A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity

Oancea, Iulia, Png, Chin Wen, Das, Indrajit, Lourie, Rohan, Winkler, Ingrid G., Eri, Rajaraman, Subramaniam, Nathan, Jinnah, H. A., McWhinney, Brett C., Levesque, Jean-Pierre, McGuckin, Michael A., Duley, John A. and Florin, Timothy H. J. (2013) A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity. Gut, 62 4: 594-605. doi:10.1136/gutjnl-2012-302274

Author Oancea, Iulia
Png, Chin Wen
Das, Indrajit
Lourie, Rohan
Winkler, Ingrid G.
Eri, Rajaraman
Subramaniam, Nathan
Jinnah, H. A.
McWhinney, Brett C.
Levesque, Jean-Pierre
McGuckin, Michael A.
Duley, John A.
Florin, Timothy H. J.
Title A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity
Journal name Gut   Check publisher's open access policy
ISSN 0017-5749
Publication date 2013-04-01
Year available 2012
Sub-type Article (original research)
DOI 10.1136/gutjnl-2012-302274
Open Access Status Not Open Access
Volume 62
Issue 4
Start page 594
End page 605
Total pages 12
Place of publication London, United Kingdom
Publisher BMJ Group
Language eng
Formatted abstract
Objective: The anti-leukemic drugs, azathioprine and 6-mercaptopurine (6MP), are important in the treatment of inflammatory bowel disease but an alternative faster-acting, less-allergenic thiopurine, 6-thioguanine (6TG), can cause hepatic veno-occlusive disease/sinusoidal obstructive syndrome (SOS). Understanding of SOS has been hindered by inability to ethically perform serial liver biopsies on patients and the lack of an animal model.

Design: Normal and C57Bl/6 mice with specific genes altered to elucidate mechanisms responsible for 6TG-SOS, were gavaged daily for upto 28d with 6TG, 6MP or methylated metabolites. Animal survival was monitored and at sacrifice a histological score of SOS, haematology and liver biochemistry were measured.

Results: Only 6TG caused SOS, which was dose related. 6TG and to a lesser extent 6MP but not methylated metabolites were associated with dose-dependent haematopoietic toxicity. SOS was not detected with nonlethal doses of 6TG. SOS did not occur in hypoxanthinephosphoribosyl transferase-deficient C57Bl/6 mice, demonstrating that 6TG-SOS requires thioguanine nucleotides. Hepatic inflammation was characteristic of SOS, and C57Bl/6 mice deficient in P- and E-selectins on the surface of vascular endothelial cells showed markedly reduced SOS, demonstrating a major role for leukocytes recruited from blood. Split dosing of 6TG markedly attenuated SOS but still effected immunosuppression and prevented spontaneous colitis in Winnie mice, which have a single nucleotide polymorphism mutation in Muc2.

Conclusion: This novel model provides clinically relevant insights into how 6TG induces SOS, and how this dangerous adverse drug reaction may be avoided by either inhibition of endothelial activation or simple changes to dosing regimens of 6TG, while still being effective treatment for colitis.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published Online First 7 July 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
School of Medicine Publications
School of Pharmacy Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 19 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 19 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sun, 31 Mar 2013, 10:31:31 EST by System User on behalf of School of Medicine