Contribution of Glutathione-S-Transferases to the Pharmacogenetics of Azathioprine

Azathioprine is a purine antimetabolite drug commonly used as immunomodulator in the treatment of various chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Azathioprine is activated in vivo after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of the enzyme glutathione-S-transferase (GST), in particular of isoforms GST-A1/GST-A2 and GST-M1, can increase its speed, leading to a faster activation of azathioprine to active thioguanine nucleotides. Moreover, GSTs may contribute to azathioprine effects by modulating GSH consumption, oxidative stress and apoptosis. Indeed, in young patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of its active metabolites. 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.