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The effect of thiopurine drugs on DNA methylation in relation to TPMT expression

Lookup NU author(s): Dr Linda Hogarth, Dr Chris Redfern, Dr Andrew Hall, Dr Holly Anderson, Marian Case, Dr Sally Coulthard

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Abstract

The thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well-established agents for the treatment of leukaemia but their main modes of action are controversial. Thiopurine methyltransferase (TPMT) metabolises thiopurine drugs and influences their cytotoxic activity. TPMT, like DNA methyltransferases (DNMTs), transfers methyl groups from S-adenosylmethionine (SAM) and generates S-adenosylhomocysteine (SAH). Since SAM levels are dependent on de novo purine synthesis (DNPS) and the metabolic products of 6-TG and 6-MP differ in their ability to inhibit DNPS, we postulated that 6-TG compared to 6-MP would have differential effects on changes in SAM and SAH levels and global DNA methylation, depending on TPMT status. To test this hypothesis, we used a human embryonic kidney cell line with inducible TPMT. Although changes in SAM and SAH levels occurred with each drug, decrease in global DNA methylation more closely reflected a decrease in DNMT activity. Inhibition was influenced by TPMT for 6-TG, but not 6-MP. The decrease in global methylation and DNMT activity with 6-MP, or with 6-TG when TPMT expression was low, were comparable to 5-aza-2′-deoxycytidine. However, this was not reflected in changes in methylation at the level of an individual marker gene (MAGE1A). The results suggest that a non-TPMT metabolised metabolite of 6-MP and 6-TG and the TPMT-metabolised 6-MP metabolite 6-methylthioguanosine 5'-monophosphate, contribute to a decrease in DNMT levels and global DNA methylation. As demethylating agents have shown promise in leukaemia treatment, inhibition of DNA methylation by the thiopurine drugs may contribute to their cytotoxic affects. © 2008 Elsevier Inc. All rights reserved.


Publication metadata

Author(s): Hogarth LA, Redfern CPF, Teodoridis J, Hall AG, Anderson HL, Case MC, Coulthard SA

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2008

Volume: 76

Issue: 8

Pages: 1024-1035

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

Publisher: Elsevier Inc.

URL: http://dx.doi.org/10.1016/j.bcp.2008.07.026

DOI: 10.1016/j.bcp.2008.07.026


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