Primaquine-induced hemolytic anemia: role of splenic macrophages in the fate of 5-hydroxyprimaquine-treated rat erythrocytes.
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 (51)Cr-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.
Bowman
Zachary S
ZS
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
Jollow
David J
DJ
McMillan
David C
DC
D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010587:Phagocytosis / Q000187:drug effects; D011319:Primaquine / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism*
D011319:Primaquine