Increased renal elimination of endogenous and synthetic pyrimidine nucleosides in concentrative nucleoside transporter 1 deficient mice.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 06 2023
01 06 2023
Historique:
received:
31
03
2022
accepted:
16
05
2023
medline:
5
6
2023
pubmed:
2
6
2023
entrez:
1
6
2023
Statut:
epublish
Résumé
Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans.
Identifiants
pubmed: 37264059
doi: 10.1038/s41467-023-38789-8
pii: 10.1038/s41467-023-38789-8
pmc: PMC10235067
doi:
Substances chimiques
Nucleosides
0
Membrane Transport Proteins
0
Pyrimidine Nucleosides
0
Carrier Proteins
0
Antimetabolites
0
Nucleoside Transport Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3175Subventions
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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