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Vol. 59, Issue 3, 586-592, March 2001
Institute of Biomedical and Life Sciences, Division of Infection
and Immunity, University of Glasgow, Glasgow, United Kingdom
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 Km value of 0.26 ± 0.03 µM and Ki 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 Km 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.
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