Departments of *Life Sciences †Medical, Surgical, and Health Sciences ∥Scuola di Dottorato di Ricerca in Scienze della Riproduzione, University of Trieste ‡Institute for Maternal and Child Health IRCCS Burlo Garofolo §Department of Prevention, Sanitary Services Agency Number 1, Trieste, Italy.
J Clin Gastroenterol. 2014 Jan;48(1):43-51. doi: 10.1097/MCG.0b013e31828b2866.
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.
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.
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.
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).
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.
研究接受巯嘌呤治疗的炎症性肠病（IBD）年轻患者中，参与巯嘌呤代谢的硫嘌呤 S-甲基转移酶（TPMT）、肌苷三磷酸焦磷酸酶（ITPA）和谷胱甘肽 S-转移酶（GST）的遗传多态性与巯嘌呤的主要代谢物硫鸟嘌呤核苷酸（TGN）和甲基化核苷酸（MMPN）浓度以及药物剂量之间的关系。
巯嘌呤广泛用于 IBD 作为免疫抑制剂，特别是在治疗类固醇难治性疾病的患者中维持缓解。巯嘌呤是一种前体药物，需要转化为其无内在活性的活性形式巯基嘌呤，然后由嘌呤补救途径的酶激活为 TGN。参与巯嘌呤代谢的基因多态性会影响治疗的疗效和毒性。
本研究纳入了 75 名至少接受 3 个月巯嘌呤治疗的年轻 IBD 患者，并对这些患者进行了相关基因的基因分型；通过高效液相色谱法在红细胞中测定 TGN 和 MMPN 代谢物。
GST-M1 缺失与较低的 TGN/剂量比相关（P=0.0030），需要更高的巯嘌呤剂量（P=0.022），以及治疗反应降低（P=0.0022）。TPMT 变异基因型与较低的 MMPN 浓度相关（P=0.0064）和增加的 TGN/剂量比相关（P=0.0035）。ITPA C94A 多态性导致 MMPN 浓度增加（P=0.037）。
本研究描述了 TPMT、ITPA 和 GST-M1 候选遗传多态性对 IBD 患者巯嘌呤药代动力学的影响，首次显示 GST-M1 基因型对巯嘌呤代谢物浓度有相关影响。
