Activation pathways of 5-fluorouracil in rat organs and in PC12 cells

Citation
L. Mascia et Pl. Ipata, Activation pathways of 5-fluorouracil in rat organs and in PC12 cells, BIOCH PHARM, 62(2), 2001, pp. 213-218
Citations number
40
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
2
Year of publication
2001
Pages
213 - 218
Database
ISI
SICI code
0006-2952(20010715)62:2<213:APO5IR>2.0.ZU;2-G
Abstract
Activation of the pyrimidine analogue 5-fluorouracil (5-FU) to the ribonucl eotide level may occur through one of the following three pathways: 1) the 5-phosphoribosyl 1-pyrophosphate (PRPP)-mediated direct transfer of ribose 5-phosphate to 5-FU as catalysed by orotate phosphoribosyltransferase; 2) t he ribose 1-phosphate (Rib1-P)-mediated addition of ribose by uridine phosp horylase, folio wed by the action of uridine kinase; and 3) the 2'-deoxyrib ose 1-phosphate (deoxyRib1-P)-mediated addition of deoxyribose, thought to be catalysed by thymidine phosphorylase, followed by the action of thymidin e kinase. Many of the conclusions as to the precise pathways by which norma l tissues and different cell lines activate uracil are indirectly derived f rom drug interactions affecting the availability of the substrates of the t hree pathways, or from measurement of activities of the enzymes metabolisin g 5-FU in normal tissues and tumours, In previous papers (Cappiello et al. Biochim Biophys Acta 1998;1425:273-81; Mascia et al. Biochim Biophys Acta 1 999;1472:93-8), we assessed the molecular mechanisms by which the natural b ase uracil is salvaged in vitro to uracil ribonucleotides and deoxyribonucl eotides in rat liver and brain. In this paper, we investigated the pathways of 5-FU activation to cytotoxic ribonucleotide and deoxyribonucleotide lev els in normal rat tissues and PC12 cell extracts. The results clearly showe d that normal rat tissues activated 5-FU mainly via the Rib1-P pathway, and to a lesser extent via the PRPP pathway. The deoxyRib1-P pathway was absen t. PC12 cells activated 5-FU mainly via the PRPP pathway and to a lesser ex tent by the other two pathways. (C) 2001 Elsevier Science Inc. All rights r eserved.