Eklund Birgitta I, Moberg My, Bergquist Jonas, Mannervik Bengt
Department of Biochemistry and Organic Chemistry, Uppsala University, Biomedical Center, Box 576, SE-751 23 Uppsala, Sweden.
Mol Pharmacol. 2006 Aug;70(2):747-54. doi: 10.1124/mol.106.025288. Epub 2006 May 22.
Azathioprine is a thiopurine prodrug clinically used for immunosuppression in the treatment of inflammatory diseases and in pharmacological regimens of organ transplantations. Its pharmacological action is based on the release of 6-mercaptopurine, but the biochemical processes underlying this biotransformation have remained obscure. In this investigation, human glutathione transferases (GSTs) from seven distinct classes were assayed with azathioprine. GSTs A1-1, A2-2, and M1-1, all abundantly expressed in human liver, displayed the highest activity among the 14 GSTs tested. The uncatalyzed reaction of azathioprine with glutathione was estimated to be less than 1% of the GST-catalyzed biotransformation. GST M1-1 is polymorphic with a frequently occurring null allele, and GSTs A1-1 and A2-2 show variable expression levels in human subjects, implying significant differences in the rate of 6-mercaptopurine release from azathioprine. Individuals expressing high GST activity are apparently predisposed for adverse reactions to azathioprine treatment, both by promoting excessively high concentrations of free 6-mercaptopurine and its toxic metabolites and by depleting cellular glutathione. These novel aspects of GST-dependent azathioprine biotransformation have not been considered previously.
硫唑嘌呤是一种硫嘌呤前体药物，临床上用于治疗炎症性疾病和器官移植的药物治疗方案中的免疫抑制。其药理作用基于6-巯基嘌呤的释放，但其生物转化的生化过程仍不清楚。在这项研究中，用硫唑嘌呤检测了来自七个不同类别的人谷胱甘肽转移酶（GST）。GST A1-1、A2-2和M1-1在人肝脏中均大量表达，在测试的14种GST中活性最高。硫唑嘌呤与谷胱甘肽的非催化反应估计不到GST催化生物转化的1%。GST M1-1具有多态性，经常出现无效等位基因，GST A1-1和A2-2在人类受试者中表现出可变的表达水平，这意味着硫唑嘌呤释放6-巯基嘌呤的速率存在显著差异。表达高GST活性的个体显然易患硫唑嘌呤治疗的不良反应，这是通过促进过高浓度的游离6-巯基嘌呤及其有毒代谢物以及消耗细胞内谷胱甘肽来实现的。GST依赖的硫唑嘌呤生物转化的这些新方面以前从未被考虑过。
