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A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity
  1. Iulia Oancea1,2,
  2. Chin Wen Png1,
  3. Indrajit Das1,
  4. Rohan Lourie1,3,
  5. Ingrid Winkler4,
  6. Rajaraman Eri1,
  7. Nathan Subramaniam5,
  8. H A Jinnah6,
  9. Brett C McWhinney7,
  10. Jean-Pierre Levesque4,
  11. Michael A McGuckin1,8,
  12. John A Duley1,3,9,
  13. Timothy H J Florin1,2,10
  1. 1IBD Team, Immunology Infection Inflammation Program, Mater Medical Research Institute, South Brisbane, Queensland, Australia
  2. 2School of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. 3Mater Pathology, Mater Health Services, South Brisbane, Queensland, Australia
  4. 4Stem Cell Laboratory, Mater Medical Research Institute, South Brisbane, Queensland, Australia
  5. 5Queensland Institute of Medical Research, Herston, Queensland, Australia
  6. 6Department of Neurology, Human Genetics, Emory University, Atlanta, Georgia, USA
  7. 7Queensland Pathology Services, Herston, Queensland, Australia
  8. 8School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
  9. 9School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia
  10. 10Mater Health Services Department of Gastroenterology, South Brisbane, Queensland, Australia
  1. Correspondence to Professor Tim Florin, UQ Department of Medicine, Mater Adult Hospital, South Brisbane, QLD 4101, Australia; t.florin{at}uq.edu.au

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 non-lethal doses of 6TG. SOS did not occur in hypoxanthine-phosphoribosyl 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.

  • Thioguanine
  • IBD
  • veno-occlusive disease
  • sinusoidal obstructive syndrome
  • nodular regenerative hyperplasia
  • 6-mercaptopurine
  • hepatic iron metabolism
  • Crohn's disease
  • mucosal infection
  • mucus
  • mucins
  • gastric mucosal barrier
  • enteric infections
  • colonic bacteria
  • azathioprine
  • mucosal barrier
  • dendritic cells

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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