Deletion of glutathione-s-transferase m1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease.
Kľúčové slová
Abstrakt
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.