Oxidative Stress and Antioxidant Defense in Malarial Parasites

Abstract

This chapter summarizes the currently available knowledge on sources of oxidative and nitrosative stress in malarial parasites, the different available detoxification pathways, and the impact on mechanisms of drug action. Plasmodium-infected red blood cells (Plasmodium IRBCs) appear to be under exogenous and endogenous oxidative stress. Malaria parasites induce oxidative stress in their host red blood cell. In the membrane of P. falciparum-parasitized cells, increasing amounts of hemichromes and band 3 aggregates have been demonstrated. Peroxidized IRBCs generate 4-hydroxyalk- 2-enals and alka-2,4-dienals, and these aldehydes are toxic to P. falciparum in vitro. Thus, the antioxidant capabilities of the parasite and RBC are of considerable significance. The majority of the peroxide-detoxifying capacity, however, seems to be provided by peroxiredoxins. Glutathione S-transferase exhibits glutathione peroxidase activity, which might contribute to the total peroxide-reducing capacity of the parasite, since the enzyme is present at very high concentrations. Superoxide dismutase (SOD) is the major enzyme involved in catabolizing the superoxide anion, resulting in production of molecular oxygen and hydrogen peroxide. P. falciparum possesses a classical 2-Cys glutaredoxin (PfGrx1) and a redox-active 1-Cys glutaredoxin-like protein (PfGLP-1). The glyoxalase system consists of glyoxalase I (GloI), glyoxalase II (GloII), and the coenzyme glutathione. It is a cyclic metabolic pathway removing toxic 2-oxoaldehydes like methylglyoxal by converting them to the corresponding nontoxic 2-hydroxycarboxylic acids like D-lactate. Artemisinin has been shown to react with glutathione (GSH) and to increase levels of lipid peroxidation.