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Research article2010Peer reviewed

Differences in cytosolic and mitochondrial 5 '-nucleotidase and deoxynucleoside kinase activities in Sprague-Dawley rat and CD-1 mouse tissues: Implication for the toxicity of nucleoside analogs in animal models

Mirzaee, S; Eriksson, Staffan; Albertioni, F

Abstract

Cytosolic and mitochondrial deoxynucleoside kinases (dNKs), as well as 5'deoxynucleotidases (5'-dNTs), control intracellular and intramitochondrial phosphorylation of natural nucleotides and nucleoside analogs used in antiviral and cancer chemotherapy. The balance in the activities of these two groups of enzymes to a large extent determines both the efficacy and side effects of these drugs. Because of the broad and overlapping substrate specificities of the nucleoside kinases and 5'-NTs, their tissue distribution and roles in the metabolism of both natural nucleosides and their analogs are still not fully elucidated. Here, the activity of dNKs: dCK and TK (TK1 and TK2) as well as 5'-dNTs: CN1, CN2 and dNT (dNT1 and dNT2) were determined in 14 different adult mouse and rat tissues. In most cases tissue activities of TK1, TK2 and dCK were 2-3-fold higher in the mouse, a similar pattern was found with CN1 and dNTs although with several exceptions, e.g., TK2 activities in muscle extracts from rats were 2-10-fold higher than in the mouse. Furthermore CN1 activities in hepatic, renal and adipose extracts were 2-3-fold higher in the rat. CN2 had higher levels in the testis, spleen, pancreas and diaphragm and lower level in the lung of mouse compared to rat tissues. The result suggests that a major difference in these activity profiles between mouse and rat may account for discrepancies in pharmacological response of the two animals to certain nucleoside compounds, and may help to improve the usefulness of animal models in future efforts of drug discovery. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Keywords

Deoxy nucleoside kinase; 5 '-Nucleotidases; Nucleoside analogs; Toxicity; Metabolism

Published in

Toxicology
2010, Volume: 267, number: 1-3, pages: 159-164 Publisher: ELSEVIER IRELAND LTD

    Associated SLU-program

    AMR: Virus

    UKÄ Subject classification

    Pharmacology and Toxicology
    Animal and Dairy Science
    Veterinary Science

    Publication identifier

    DOI: https://doi.org/10.1016/j.tox.2009.11.009

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/48572