IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - relation to TPMT activity and metabolite concentrations
IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - relation to TPMT activity and metabolite concentrations
复制标题
DOI：
10.1111/j.1365-2125.2007.02985.x
复制
发表时间：
2008-01-01
影响因子：
3.4
通讯作者：
Almer, Sven
中科院分区：
文献类型：
--
作者：
Haglund, Sofie;Taipalensuu, Jan;Almer, Sven
硫唑嘌呤和6-巯基嘌呤是用于炎症性肠病（IBD）的类固醇保留药物。硫嘌呤甲基转移酶（TPMT）的多态性对硫嘌呤代谢和不良事件的发生具有重要意义。其他硫嘌呤代谢酶的作用还不太为人所知。本研究探讨了肌苷-5 '-单磷酸脱氢酶（IMPDH）的作用，IMPDH是鸟嘌呤核苷酸从头合成的关键酶，也是硫代嘌呤代谢途径中的关键酶。IMPDH，TPMT和代谢产物的浓度进行了研究，在50例IBD患者稳定的巯基嘌呤治疗。在外周血单核细胞中测量IMPDH活性。在红细胞中测量TPMT活性、6-甲基硫代肌苷5 '-单磷酸（meTIMP）和6-硫代鸟嘌呤核苷酸（6-TGN）浓度，这是硫嘌呤临床监测的当前实践。结果在健康献血者（中位数13.1，范围4.7 - 24.2 nmol mg（-1）蛋白h（-1））和IBD患者（中位数14.0，范围7.0 - 21.7）中观察到广泛的IMPDH活性。IMPDH活性与剂量标准化的meTIMP浓度呈负相关（r（s）=-0.31，P =0.03），与6-TGN浓度及meTIMP/6-TGN比值无明显相关性。TPMT活性与代谢物浓度之间无显著相关性。结论尽管METIMP浓度与IMPDH活性呈负相关，但IMPDH在平衡甲基化和磷酸化代谢物形成中的作用并不明显。总的来说，这些结果引起了对硫嘌呤代谢的既定观点的质疑。
AIMS Azathioprine and 6-mercaptopurine are steroid-sparing drugs used in inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and occurrence of adverse events. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the role of inosine-5'-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo synthesis of guanine nucleotides and also strategically positioned in the metabolic pathway of thiopurines.METHODS IMPDH was measured in 100 healthy blood donors. IMPDH, TPMT and metabolite concentrations were studied in 50 patients with IBD on stable thiopurine therapy. IMPDH activity was measured in peripheral blood mononuclear cells. TPMT activity, 6-methylthioinosine 5'-monophosphate (meTIMP) and 6-thioguanine nucleotide (6-TGN) concentrations were measured in red blod cells, which is the current practice in clinical monitoring of thiopurines. Enzyme activities were related to metabolite concentrations and clinical characteristics.RESULTS A wide range of IMPDH activity was observed both in healthy blood donors (median 13.1, range 4.7 - 24.2 nmol mg(-1) protein h(-1)) and IBD patients (median 14.0, range 7.0 - 21.7). There was a negative correlation between IMPDH activity and dose-normalized meTIMP concentrations (r(s)= - 0.31, P=0.03), but no evident correlation to 6-TGN concentration or the meTIMP/6-TGN ratio. There were no significant correlations between TPMT activity and metabolite concentrations.CONCLUSION Even though the meTIMP concentrations correlated inversely to the IMPDH activity, the role of IMPDH in balancing the formation of methylated and phosphorylated metabolites was not evident. Taken together, the results give cause to question established opinions about thiopurine metabolism.