resistant to the morphologic effects of chloroquine. Although the ring stage parasites failed to mature in the presence of chloroquine, some of them switched on hemoglobin ingestion and became stuffed with hemoglobin-filled vesicles, indicating a distal block in catabolism. In fact, we demonstrated a high-grade block in hemozoin production during a 22 h incubation of synchronized ring forms; ferriprotoporphyrin IX (FP) incorporation into the beta-hematin of hemozoin decreased from 900 to 50 pmol/10(6) parasitized erythrocytes. We propose that the primary effect of chloroquine on hemoglobin catabolism is to block FP polymerization to beta-hematin. Secondarily, toxic FP and FP-chloroquine complexes accumulate and are available to exert their several toxicities, which include inhibition of hemoglobin-degrading proteases and membrane damage. As a consequence, maturation is arrested and eventually the parasites die and lyse.