Dubinsky M C, Lamothe S, Yang H Y, Targan S R, Sinnett D, Théorêt Y, Seidman E G
Division of Gastroenterology and Nutrition, University of Montréal, Montréal, Québec, Canada.
Gastroenterology. 2000 Apr;118(4):705-13. doi: 10.1016/s0016-5085(00)70140-5.
BACKGROUND & AIMS: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype.
Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype.
Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy.
6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.
6-巯基嘌呤（6-MP）的作用是通过其在细胞内转化为6-硫鸟嘌呤（6-TG）和6-甲基巯基嘌呤（6-MMP）核苷酸代谢产物来介导的，后者由硫嘌呤甲基转移酶（TPMT）进行基因控制。我们试图确定最佳治疗性6-MP代谢产物水平及其与药物诱导毒性和TPMT基因型的相关性。
测定了92例炎症性肠病儿科患者的治疗反应，并同时检测了血液学、胰腺和肝脏实验室参数，将其与红细胞代谢产物水平和TPMT基因型进行比较。
临床反应与6-TG水平高度相关（P < 0.0001），但与任何其他变量均无相关性，包括6-MMP水平、药物剂量、性别和同时服用的药物。当6-TG水平> 235 pmol/8×10⁸红细胞时，治疗反应频率增加（P < 0.001）。肝毒性与6-MMP水平升高相关（> 5700 pmol/8×10⁸红细胞；P < 0.05）。虽然白细胞减少与较高的6-TG水平相关（P < 0.03），但仅在8%的反应者中观察到。TPMT杂合子患者（8/92）的6-TG水平较高（P < 0.0001），且所有患者对治疗均有反应。
6-MP代谢产物水平和TPMT基因分型可帮助临床医生优化对6-MP的治疗反应，并识别药物诱导毒性风险增加的个体。
