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Interaction of nucleoside‐derivatives with the human Na + /nucleoside cotransporters CNT1 and CNT3
Author(s) -
Gorraitz Edurne,
Sanmartin Carmen,
ErrastiMurugarren Ekaitz,
Casado Francisco J.,
PastorAnglada Marçal,
Lostao M. Pilar
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.133
Subject(s) - uridine , nucleoside , adenosine , biochemistry , pyrimidine , nucleoside transporter , chemistry , biology , transporter , rna , gene
CNT1 and CNT3 are transporters involved in anticancer and antiviral nucleoside‐derived drug uptake. Human CNT1 (hCNT1) transports pyrimidine nucleosides and is inhibited by adenosine. Human CNT3 (hCNT3) transports both pyrimidine and purine nucleosides. We have synthesized adenosine and uridine derivatives and investigated their interaction with hCNT1 and hCNT3 using the two‐electrode voltage clamp technique applied to Xenopus laevis oocytes expressing these transporters. Uridine and adenosine were functionalized with aromatic system with linear aliphatic chain of variable length and variable functional groups in position 4′. hCNT1 transported the uridine‐derivatives with the same affinity than uridine (K 0.5 ≈ 45 μM) and 20–50 % reduction in the maximum transport rate (I max ). hCNT3 behavior was similar (K 0.5 ≈ 7 μM). The adenosine‐derivatives were inhibitors of hCNT1 with K i 2–5 times higher than that for adenosine (6 μM). These molecules, however, were transported by hCNT3 with higher K 0.5 than adenosine (0.7 mM vs 18 μM) but similar I max . Only one derivative showed same K 0.5 than adenosine but a 50 % reduction in I max . In summary, both hCNT1 and hCNT3 can transport bulky derivates of uridine and adenosine with similar affinities and maximum transport rates.