Generation of Free Radicals and Enhancement of Hemin-induced Membrane Damage by a Catechol Iron Chelator in Plasmodium falciparum

We investigated whether FR160, a catechol iron chelator, affects the redox catalytic activity of heme towards membrane lipid, a more physiologically relevant oxidizable substrate. Formation of malondialdehyde (MDA), a major final product of lipid peroxidation initiated by reactive oxygen species, is used as indicator of membrane lipid oxidation. FR160 enhances the ability of hemin to generate MDA by 56%. Vitamin E, an oxygen-radical scavenger, decreases by 30% the formation of MDA by hemin in combination with FR160. When incubated in the presence of hemin, FR160 or artemisinin, alone, react with the amine groups of β-alanylhistidine (β-AH) and decreases the NBDF-reactive amines of β-AH. At 48 h of incubation in the presence of hemin, FR160 induces considerable decrease of NBDF-reactive amine of β-AH by 50%. The iron chelator FR160 acts by generation of radical species and enhance of hemin-catalysed oxidation of membrane lipids. FR160 neither affects the chemical heme crystallization activity nor the production of hemozoin in P. falciparum parasites.