Deletion of glutathione-S-transferase M1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease

Gabriele Stocco, Eva Cuzzoni, Sara De Iudicibus, Raffaella Franca, Diego Favretto, Noelia Malusà, Margherita Londero, Gabriele Cont, Fiora Bartoli, Stefano Martelossi, Alessandro Ventura, Giuliana Decorti

Research output: Contribution to journalArticle

Abstract

GOALS: 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. STUDY: 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.

Original languageEnglish
Pages (from-to)43-51
Number of pages9
JournalJournal of Clinical Gastroenterology
Volume48
Issue number1
DOIs
Publication statusPublished - Jan 2014

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Azathioprine
Inflammatory Bowel Diseases
Thioguanine
Nucleotides
Pyrophosphatases
Inosine Triphosphate
Transferases
Genetic Polymorphisms
Genotype
glutathione S-transferase M1
6-Mercaptopurine
Prodrugs
Enzymes
Immunosuppressive Agents
Glutathione Transferase
Genes
Pharmacokinetics
Erythrocytes
Steroids
High Pressure Liquid Chromatography

Keywords

  • azathioprine
  • glutathione-S-transferases
  • inflammatory bowel disease
  • pharmacogenetics
  • thiopurine-S-methyl-transferase

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Deletion of glutathione-S-transferase M1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. / Stocco, Gabriele; Cuzzoni, Eva; De Iudicibus, Sara; Franca, Raffaella; Favretto, Diego; Malusà, Noelia; Londero, Margherita; Cont, Gabriele; Bartoli, Fiora; Martelossi, Stefano; Ventura, Alessandro; Decorti, Giuliana.

In: Journal of Clinical Gastroenterology, Vol. 48, No. 1, 01.2014, p. 43-51.

Research output: Contribution to journalArticle

Stocco, Gabriele ; Cuzzoni, Eva ; De Iudicibus, Sara ; Franca, Raffaella ; Favretto, Diego ; Malusà, Noelia ; Londero, Margherita ; Cont, Gabriele ; Bartoli, Fiora ; Martelossi, Stefano ; Ventura, Alessandro ; Decorti, Giuliana. / Deletion of glutathione-S-transferase M1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. In: Journal of Clinical Gastroenterology. 2014 ; Vol. 48, No. 1. pp. 43-51.
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T1 - Deletion of glutathione-S-transferase M1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease

AU - Stocco, Gabriele

AU - Cuzzoni, Eva

AU - De Iudicibus, Sara

AU - Franca, Raffaella

AU - Favretto, Diego

AU - Malusà, Noelia

AU - Londero, Margherita

AU - Cont, Gabriele

AU - Bartoli, Fiora

AU - Martelossi, Stefano

AU - Ventura, Alessandro

AU - Decorti, Giuliana

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N2 - GOALS: 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. STUDY: 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.

AB - GOALS: 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. STUDY: 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.

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