Oxidant stress in malaria as probed by stable nitroxide radicals in erythrocytes infected with Plasmodium berghei. The effects of primaquine and chloroquine.
Erythrocytes from normal mice and mice infected with the malarial parasite Plasmodium berghei reduce the water-soluble spin probes 2,2,6,6-tetramethylpiperidine-4-hydroxy-N-oxyl (TEMPOL), 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and 2,2,6,6-tetramethylpiperidine-4-keto-N-oxyl (TEMPONE) at similar rates under both air and N2 atmospheres. The ESR signal of the lipid-soluble spin probe 5-doxyl-stearate is stable on incorporation into erythrocytes from normal mice. In contrast, parasitized red cells reduce this nitroxide probe, at a rate which increases with the level of parasitemia. Inhibitors of electron transport such as KCN and NaN3, increase the rate of reduction. We propose that nitroxide reduction occurs via the electron transport chain in the parasite. The antimalarial drug primaquine causes reduction of both water-soluble and lipid-soluble spin probes. This action of primaquine is independent of its ability to release H2O2 from oxyhemoglobin, and is ascribed to the ability of primaquine to accelerate flux through the hexose monophosphate shunt. The increased production of NADPH results in increased rates of reduction of the nitroxide radicals. Methylene blue, which also increases flux through the shunt, is even more effective than primaquine at reducing the nitroxides. Chloroquine has no such effect. Parasitized mice treated with chloroquine six hours prior to ESR measurements show less nitroxide reducing capacity than do untreated mice. Chloroquine is known to decrease flux through the hexose monophosphate shunt. The metabolic influences of the two antimalarial drugs are, thus, quite different.
Deslauriers
R
R
Division of Biological Sciences, National Research Council of Canada, Ottawa, Ontario.
Butler
K
K
Smith
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IC
D000388:Air; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000378:metabolism*; D004579:Electron Transport / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D009584:Nitrogen; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D010962:Plasmodium berghei / Q000187:drug effects* / Q000378:metabolism; D011319:Primaquine / Q000494:pharmacology*; D012995:Solubility; D013113:Spin Labels / Q000378:metabolism*; D014216:Triacetoneamine-N-Oxyl / Q000378:metabolism*
D003497:Cyclic N-Oxides; D005609:Free Radicals; D013113:Spin Labels; D014216:Triacetoneamine-N-Oxyl; C005072:5-doxylstearic acid; D002738:Chloroquine; D006861:Hydrogen Peroxide; D011319:Primaquine; D009584:Nitrogen; C001803:tempol; C003959:TEMPO