title: Deletion of glutathione-s-transferase m1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease.
abstract: OBJECTIVE
  To investigate, in young patients with inflammatory bowel disease (IBD) treated with azathioprine, the association between genetic polymorphisms of thiopurine-S-methyl-transferase (TPMT), inosine-triphosphate-pyrophosphatase (ITPA), and glutathione-S-transferases (GST), involved in azathioprine metabolism, the concentration of the main metabolites of azathioprine, thioguanine nucleotides (TGNs) and the methylated nucleotides (MMPN), and the dose of the medication.
  
  
  BACKGROUND
  Azathioprine is widely used in IBD as an immunosuppressive agent, particularly to maintain remission in patients with steroid refractory disease. Azathioprine is a prodrug and requires conversion to its active form mercaptopurine, which has no intrinsic activity, and is activated by the enzymes of the purine salvage pathway to TGNs. Polymorphisms in genes of enzymes involved in azathioprine metabolism influence the efficacy and toxicity of treatment.
  
  
  METHODS
  Seventy-five young patients with IBD treated with azathioprine at least for 3 months were enrolled and genotyped for the selected genes; for these patients, TGN and MMPN metabolites were measured by high performance liquid chromatography in erythrocytes.
  
  
  RESULTS
  GST-M1 deletion was associated with lower TGN/dose ratio (P=0.0030), higher azathioprine dose requirement (P=0.022), and reduced response to therapy (P=0.0022). TPMT variant genotype was associated with lower MMPN concentration (P=0.0064) and increased TGN/dose ratio (P=0.0035). ITPA C94A polymorphism resulted in an increased MMPN concentration (P=0.037).
  
  
  CONCLUSIONS
  This study describes the effect of candidate genetic polymorphisms in TPMT, ITPA, and GST-M1 on azathioprine pharmacokinetics in IBD patients, showing, for the first time, relevant effects of GST-M1 genotype on azathioprine metabolites concentration.
authors.affiliation: Departments of *Life Sciences †Medical, Surgical, and Health Sciences ∥Scuola di Dottorato di Ricerca in Scienze della Riproduzione, University of Trieste ‡Institute for Maternal and Child Health IRCCS Burlo Garofolo §Department of Prevention, Sanitary Services Agency Number 1, Trieste, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stocco
authors.forename: Eva
authors.initials: E
authors.lastname: Cuzzoni
authors.forename: Sara
authors.initials: S
authors.lastname: De Iudicibus
authors.forename: Raffaella
authors.initials: R
authors.lastname: Franca
authors.forename: Diego
authors.initials: D
authors.lastname: Favretto
authors.forename: Noelia
authors.initials: N
authors.lastname: Malusà
authors.forename: Margherita
authors.initials: M
authors.lastname: Londero
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cont
authors.forename: Fiora
authors.initials: F
authors.lastname: Bartoli
authors.forename: Stefano
authors.initials: S
authors.lastname: Martelossi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ventura
authors.forename: Giuliana
authors.initials: G
authors.lastname: Decorti
mesh_terms: D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics; D013873:Thionucleotides / Q000378:metabolism; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D005982:Glutathione Transferase; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D013873:Thionucleotides; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase