CHARACTERIZATION OF THE ENHANCED TRANSPORT OF L-LACTATE AND D-LACTATEINTO HUMAN RED-BLOOD-CELLS INFECTED WITH PLASMODIUM-FALCIPARUM SUGGESTS THE PRESENCE OF A NOVEL SATURABLE LACTATE PROTON COTRANSPORTER

Human erythrocytes parasitized with the malarial protozoan Plasmodium falciparun showed rates of L-lactate, D-lactate, and pyruvate uptake m any fold greater than control cells. Thus it was necessary to work at 0 degrees C to resolve true initial rates of transport. Studies on the dependence of the rate of transport on substrate concentration implie d the presence in parasitized cells of both a saturable mechanism bloc ked by alpha-cyano-4-hydroxycinnamate (CHC) and a nonsaturable mechani sm insensitive to CHC. The former was dominant at physiological substr ate concentrations with K-m values for pyruvate and D-lactate of 2.3 a nd 5.2 mM, respectively, with no stereoselectivity for L- over D-lacta te. CHC was significantly less effective as an inhibitor of lactate tr ansport in parasitized erythrocytes than in uninfected cells, whereas p-chloromercuribenzenesulfonate, a potent inhibitor in control cells, gave little or no inhibition of lactate transport into parasitized ery throcytes. Inhibition of transport into infected cells was also observ ed with phloretin, furosemide, niflumic acid, stilbenedisulfonate deri vatives, and 5-nitro-2-(3-phenylpropylamino)benzoic acid at concentrat ions similar to those that inhibit the lactate carrier of control eryt hrocytes. These compounds were more effective inhibitors of the rapid transport of chloride into infected cells than of lactate transport, w hereas CHC was more effective against lactate transport. This implies that different pathways are involved in the parasite-induced transport pathways for lactate and chloride. The transport of L-lactate into in fected erythrocytes was also inhibited by D-lactate, pyruvate, 2-oxobu tyrate, and 2-hydroxybutyrate, The intracellular accumulation of L-lac tate at equilibrium was dependent on the transmembrane pH gradient, su ggesting a protogenic transport mechanism. Our data are consistent wit h lactate and pyruvate having direct access to the malarial parasite, perhaps via the proposed parasitophorous duct or some close contact be tween the host cell and parasite plasma membranes, with transport acro ss the latter by both a proton-linked carrier (CHC-sensitive, saturabl e, and the major route) and free diffusion of the undissociated acid ( CHC-insensitive, unsaturable, and a minor route).