谷胱甘肽-S-转移酶基因型与硫唑嘌呤在年轻炎症性肠病患者中的不良反应

Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease.

作者信息

Stocco Gabriele, Martelossi Stefano, Barabino Arrigo, Decorti Giuliana, Bartoli Fiora, Montico Marcella, Gotti Annalisa, Ventura Alessandro

机构信息

Department of Biomedical Sciences, University of Trieste, Trieste, Italy.

出版信息

Inflamm Bowel Dis. 2007 Jan;13(1):57-64. doi: 10.1002/ibd.20004.

DOI:10.1002/ibd.20004

PMID:17206640

Abstract

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).

CONCLUSION

Patients with IBD with a wildtype GST-M1 genotype present increased probability of developing adverse effects and increased incidence of lymphopenia during azathioprine treatment.

摘要

背景

硫唑嘌呤（6-巯基嘌呤的前体药物）的药物不良反应发生在15%-38%的患者中，且大多数不能用硫嘌呤甲基转移酶（TPMT）缺乏来解释。已知硫唑嘌呤会导致谷胱甘肽耗竭，与低活性细胞相比，高谷胱甘肽-S-转移酶（GST）活性细胞中的谷胱甘肽消耗更大；此外，一些报告表明GST可能在谷胱甘肽与硫唑嘌呤的反应中起直接作用。因此，研究了GST-M1、GST-P1、GST-T1和TPMT基因多态性与硫唑嘌呤不良反应之间的关联。

方法

纳入70例接受硫唑嘌呤治疗的炎症性肠病（IBD）患者，并回顾性确定临床数据。通过聚合酶链反应（PCR）检测从血样中提取的DNA进行TPMT和GST基因分型。

结果

15例患者出现不良反应（21.4%）；与未出现不良反应的患者相比，发生硫唑嘌呤药物不良反应的患者中GST-M1无效基因型的比例显著降低（比值比[OR]=0.18，95%置信区间[CI]=0.037-0.72，P=0.0072）。TPMT突变杂合子患者出现不良反应的概率略有显著增加（OR=6.38，95%CI=0.66-84.1，P=0.062）。此外，在55例未出现不良反应的患者中，与未出现硫唑嘌呤这种效应的患者相比，出现淋巴细胞减少的患者中GST-M1无效基因型的比例显著降低（OR=0.15，95%CI=0.013-1.08，P=0.032）。