Abstract
The trypanocidal action of pentamidine is dependent on the rapid, selective accumulation of this drug by the parasite. We have investigated pentamidine transport by the bloodstream and procyclic life cycle stages of Trypanosoma brucei brucei. In bloodstream forms, 50 to 70% of [3H]pentamidine was transported by an adenosine-sensitive pentamidine transporter (ASPT1) that displayed a K m value of 0.26 ± 0.03 μM and K i values of 0.45 ± 0.04 and 2.5 ± 0.8 μM for adenine and berenil, respectively. These values are very similar to those for inhibition of [3H]adenosine uptake by the P2 adenosine/adenine transporter, suggesting that ASPT1 and P2 may be identical. The remaining 30 to 50% of [3H]pentamidine transport was mediated by a low-capacity high-affinity pentamidine transporter (HAPT1) and a high-capacity low-affinity pentamidine transporter (LAPT1), with K m values of 36 ± 6 nM and 56 ± 8 μM, respectively. HAPT1 was inhibited by propamidine but displayed only low affinity to berenil and stilbamidine, whereas LAPT1 was not inhibited by any of these diamidines. Neither transporter was inhibited by melarsen oxide. In procyclics, an HAPT1-analog (procyclic pentamidine transporter; PPT1) was characterized, but no adenosine-sensitive pentamidine transport could be detected. Treatment with ionophores revealed that PPT1 may be a proton/pentamidine cotransporter.
Footnotes
- Received September 13, 2000.
- Accepted December 1, 2000.
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Send reprint requests to: Harry P. De Koning, Inst. of Biomedical and Life Sciences, Division of Infection and Immunity, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK. E-mail: h.de-koning{at}bio.gla.ac.uk
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Most of this work was funded by the Wellcome Trust, but part was performed at the School of Biological Sciences of the University of Manchester with the financial support of the Research Division of Biochemistry.
- The American Society for Pharmacology and Experimental Therapeutics
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