Kinetics and molecular characteristics of arginine transport by Leishmania donovani promastigotes

Kandpal, Mamta; Fouce, Rafael Balaña; Pal, Ajay; Guru, P. Y.; Tekwani, Babu L.

doi:10.1016/0166-6851(95)00042-y

Cited by 58 publications

(45 citation statements)

References 22 publications

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“…Pentamidine is known to inhibit several transport systems on the surface of eukaryotic cells (Kandpal et al, 1995;Kleyman et al, 1995;Navas et al, 1996;de Koning and Jarvis, 1999). It is possible that pentamidine may exert its antimalarial effect by inhibiting the transport of essential nutrients or metabolites across the host erythrocyte membrane.…”

Section: Resultsmentioning

confidence: 99%

Diamidine Compounds: Selective Uptake and Targeting inPlasmodium falciparum

et al. 2001

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Section: Resultsmentioning

confidence: 99%

Diamidine Compounds: Selective Uptake and Targeting inPlasmodium falciparum

et al. 2001

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“…Efforts to identify a physiological substrate for the transporter were unsuccessful, although because arginine and other basic amino acids failed to inhibit uptake it appears unlikely that pentamidine enters these parasites with a basic amino acid transporter, as was previously suggested (40,41). Polyamines also failed to inhibit a Initial rate of 4 M pentamidine uptake was determined with different drugs added at 100 M. Results were normalized to the control value.…”

Section: Discussionmentioning

confidence: 99%

“…The P2 adenosine transporter of Trypanosoma brucei (23) appears to play some part in the transport of this drug, although the situation is complex (24,47), with at least two additional transporters also capable of carrying the drug (29). In Leishmania donovani, pentamidine was found to be a competitive inhibitor of arginine transport (40,41) and a noncompetitive inhibitor of putrescine and spermidine transport in Leishmania infantum (51), L. donovani, and L. mexicana (12). With the exception of the P2 nucleoside transporter in T. brucei, the physiological roles of the carrier proteins which accumulate pentamidine have yet to be identified.…”

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confidence: 99%

Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion

Basselin

Denise

Coombs

et al. 2002

Antimicrob Agents Chemother

136

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The uptake of [3 H]pentamidine into wild-type and drug-resistant strains of Leishmania mexicana was compared. Uptake was carrier mediated. Pentamidine-resistant parasites showed cross-resistance to other toxic diamidine derivatives. A substantial decrease in accumulation of the drug accompanied the resistance phenotype, although the apparent affinity for pentamidine by its carrier was not altered when initial uptake velocity was measured. The apparent V max , however, was reduced. An efflux of pentamidine could be measured in both wild-type and resistant cells. Only a relatively small proportion of the total accumulated pentamidine was available for efflux in wild-type cells, while in resistant cells the majority of loaded pentamidine was available for release. Pharmacological reagents which diminish the mitochondrial membrane potential reduced pentamidine uptake in wild-type parasites, and the mitochondrial membrane potential was shown to be reduced in resistant cells. A fluorescent analogue of pentamidine, 4,6-diamidino-2-phenylindole, accumulated in the kinetoplast of wild-type but not resistant parasites. These data together indicate that diamidine drugs accumulate in the Leishmania mitochondrion and that the development of the resistance phenotype is accompanied by lack of mitochondrial accumulation of the drug and its exclusion from the parasites.

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“…Beside L-arginine usage by iNOS in classically activated Ms (15,23) and by arginase in alternatively activated Ms (17), it has been reported that in vitro cultured Leishmania parasites can also directly acquire and utilize L-arginine from the extracellular milieu for polyamine synthesis (18,30). Although the exact pathways by which Leishmania can access the L-arginine pool within the host Ms remain unclear, it is possible that cellular L-arginine transport may be directed toward the parasites residing within the cells.…”

mentioning

confidence: 99%