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Three Faces of Mercaptopurine Cytotoxicity in vitro: Methylation, Nucleotide Homeostasis and Deoxythioguanosine in DNA

Lookup NU author(s): Dr Sally Coulthard, Sarah McGarrity, Dr Kiran Sahota, Philip Berry, Dr Chris Redfern

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Mercaptopurine (MP) is a cytotoxic thiopurine important for the treatment of cancer and autoimmune diseases. MP and other thiopurine drugs undergo extensive intracellular metabolism but the mechanisms of action are poorly characterised. In particular, it is unknown how different metabolites contribute to cytotoxicity and incorporation of thiopurine bases into DNA. The aim of this study was to ask whether cytotoxicity results from the incorporation of thioguanosine nucleotides into DNA, an alternative thiopurine metabolite, or a combination of factors. Therefore, we measured the cytotoxicity, metabolism, and incorporation of thioguanosine into DNA in response to MP or MP metabolites. Thiopurine metabolites varied in cytotoxicity, with methyl-thioinosine- mono-phosphate and thioguanosine-tri-phosphate the most toxic, and the methyl-thioguanosine nucleotides the least. We show, using liquid chromatography-tandem mass spectrometry, how different metabolites may perturb biochemical pathways, particularly disrupting guanosine nucleotide homeostasis which may contribute to the mechanism of action of thiopurines. Although there was no correlation between metabolite cytotoxicity and the levels of 6-methylthioinosine-mono-phosphate or thioguanosine incorporation into DNA as individual factors, a combined analysis suggested that these factors together had a major influence on cytotoxicity. This study emphasises the importance of enzymes of nucleotide homeostasis, methylation and demethylation in thiopurine effects. These results will facilitate the development of dynamic biochemical models of thiopurine biochemistry which will improve our understanding of mechanisms of action in relevant target tissues.


Publication metadata

Author(s): Coulthard SA, McGarrity S, Sahota K, Berry P, Redfern CPF

Publication type: Article

Publication status: Published

Journal: Drug Metabolism and Disposition

Year: 2018

Volume: 46

Issue: 8

Pages: 1191-1199

Print publication date: 01/08/2018

Online publication date: 12/06/2018

Acceptance date: 01/06/2018

ISSN (print): 0090-9556

ISSN (electronic): 1521-009X

Publisher: American Society for Pharmacology and Experimental Therapeutics

URL: https://doi.org/10.1124/dmd.118.081844

DOI: 10.1124/dmd.118.081844


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