Homeostatic control of uridine and the role of uridine phosphorylase: a biological and clinical update.
Uridine, a pyrimidine nucleoside essential for the synthesis of RNA and bio-membranes, is a crucial element in the regulation of normal physiological processes as well as pathological states. The biological effects of uridine have been associated with the regulation of the cardio-circulatory system, at the reproduction level, with both peripheral and central nervous system modulation and with the functionality of the respiratory system. Furthermore, uridine plays a role at the clinical level in modulating the cytotoxic effects of fluoropyrimidines in both normal and neoplastic tissues. The concentration of uridine in plasma and tissues is tightly regulated by cellular transport mechanisms and by the activity of uridine phosphorylase (UPase), responsible for the reversible phosphorolysis of uridine to uracil. We have recently completed several studies designed to define the mechanisms regulating UPase expression and better characterize the multiple biological effects of uridine. Immunohistochemical analysis and co-purification studies have revealed the association of UPase with the cytoskeleton and the cellular membrane. The characterization of the promoter region of UPase has indicated a direct regulation of its expression by the tumor suppressor gene p53. The evaluation of human surgical specimens has shown elevated UPase activity in tumor tissue compared to paired normal tissue.
Pizzorno
Giuseppe
G
Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Giuseppe.Pizzorno@yale.edu
Cao
Deliang
D
Leffert
Janine J
JJ
Russell
Rosalind L
RL
Zhang
Dekai
D
Handschumacher
Robert E
RE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001693:Biological Transport, Active; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D015971:Gene Expression Regulation, Enzymologic; D016158:Genes, p53; D006706:Homeostasis; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013347:Subcellular Fractions / Q000378:metabolism; D014529:Uridine / Q000008:administration & dosage / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
D000970:Antineoplastic Agents; D014746:Vimentin; D014543:Uridine Phosphorylase; D005472:Fluorouracil; D014529:Uridine