PT  - JOURNAL ARTICLE
AU  - Zachary S. Bowman
AU  - David J. Jollow
AU  - David C. McMillan
TI  - Primaquine-Induced Hemolytic Anemia: Role of Splenic Macrophages in the Fate of 5-Hydroxyprimaquine-Treated Rat Erythrocytes
AID  - 10.1124/jpet.105.090407
DP  - 2005 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 980--986
VI  - 315
IP  - 3
4099  - http://jpet.aspetjournals.org/content/315/3/980.short
4100  - http://jpet.aspetjournals.org/content/315/3/980.full
SO  - J Pharmacol Exp Ther2005 Dec 01; 315
AB  - 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 51Cr-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. The American Society for Pharmacology and Experimental Therapeutics