Intracellular parasite killing induced by electron carriers. II. Correlation between parasite killing and the induction of oxidative events in macrophages.
Mouse peritoneal macrophages infected with Leishmania parasites were exposed in vitro to the electron carriers methylene blue (MB), toluidine blue 0 (TB), phenazine methosulfate (PMS) and crystal violet (CV). This led to parasite destruction without harm to the macrophages. The kinetics of intracellular killing depended on both the drug concentration and the duration of exposure; over 80% of the microorganisms were inactivated within 2.5 min of incubation of the parasitized cells with 10(-4) M MB. On a molar basis, the drugs were considerably more active against intracellular compared to free parasites, suggesting that the macrophages themselves play a role in the observed anti-parasite toxicity. Intracellular killing by macrophages exposed to MB, TB and PMS correlated with the stimulation of oxygen uptake and hexose monophosphate shunt activity in the cells. Cytochrome c markedly inhibited MB-induced intracellular parasite destruction as well as completely blocking parasite killing in macrophages activated by lymphokines, pointing to O-2, H2O2 or products derived therefrom as possible mediators of macrophage toxic activity in both instances. Cytochrome c did not protect free parasites from the direct toxicity of the drug, however. Lipopolysaccharide promoted parasite destruction by lymphokine-activated macrophages, but failed to do so for electron carrier-stimulated cells. These observations suggest that intracellular killing induced by electron carriers results from a direct interaction of the drugs with cellular redox systems, leading to the generation of oxygen metabolites toxic for the parasites.
D000818:Animals; D005840:Gentian Violet / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D008751:Methylene Blue / Q000494:pharmacology*; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010619:Phenazines / Q000494:pharmacology*; D014048:Tolonium Chloride / Q000494:pharmacology*
D010619:Phenazines; D014048:Tolonium Chloride; D008773:Methylphenazonium Methosulfate; D005840:Gentian Violet; D010100:Oxygen; D008751:Methylene Blue