The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

Abstract

Azathioprine (AZA) is a thiopurine prodrug which is widely used in patients with inflammatory bowel disease (IBD). However, the use is limited in one-third of patients because of adverse drug reactions (ADRs) or a lack of clinical response. It has been considered that the polymorphic enzyme thiopurine S-methyltransferase (TPMT) plays an important role in the in vivo process of AZA and the occurrence of its myelotoxicity. Glutathione S-transferase (GST) mutation is another pharmacogenetic polymorphism which is probably involved in AZA metabolism and tolerance. The aim of this study was to investigate the association among GST polymorphism, enzyme activity and AZA-related ADRs in Chinese Han patients with IBD. We found that the patients who became neutropenic had a significantly higher GSTs activity when compared with of the patients who did not develop ADRs (analysis of variance, P < 0.001). There was also a significant underrepresentation of GSTP1*-105V allele among patients developing ADRs (odds ratio [OR] = 0.125, 95% confidence interval [CI] = 0.022-0.709, P = 0.0012). The patients with higher GST activity constituted a pharmacogenetic high risk group for leucopenia during AZA treatment. GST-P1 Ile105/Ile105 genotype appeared to be a promising marker indicating predisposition to AZA-related ADRs.

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

“…In contrast, a significant lower risk for female patients to develop leukopenia was found after correcting for age, concomitant steroid or infliximab treatment and TPMT and NUDT15 genotype OR 0.2 (95% CI 0.0‐0.9) . Seven other studies did not find an association for gender . The majority of studies showed no association between age and TIL .…”

“…A detailed summary of results of 10 studies that investigated the association of other gene variants or enzymatic activity and TIL can be found in Table …”

“…Glutathione S‐transferase (GST) is thought to catalyse the conversion of AZA into 6‐MP (Figure ) . Glutathione S‐transferase pi 1 ( GSTP1 ) Val105 and glutathione S‐transferase mu 1 ( GSTM1 ) hetero‐ and homozygote variant carriers had a significantly lower risk for TIL compared to wild‐type patients (OR 0.16 (95% CI 0.04‐0.74) and OR 0.34 (95% CI 0.12‐0.92) respectively) . No lower risks were found for glutathione S‐transferase theta 1 ( GSTT1 ) and glutathione S‐transferase alpha 1 ( GSTA1 ) variant carriers.…”

“…GSTs activity in patients with leukopenia was significantly higher than in patients without leukopenia (3.49 ± 0.09 vs 3.14 ± 0.04 U/gHb, P = 0.001). Multivariable logistic regression analysis revealed that only GSTP1 variants and GST activity were significantly associated with TIL (OR 0.13 and OR 11.7 respectively) …”

“…In contrast, a randomised controlled trial comparing AZA monotherapy with AZA therapy combined with olsalazine showed significant lower mean WBC counts in the combination treatment group (4.65 ± 0.4 vs 4.05 ± 0.3) . Eight studies found no significant effect of concomitant 5‐ASA use on the development of TIL . In contrast, a threefold higher risk for leukopenia was found for concomitant 5‐ASA use after correction for baseline WBC count in multivariable regression analysis and a significant higher leukopenia rate in the concomitant 5‐ASA group compared to patients without concomitant 5‐ASA use were found in two Chinese cohort studies .…”