Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease.
BACKGROUND
Adverse drug reactions to azathioprine, the prodrug of 6-mercaptopurine, occur in 15%-38% of patients and the majority are not explained by thiopurine-S-methyltransferase (TPMT) deficiency. Azathioprine is known to induce glutathione depletion and consumption of glutathione is greater in cells with high glutathione-S-transferase (GST) activity compared with those with low activity; moreover, some reports indicate that GST might play a direct role in the reaction of glutathione with azathioprine. The association between polymorphisms of GST-M1, GST-P1, GST-T1, and TPMT genes and the adverse effects of azathioprine was therefore investigated.


METHODS
Seventy patients with inflammatory bowel disease (IBD), treated with azathioprine, were enrolled and clinical data were retrospectively determined. TPMT and GST genotyping were performed by polymerase chain reaction (PCR) assays on DNA extracted from blood samples.


RESULTS
Fifteen patients developed adverse effects (21.4%); there was a significant underrepresentation of the GST-M1 null genotype among patients developing adverse drug reactions to azathioprine (odds ratio [OR] = 0.18, 95% confidence interval [CI] = 0.037-0.72, P = 0.0072) compared with patients who did not develop adverse effects. Patients heterozygous for TPMT mutations presented a marginally significant increased probability of developing adverse effects (OR = 6.38, 95% CI = 0.66-84.1, P = 0.062). Moreover, among the 55 patients who did not develop adverse effects, there was a significant underrepresentation of the GST-M1 null genotype among patients who displayed lymphopenia as compared with those that did not display this effect of azathioprine (OR = 0.15, 95% CI = 0.013-1.08, P = 0.032).


CONCLUSIONS
Patients with IBD with a wildtype GST-M1 genotype present increased probability of developing adverse effects and increased incidence of lymphopenia during azathioprine treatment.
Stocco
Gabriele
G
Department of Biomedical Sciences, University of Trieste, Trieste, Italy. stoccog@units.it
Martelossi
Stefano
S
Barabino
Arrigo
A
Decorti
Giuliana
G
Bartoli
Fiora
F
Montico
Marcella
M
Gotti
Annalisa
A
Ventura
Alessandro
A
D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000235:genetics
D001379:Azathioprine; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human