Structure-inhibitory profiles of nucleosides for the human intestinal N1 and N2 Na+-nucleoside transporters.
OBJECTIVE
To determine the structure-inhibitory profiles of nucleosides for the N1 and N2 Na+-nucleoside transporters of the human intestine.


METHODS
The uptake of 3H-labeled prototypic substrates of the N1 (inosine) and N2 (thymidine) transporters into human intestinal brush border membrane vesicles was measured by a rapid filtration technique in the presence and absence of various uridine and adenosine analogs and antiviral and anticancer nucleoside drugs (100 and 1000 microM).


RESULTS
In the ribose ring, the 3'-oxygen is required for inhibition of uptake of nucleosides by both the N1 and N2 transporters. The structural requirements for such inhibition differ with respect to modifications on the 5' position of the sugar ring or on the base. The N2 transporter is more tolerant to these substitutions than is the N1 transporter. The 6 position on uracil and the 8 position on adenine are critical for inhibition of uptake of nucleosides by both the N1 and N2 nucleoside transporters.


CONCLUSIONS
These data are the first evidence that the binding site(s) of the human N1 and N2 transporters differ in their interaction with analogs of their common substrates, uridine and adenosine. Such studies can provide insight into the critical structural determinants of the substrate necessary for recognition by the Na+-nucleoside transporters of the human intestine.
Patil
S D
SD
Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
Ngo
L Y
LY
Unadkat
J D
JD
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007288:Inosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D026901:Membrane Transport Proteins; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009705:Nucleosides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives / Q000494:pharmacology
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D009705:Nucleosides; C065171:cif nucleoside transporter; D007288:Inosine; D000241:Adenosine; D013936:Thymidine; D014529:Uridine