title: Abnormalities in uridine homeostatic regulation and pyrimidine nucleotide metabolism as a consequence of the deletion of the uridine phosphorylase gene.
abstract: We report in the present study the critical role of uridine phosphorylase (UPase) in uridine homeostatic regulation and pyrimidine nucleotide metabolism, employing newly developed UPase-/- mice. Our data demonstrate that the abrogation of UPase activity led to greater than a 6-fold increase in uridine concentrations in plasma, a 5-6-fold increase in lung and gut, and a 2-3-fold increase in liver and kidney, as compared with wild type mice. Urine uridine levels increased 24-fold normal in UPase-/- mice. Uridine half-life and the plasma retention of pharmacological doses of uridine were significantly prolonged. Further, in these UPase-/- mice, abnormal uridine metabolism led to disorders of various nucleotide metabolisms. In the liver, gut, kidney, and lung of UPase-/- mice, total uridine ribonucleotide concentrations increased 2-3 times as compared with control mice. Cytidine ribonucleotides and adenosine and guanosine ribonucleotides also increased, although to a lesser extent, in these organs. Most significant deoxyribonucleotide changes were present in the gut and lung of UPase-/- mice. In these tissues, dTTP concentration increased more than 4-fold normal, and dCTP, dGTP, and dATP concentrations rose 1-2 times normal. In kidney, dTTP concentration increased 2-fold normal, and dCTP and dGTP concentrations rose less than 1-fold normal. In addition, the accumulated uridine in plasma and tissues efficiently reduced 5-fluorouracil host toxicity and altered the anesthetic effect of pentobarbital. These data indicate that UPase is a critical enzyme in the regulation of uridine homeostasis and pyrimidine nucleotide metabolism, and 5-fluorouracil activity.
authors.affiliation: Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
authors.forename: Janine J
authors.initials: JJ
authors.lastname: Leffert
authors.forename: James
authors.initials: J
authors.lastname: McCabe
authors.forename: Bradford
authors.initials: B
authors.lastname: Kim
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pizzorno
mesh_terms: D000241:Adenosine / Q000737:chemistry; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015139:Blotting, Southern; D003562:Cytidine / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000737:chemistry; D005472:Fluorouracil / Q000494:pharmacology; D017353:Gene Deletion; D006151:Guanosine / Q000737:chemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009711:Nucleotides / Q000737:chemistry; D010424:Pentobarbital / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000737:chemistry; D013942:Thymine Nucleotides / Q000737:chemistry; D013997:Time Factors; D014018:Tissue Distribution; D014529:Uridine / Q000737:chemistry* / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003854:Deoxyribonucleotides; D009711:Nucleotides; D011743:Pyrimidines; D012333:RNA, Messenger; D012265:Ribonucleotides; D013942:Thymine Nucleotides; D006151:Guanosine; D003562:Cytidine; D014543:Uridine Phosphorylase; D004259:DNA-Directed DNA Polymerase; D010424:Pentobarbital; D000241:Adenosine; C030986:pyrimidine; C024157:thymidine 5'-triphosphate; D005472:Fluorouracil; D014529:Uridine