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World J Gastroenterol. Apr 7, 2014; 20(13): 3534-3541
Published online Apr 7, 2014. doi: 10.3748/wjg.v20.i13.3534
Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?
Gabriele Stocco, Marco Pelin, Raffaella Franca, Sara De Iudicibus, Eva Cuzzoni, Diego Favretto, Stefano Martelossi, Alessandro Ventura, Giuliana Decorti
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy
Raffaella Franca, Sara De Iudicibus, Diego Favretto, Stefano Martelossi, Alessandro Ventura, Institute for Maternal and Child Health IRCCS Burlo Garofolo, I-34137 Trieste, Italy
Eva Cuzzoni, Alessandro Ventura, Department of Medical, Surgical and Health Sciences, University of Trieste, I-34127 Trieste, Italy
Author contributions: All authors participated in the preparation, writing and discussion of the manuscript.
Correspondence to: Gabriele Stocco, PhD, Department of Life Sciences, University of Trieste, via A. Fleming 22, I-34127 Trieste, Italy. stoccog@units.it
Telephone: +39-40-5588634 Fax: +39-40-5588634
Received: October 31, 2013
Revised: December 30, 2013
Accepted: January 19, 2014
Published online: April 7, 2014
Abstract

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

Keywords: Inflammatory bowel disease, Azathioprine, Pharmacogenetics, Glutathione-S-transferase, Pediatric patients

Core tip: Polymorphisms of glutathione-S-transferase-M1 may influence azathioprine effects in young patients with inflammatory bowel disease by increasing the drug activation and by modulating oxidative stress and apoptosis.