title: The effect of mefloquine and volume-regulated anion channel inhibitors on induced transport in Plasmodium falciparum-infected human red blood cells.
abstract: The malaria parasite Plasmodium falciparum activates new permeation pathways (NPP) in the host cell membrane of infected human red blood cells (RBCs), which are permeable to anions, cations and a range of organic solutes. It has been suggested from inhibitor and substrate selectivity studies that the NPP may be identical to the volume-activated anion channel (VRAC) present in many mammalian cell types. Here we have tested several known inhibitors of VRAC on the transport of choline and lactate in malaria-infected human RBCs and on parasite growth. Mefloquine, tamoxifen and clomiphene were all without effect on malaria-induced transport at concentrations up to 10 microM and only mefloquine (IC(50) = 24 nM) and, to a lesser degree, clomiphene (IC(50) = 6.2 microM) inhibited parasite growth below this level. It is concluded that the antimalarial effect of mefloquine does not involve the inhibition of malaria-induced transport via the NPP and there is no evidence at present for VRAC and the NPP being identical.
authors.affiliation: University Laboratory of Physiology, Oxford, Parks Road, Oxford OX1 3PT, UK. henry.staines@physiol.ox.ac.uk
authors.forename: Henry M
authors.initials: HM
authors.lastname: Staines
authors.forename: Belinda C
authors.initials: BC
authors.lastname: Dee
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
authors.forename: J Clive
authors.initials: JC
authors.lastname: Ellory
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D002996:Clomiphene / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D019344:Lactic Acid / Q000378:metabolism; D016778:Malaria, Falciparum; D015767:Mefloquine / Q000494:pharmacology*; D010963:Plasmodium falciparum; D018272:Porins / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology; D050994:Voltage-Dependent Anion Channels
chemical_list: D000962:Antimalarials; D007473:Ion Channels; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D013629:Tamoxifen; D002996:Clomiphene; D019344:Lactic Acid; D002794:Choline; D015767:Mefloquine