Implication of intracellular glutathione and its related enzymes on resistance of malaria parasites to the antimalarial drug arteether

The control of malaria has been complicated by the increasing resistance of malarial parasites to multiple drugs. However, artemisinin-based drugs offer hope in the fight against drug-resistant parasites. The mode of action of these drugs remains unclear, but evidence suggests a role for free radicals in their mechanism of action. In this study, we examined the relationship between the intracellular levels of glutathione (GSH) and antioxidant enzymes and resistance to the artemisinin-based drug arteether in experimentally selected arteether-resistant Plasmodium vinckei. GSH plays a critical role in the detoxification and protection of cells against oxidative stress. Our comparative studies showed a significant (2.9-fold) increase in the GSH level in arteether-resistant parasites as compared to arteether-sensitive parasites. Simultaneously, significantly increased activities of glutathione reductase, glutathione-S transferase and glucose-6-phosphate dehydrogenase and decreased activity of superoxide dismutase were recorded in resistant parasites; the activity of glutathione peroxidase was comparable in arteether-sensitive and -resistant parasites. Artemisinin derivatives act by generating free radicals and our results indicate that glutathione's antioxidant effects may counteract that drug effect and thereby contribute to the parasites' resistance to arteether and other artemisinin-based antimalarials.