Toggle Main Menu Toggle Search

ePrints

Azathioprine with Allopurinol: Lower Deoxythioguanosine in DNA and Transcriptome Changes Indicate Mechanistic Differences to Azathioprine Alone

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

Downloads


Licence

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


Abstract

Background: Use ofazathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) by-passes side effects, improves efficacy and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine (AZA) and LDAA treatments work by similar mechanisms, using incorporation of the metabolite deoxythioguanosine into patient DNA, white-blood cell counts and transcriptome analysis as biological markers of drug effect. Methods: DNA was extracted from peripheral whole-blood from IBD patients treated with AZA or LDAA, and analysed for DNA-incorporated deoxythioguanosine. Measurement of red-blood cell (RBC) thiopurine metabolites was part of usual clinical practice, and pre- and on-treatment (12 weeks) blood samples were used for transcriptome analysis. Results: There were no differences in reduction of white-cell counts between the two treatment groups but patients on LDAA had lower DNA-incorporated deoxythioguanosine than those on AZA; for both groups, incorporated deoxythioguanosine was lower in patients on thiopurines for 24 weeks or more (maintenance of remission) compared to patients treated for less than 24 weeks (achievement of remission). Patients on LDAA had higher levels of RBC thioguanine nucleotides than those on AZA, but there was no correlation between these, or their methylated metabolites, and incorporated deoxythioguanosine. Transcriptome analysis suggested down-regulation of immune responses consistent with effective immunosuppression in patients receiving LDAA, with evidence for different mechanisms of action between the two therapies. Conclusions: LDAA is biologically effective despite lower deoxythioguanosine incorporation into DNA, and has different mechanisms of action compared to standard-dose azathioprine.


Publication metadata

Author(s): Coulthard SA, Berry P, McGarrity S, McLaughlin S, Ansari A, Redfern CPF

Publication type: Article

Publication status: Published

Journal: Inflammatory Bowel Diseases

Year: 2017

Pages: e-pub ahead of print

Online publication date: 27/04/2017

Acceptance date: 20/03/2017

ISSN (print): 1078-0998

ISSN (electronic): 1536-4844

Publisher: Wolters Kluwer Health, Inc.

URL: http://doi.org/10.1097/MIB.0000000000001131

DOI: 10.1097/MIB.0000000000001131

PubMed id: 28452864


Altmetrics

Altmetrics provided by Altmetric


Actions

    Link to this publication


Share