Qinghaosu-mediated oxidation in normal and abnormal erythrocytes.
Qinghaosu, a potent antimalarial agent, has recently been shown to act via oxidative mechanisms. Hence, we have investigated what effect qinghaosu has on cellular oxidation in normal and oxidant-sensitive red blood cells (RBCs). At 500 mumol/L, qinghaosu was found to directly alter red cell deformability (DI) in both normal (hemoglobin AA) and abnormal (hemoglobins SS, AE, and EE) RBCs, with the maximum DI being 70% to 80% of that of untreated RBCs. Although concentrations of less than or equal to 200 mumol/L qinghaosu had a minimal effect on the maximum DI, qinghaosu was found to act as an efficient prooxidant at these concentrations. Cellular deformability was lost more rapidly in response to exogenous oxidants in the qinghaosu-treated RBCs than in control cells. Hemoglobin SS and EE RBCs pretreated with qinghaosu demonstrated a much more rapid decrease in cellular deformability than did the control RBCs in response to exogenous oxidants. Additionally, qinghaosu resulted in a dose-dependent increase in red cell lysis and methemoglobin generation while decreasing reduced glutathione concentration. As a consequence of qinghaosu challenge, a decrease in unsaturated fatty acids was noted. Deoxyqinghaosu, which lacks the endoperoxide bridge and is pharmacologically inactive, did not affect cellular deformability and did not function as a prooxidant. Additionally, deoxyqinghaosu had no effect on fatty acid composition, red cell lysis, methemoglobin generation, or reduced glutathione concentration. In conclusion, although the oxidative effects of qinghaosu on uninfected erythrocytes were only seen at concentrations much greater than that necessary for antimalarial activity, these results confirm the proposition that qinghaosu may act via oxidative mechanisms. Furthermore, qinghaosu-mediated oxidation was significantly increased in erythrocytes characterized by enhanced oxidant sensitivity caused by unstable hemoglobins.
Scott
M D
MD
Children's Hospital Oakland Research Institute, CA 94609.
Meshnick
S R
SR
Williams
R A
RA
Chiu
D T
DT
Pan
H C
HC
Lubin
B H
BH
Kuypers
F A
FA
D037621:Artemisinins; D004907:Erythrocyte Deformability / Q000187:drug effects; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D005227:Fatty Acids / Q000097:blood; D005978:Glutathione / Q000097:blood; D006801:Humans; D008706:Methemoglobin / Q000032:analysis; D009994:Osmolar Concentration; D010084:Oxidation-Reduction / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*
D037621:Artemisinins; D005227:Fatty Acids; D012717:Sesquiterpenes; D008706:Methemoglobin; C031327:artemisinin; D005978:Glutathione