Decreased Redox-Sensitive Erythrocyte Cation Channel Activity in Aquaporin 9-Deficient Mice
Phlorizin (phloretin-2-beta-glucoside) is a drug which effectively inhibits intraerythrocytic malaria growth in in vitro cultures of Plasmodium falciparum IC50 = 16 +/- 7 microM). Work with synchronously grown cultures indicates that susceptibility to phlorizin is apparent at the trophozoite stage and onward, and that 2-8 hours exposure to the drug causes an irreversible arrest of parasite growth. The drug has also been found to inhibit pores which are induced by the parasite in the host cell membrane (IC50 = 17 +/- 2 microM) and which are apparently essential for intraerythrocytic growth. The effect on the pores is apparent soon after exposure of the cells to the drug and can be reversed, although extensive washing and incubation in culture conditions are required to achieve it. The results of this study indicate that the putative site of action of phlorizin on the pores is on the cytoplasmic surface of the host cell membrane. The drug which normally cannot permeate uninfected red cells, gains access to the cytoplasm via the pores, appearing in the host cell membrane. Those become eventually the target of phlorizin itself. The proposed mechanism of action of phlorizin on malarial growth invokes blockade of the pores, although additional effects of the drug on intraerythrocytic parasites cannot be ruled out.