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

Avinash K. Persaud, Matthew C. Bernier, Michael A. Massey, Shipra Agrawal, Tejinder Kaur, Debasis Nayak, Zhiliang Xie, Brenna Weadick, Ruchika Raj, Kasey Hill, Nicole Abbott, Arnav Joshi, Nadeen Anabtawi, Claire Bryant, Arpad Somogyi, Zobeida Cruz-Monserrate, Foued Amari, Vincenzo Coppola, Alex Sparreboom, Sharyn D. Baker, Jashvant D. Unadkat, Mitch A. Phelps and Rajgopal Govindarajan ()
Additional contact information
Avinash K. Persaud: The Ohio State University
Matthew C. Bernier: The Ohio State University
Michael A. Massey: The Ohio State University
Shipra Agrawal: Stony Brook University
Tejinder Kaur: The Ohio State University
Debasis Nayak: The Ohio State University
Zhiliang Xie: The Ohio State University
Brenna Weadick: The Ohio State University
Ruchika Raj: The Ohio State University
Kasey Hill: The Ohio State University
Nicole Abbott: The Ohio State University
Arnav Joshi: The Ohio State University
Nadeen Anabtawi: The Ohio State University
Claire Bryant: Nationwide Children’s Hospital
Arpad Somogyi: The Ohio State University
Zobeida Cruz-Monserrate: The Ohio State University
Foued Amari: Ohio State University Comprehensive Cancer Center, The Ohio State University
Vincenzo Coppola: Ohio State University Comprehensive Cancer Center, The Ohio State University
Alex Sparreboom: The Ohio State University
Sharyn D. Baker: The Ohio State University
Jashvant D. Unadkat: University of Washington
Mitch A. Phelps: The Ohio State University
Rajgopal Govindarajan: The Ohio State University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38789-8

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