Increased renal elimination of endogenous and synthetic pyrimidine nucleosides in concentrative nucleoside transporter 1 deficient mice

Nat Commun. 2023 Jun 1;14(1):3175. doi: 10.1038/s41467-023-38789-8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antimetabolites
  • Carrier Proteins / metabolism
  • Humans
  • Kidney / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice
  • Nucleoside Transport Proteins / metabolism
  • Nucleosides* / metabolism
  • Pyrimidine Nucleosides*
  • Renal Elimination


  • Nucleosides
  • Membrane Transport Proteins
  • Pyrimidine Nucleosides
  • Carrier Proteins
  • Antimetabolites
  • Nucleoside Transport Proteins