Transport characteristics of mouse concentrative nucleoside transporter 1.
Concentrative nucleoside transporter 1 (CNT1, SLC28A1) is a key molecule for determining the pharmacokinetic/pharmacodynamic profile of a candidate compound derived from a pyrimidine nucleoside, but there is no available information on the differences in the functional profile of this ortholog between man and mouse. Here, using a clone of mouse CNT1 (mCNT1), we investigated its transport characteristics and substrate specificity for synthetic nucleoside analogues, and compared them with those of human CNT1 (hCNT1). In mCNT1-transfected Cos-7 cells, pyrimidine, but not purine, nucleosides showed sodium- and concentration-dependent uptake, and uridine uptake was competitively inhibited by uridine analogues, the rank order of the inhibitory effects being 5-bromouridine>3'-deoxyuridine>2'-deoxyuridine. cis- and trans-Inhibition studies involving synthetic nucleoside drugs revealed that gemcitabine and zidovudine greatly inhibited [(3)H]uridine uptake mediated by mCNT1 in the both cases, while cytarabine and zalcitabine showed small cis-inhibitory effect, and no trans-inhibitory effect on the uptake. These results demonstrate that the transport characteristics of mCNT1 are almost the same as those of hCNT1, suggesting that mice may be a good animal model in evaluation of pyrimidine nucleoside analogues as to their applicability in human therapy.
Niitani
Miho
M
Department of Environmental Biochemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Nishida
Kentaro
K
Okuda
Hiroto
H
Nagai
Katsuhito
K
Fujimoto
Sadaki
S
Nagasawa
Kazuki
K
D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D009705:Nucleosides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012964:Sodium / Q000378:metabolism; D013045:Species Specificity; D013237:Stereoisomerism; D013379:Substrate Specificity
D026901:Membrane Transport Proteins; D009705:Nucleosides; C065171:cif nucleoside transporter; D012964:Sodium