Moreno-Guerrero Silvia Selene, Ramírez-Pacheco Arturo, Dorantes-Acosta Elsa María, Medina-Sanson Aurora
Departamento de Hemato-Oncología, Hospital Infantil de México Federico Gómez.
Rev Invest Clin. 2013 Mar-Apr;65(2):156-64.
Thiopurine S-Methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs, such as 6-mercaptopurine, 6-thioguanine and azathioprine, leading to their inactivation. Individuals who carry TPMT allele variants are more likely to experience life-threatening toxicity when these drugs are given at a standard dose. Wildtype phenotype TPMT*1 exhibits high level of catalytic activity, while all variants manifest with a decreased enzymatic activity. Ethnic-related differences in the distribution of TPMT variant alleles have been found. In Mexico, limited information is available; so far only two studies have been published and clear differences exist between them.
Allelic variants and genotypes of the TPMT gene were determined in 240 Mexican children with leukemia and solid tumors using DNA extracted from peripheral blood. Polymorphisms G460A and A719G were identified by PCR-RFLP and G238C by the specific-allele PCR assay. The enzyme variants were detected by allelic discrimination.
Homozygous wild-type genotype TPMT1/TPMT1 was found in 173 patients (72.1%); 67 cases (27.9%) were heterozygous: 18 with genotype TPMT1/TPMT3B (7.5%), 17 TPMT1/TPMT3C (7.1%), 16 TPMT1/TMPT2 (6.7%), 14 TPMT1/TPMT3A (5.8%), and 2 (0.8%) were homozygous for two variants: TPMT2/ TPMT3B in both. The allele frequencies were TPMT1 in 411 (85.62%), TPMT3B in 20 (4.1%), TPMT2 in 18 (3.75%), TPMT3C in 17 (3.55%) and TPMT*3A in 14 (2.9%).
A high frequency and diversity of variant TPMT genotypes was found in this series with predominance of the TPMT*3B allele.
硫嘌呤S-甲基转移酶（TPMT）催化硫嘌呤类药物（如6-巯基嘌呤、6-硫鸟嘌呤和硫唑嘌呤）的S-甲基化反应，导致这些药物失活。携带TPMT等位基因变异的个体在接受标准剂量的这些药物治疗时，更有可能出现危及生命的毒性反应。野生型表型TPMT*1表现出高水平的催化活性，而所有变异型的酶活性均降低。已发现TPMT变异等位基因分布存在种族差异。在墨西哥，相关信息有限；到目前为止，仅发表了两项研究，且二者存在明显差异。
采用从外周血提取的DNA，对240例患有白血病和实体瘤的墨西哥儿童的TPMT基因的等位基因变异和基因型进行检测。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）鉴定G460A和A719G多态性，通过等位基因特异性PCR检测G238C。通过等位基因鉴别检测酶变异。
173例患者（72.1%）为纯合野生型基因型TPMT1/TPMT1；67例（27.9%）为杂合子：18例基因型为TPMT1/TPMT3B（7.5%），17例TPMT1/TPMT3C（7.1%），16例TPMT1/TMPT2（6.7%），14例TPMT1/TPMT3A（5.8%），2例（0.8%）为两种变异的纯合子：均为TPMT2/TPMT3B。等位基因频率分别为：TPMT1占411个（85.62%），TPMT3B占20个（4.1%），TPMT2占18个（3.75%），TPMT3C占17个（3.55%），TPMT*3A占14个（2.9%）。
在本研究系列中发现TPMT变异基因型的频率较高且具有多样性，其中TPMT*3B等位基因占优势。
