Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?
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.
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Gabriele
G
Stocco
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Marco
M
Pelin
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Raffaella
R
Franca
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Sara
S
De Iudicibus
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Eva
E
Cuzzoni
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Diego
D
Favretto
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Stefano
S
Martelossi
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Alessandro
A
Ventura
Gabriele Stocco, Marco Pelin, Giuliana Decorti, Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.
Giuliana
G
Decorti
D000818:Animals; D017209:Apoptosis; D001379:Azathioprine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics*; D015122:Mercaptopurine / Q000737:chemistry; D018384:Oxidative Stress; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D005982:Glutathione Transferase; D005978:Glutathione; D001379:Azathioprine
Azathioprine; Glutathione-S-transferase; Inflammatory bowel disease; Pediatric patients; Pharmacogenetics