Uptake of Diamidine Drugs by the P2 Nucleoside Transporter in Melarsen-sensitive and -resistant Trypanosoma brucei brucei

• Published in: The Journal of biological chemistry 1995-11, Vol.270 (47), p.28153-28157
• Main Authors: Carter, N S, Berger, B J, Fairlamb, A H
• Format: Article
• Language: English
• Subjects: Adenosine - metabolism; Animals; Arsenicals - metabolism; Arsenicals - pharmacology; Biological Transport; Carrier Proteins - metabolism; Drug Resistance; Kinetics; Pentamidine - metabolism; Pentamidine - pharmacology; Species Specificity; Structure-Activity Relationship; Trypanosoma brucei brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.270.47.28153

The African trypanosome, Trypanosoma brucei brucei , possesses at least two nucleoside transporter systems designated P1 and P2, the latter being implicated in the selective uptake of melaminophenyl arsenical drugs. Since arsenical-resistant trypanosomes show cross-resistance in vivo to aromatic diamidines, we have investigated whether these drugs are also substrates for the P2 nucleoside transporter. In melarsen-sensitive T. b. brucei , the diamidines, including the commonly used trypanocides, pentamidine and berenil, were found to abrogate lysis induced by the P2 transport of melarsen oxide in vitro . Measurement of [ ring - H]pentamidine transport in melarsen-sensitive T. b. brucei , demonstrated that uptake is carrier-mediated, with a K of 0.84 μM and a V of 9.35 pmol s (10 cells) . Pentamidine transport appears to be P2-mediated in these cells, as pentamidine strongly inhibited uptake of [2′,5′,8- H]adenosine by the P2 transporter, with a K of 0.56 μM. Furthermore, [ ring - H]pentamidine transport was blocked by a number of P2 transporter substrates and inhibitors, as well as by other diamidine drugs. Analysis of the uptake of pentamidine and other diamidines in melarsen-resistant trypanosomes in vitro and in vivo , which also show differential levels of resistance to these compounds in vivo , indicated that P2 transport was altered in these cells and that accumulation of these drugs was markedly reduced.