Primaquine-induced hemolytic anemia: Role of splenic macrophages in the fate of 5-hydroxyprimaquine-treated rat erythrocytes
Primaquine-induced hemolytic anemia: Role of splenic macrophages in the fate of 5-hydroxyprimaquine-treated rat erythrocytes
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DOI：
10.1124/jpet.105.090407
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
McMillan, DC
中科院分区：
文献类型：
--
作者：
Bowman, ZS;Jollow, DJ;McMillan, DC
已知伯氨喹诱导的溶血性贫血是由于受损（但完整）的红细胞被脾过早隔离所致。我们先前已经证明，酚类代谢物5-羟基伯氨喹（5- HPQ）是大鼠中的直接作用溶血剂，这表明5- HPQ是伯氨喹溶血反应的介体。为了研究体外暴露于5- HPQ后红细胞在体内的命运，将大鼠Cr-51标记的红细胞与溶血浓度的5- HPQ孵育，然后静脉内重新给药大鼠。测量血液中放射性损失以及脾脏和肝脏摄取的时间过程。在给予5-HPQ处理红细胞的大鼠中，与溶剂对照相比，观察到放射性从循环中的清除率增加。血液放射性损失伴随着脾脏中出现的放射性相应增加，但肝脏中未出现。当用氯膦酸盐负载的脂质体预处理大鼠以消耗脾巨噬细胞时，从循环中清除放射性的速率降低，并且脾脏的摄取显著减少。使用J774 A在体外证实了5- HPQ处理的红细胞的吞噬清除作用。1巨噬细胞系。此外，用马来酸二乙酯耗竭红细胞GSH显著增强5- HPQ处理的红细胞的体外吞噬作用。数据表明，脾巨噬细胞负责清除5- HPQ处理的红细胞，并支持该代谢产物是母体化合物给药后诱导的溶血性贫血的贡献者的假设。
Primaquine- induced hemolytic anemia is known to result from premature sequestration of damaged ( but intact) erythrocytes by the spleen. We have shown previously that a phenolic metabolite, 5- hydroxyprimaquine ( 5- HPQ), is a direct- acting hemolytic agent in rats, suggesting that 5- HPQ is a mediator of the hemolytic response to primaquine. To investigate the fate of erythrocytes in vivo after in vitro exposure to 5- HPQ, rat Cr-51-labeled erythrocytes were incubated with hemolytic concentrations of 5- HPQ and then readministered intravenously to rats. The time course of loss of radioactivity from blood and uptake into the spleen and liver was measured. In rats given 5- HPQ-treated erythrocytes, an increased rate of removal of radioactivity from the circulation was observed as compared with the vehicle control. The loss of blood radioactivity was accompanied by a corresponding increase in radioactivity appearing in the spleen but not in the liver. When rats were pretreated with clodronate- loaded liposomes to deplete splenic macrophages, there was a decreased rate of removal of radioactivity from the circulation and a markedly diminished uptake into the spleen. A role for phagocytic removal of 5- HPQ- treated red cells was confirmed in vitro using the J774A. 1 macrophage cell line. Furthermore, depletion of red cell GSH with diethyl maleate significantly enhanced in vitro phagocytosis of 5- HPQ- treated red cells. The data indicate that splenic macrophages are responsible for removing 5- HPQ- treated red cells and support the postulate that this metabolite is a contributor to the hemolytic anemia induced after administration of the parent compound.