日本受试者的硫嘌呤S-甲基转移酶活性：不同硫嘌呤甲基转移酶（TPMT）基因型中6-巯基嘌呤6-甲基化的代谢活性
Thiopurine S-methyltransferase activity in Japanese subjects: metabolic activity of 6-mercaptopurine 6-methylation in different TPMT genotypes.
作者信息
Nishida Akihito, Kubota Takahiro, Yamada Yasuhiko, Higashi Katsumi, Kitamura Kiyoshi, Nakahara Kazuhiko, Iga Tatsuji
机构信息
Department of Pharmacy, Faculty of Medicine, University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan.
出版信息
Clin Chim Acta. 2002 Sep;323(1-2):147-50. doi: 10.1016/s0009-8981(02)00184-5.
BACKGROUND
Thiopurine S-methyltransferase (TPMT), which exhibits autosomal codominant polymorphism, plays an important role in the metabolism of thiopurine drugs such as mercaptopurine, thioguanine and azathioprine. Decreased activity of TPMT is associated with severe hematopoietic toxicity after administration of standard doses of these drugs.
METHODS
We developed a specific high-performance liquid chromatographic (HPLC) assay for measuring 6-methylmercaptopurine (6-MMP) formed from 6-mercaptopurine (6-MP) in red blood cells (RBC) lysates. The assay was used to study the distribution of TPMT activities in 44 healthy Japanese subjects with different TPMT genotypes.
RESULTS
The TPMT activities in the subjects ranged from 17.9 to 37.1 pmol/h/mgHb. The TPMT activity of one subject with TPMT*1/3C (17.9 pmol/h/mgHb) was 40% lower than the mean value of TPMT activities in 43 subjects with TPMT1/*1 (29.6+/-4.3 pmol/h/mgHb).
CONCLUSIONS
This sensitive and reproducible HPLC assay for determination of TPMT activity in RBC clinical studies has been designed to optimize dosage regimens of thiopurine drugs.
背景
硫嘌呤甲基转移酶（TPMT）呈常染色体共显性多态性，在硫嘌呤类药物如巯嘌呤、硫鸟嘌呤和硫唑嘌呤的代谢中起重要作用。TPMT活性降低与给予这些药物标准剂量后严重的造血毒性相关。
方法
我们开发了一种特异性高效液相色谱（HPLC）分析法，用于测定红细胞（RBC）裂解液中由6-巯基嘌呤（6-MP）形成的6-甲基巯基嘌呤（6-MMP）。该分析法用于研究44名具有不同TPMT基因型的健康日本受试者中TPMT活性的分布。
结果
受试者的TPMT活性范围为17.9至37.1 pmol/h/mgHb。一名TPMT*1/3C受试者的TPMT活性（17.9 pmol/h/mgHb）比43名TPMT1/*1受试者的TPMT活性平均值（29.6±4.3 pmol/h/mgHb）低40%。
结论
这种用于在RBC临床研究中测定TPMT活性的灵敏且可重复的HPLC分析法旨在优化硫嘌呤类药物的给药方案。
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