Kurzawski Mateusz, Dziewanowski Krzysztof, Gawrońska-Szklarz Barbara, Domański Leszek, Droździk Marek
Department of Pharmacology, Pomeranian Medical University, Szczecin, Poland.
Ther Drug Monit. 2005 Aug;27(4):435-41. doi: 10.1097/01.ftd.0000164393.09402.c9.
Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. TPMT activity exhibits an interindividual variability, mainly as a result of genetic polymorphism. Patients with intermediate or deficient TMPT activity are at risk for toxicity after receiving standard doses of thiopurine drugs. It has previously been reported that 3 variant alleles: TPMT*2, *3A, and *3C are responsible for over 95% cases of low enzyme activity. The purpose of this study was to explore the association between these polymorphisms and the occurrence of azathioprine adverse effects in 112 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. TPMT genetic polymorphism was determined using PCR-RFLP and allele-specific PCR methods. Azathioprine dose, leukocyte, erythrocyte, and platelet counts, graft rejection episodes, as well as cyclosporine levels were analyzed throughout the first year after organ transplantation. We found the frequency of leukopenia episodes (WBC < 4.0 x 10(9)/L) significantly higher in heterozygous patients (53.8%) compared with those with TPMT wild-type genotype (23.5%). One patient, who was a compound homozygote (3A/*3C), experienced severe azathioprine-related myelotoxicity each time after receiving the standard drug dose. Our results suggest that polymorphisms in TPMT gene may be responsible for approximately 12.5% of all leukopenia episodes in renal transplant recipients treated with azathioprine. Genotyping for the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.
硫嘌呤甲基转移酶（TPMT）是一种催化硫嘌呤类药物（如6-巯基嘌呤、6-硫鸟嘌呤和硫唑嘌呤）S-甲基化的酶。TPMT活性存在个体间差异，主要是由于基因多态性所致。TPMT活性中等或缺乏的患者在接受标准剂量硫嘌呤类药物后有发生毒性反应的风险。此前有报道称，3种变异等位基因：TPMT*2、3A和3C导致了95%以上低酶活性病例。本研究的目的是探讨这些多态性与112例接受硫唑嘌呤、环孢素和泼尼松三联免疫抑制治疗的肾移植受者中硫唑嘌呤不良反应发生情况之间的关联。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和等位基因特异性PCR方法测定TPMT基因多态性。在器官移植后的第一年对硫唑嘌呤剂量、白细胞、红细胞和血小板计数、移植排斥反应发作情况以及环孢素水平进行分析。我们发现，杂合子患者（53.8%）白细胞减少发作（白细胞<4.0×10⁹/L）的频率显著高于TPMT野生型基因型患者（23.5%）。一名复合纯合子（3A/*3C）患者每次接受标准药物剂量后均出现严重的硫唑嘌呤相关骨髓毒性。我们的结果表明，TPMT基因多态性可能导致接受硫唑嘌呤治疗的肾移植受者中约12.5%的白细胞减少发作。对主要的TPMT变异等位基因进行基因分型可能是预防硫唑嘌呤毒性和优化免疫抑制治疗的一项有价值的工具。
