Keuzenkamp-Jansen C W, De Abreu R A, Blom H J, Bökkerink J P, Trijbels J M
Laboratory of Pediatrics, University Hospital St. Radboud, Nijmegen, The Netherlands.
Biochem Pharmacol. 1996 May 3;51(9):1165-71. doi: 10.1016/0006-2952(96)00032-9.
6-mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleotides. Thiopurine methylation occurs to a large extent in vivo and in vitro. In this reaction, S-adenosyl-L-methionine (AdoMet), produced from methionine and ATP, is converted into S-adenosyl-L-homocysteine (AdoHcy) which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts, AdoMet: AdoHcy ratio and DNA methylation decrease after incubation with 6MP. The aim of the present study was to investigate the influence of high-dose 6MP on the methylation capacity in children with acute lymphoblastic leukemia. Five patients received 4 courses with high-dose intravenous MTX (5' g.m-2 in 24 hr) immediately followed by high-dose 6MP (1300 mg.m-2 in 24 hr). Five control patients received high-dose MTX and oral 6MP (25 mg.m -2 daily for 8 weeks). Leucovorin rescue was started at 36 hr in both groups. In the intravenous 6MP group, 6-methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were detectable in plasma in concentrations of 0.3-2.6 muM (6MP steady state levels: 11.6 muM). In red blood cells, mean methylthioinosine nucleotide levels were one third of those of ATP (13.1 nmol/10(8)). AdoHcy levels (10 pmol/10(8)) remained constant in both groups and AdoMet was not detectable ( < 20 pmol/10(8)). In both groups, plasma homocysteine increased and methionine decreased following administration of MTX. The delay in the recovery of methionine in the intravenous 6MP group after MTX infusion is probably the result of an increased demand on methyl groups during 6MP infusion.
6-巯基嘌呤（6MP）的细胞毒性由硫鸟嘌呤和甲硫基肌苷核苷酸引起。硫嘌呤甲基化在体内和体外均大量发生。在该反应中，由甲硫氨酸和ATP产生的S-腺苷-L-甲硫氨酸（AdoMet）转化为S-腺苷-L-高半胱氨酸（AdoHcy），而后者又水解为高半胱氨酸。高半胱氨酸再甲基化为甲硫氨酸的过程受到甲氨蝶呤（MTX）的抑制。在培养的淋巴母细胞中，与6MP孵育后，AdoMet：AdoHcy比值和DNA甲基化降低。本研究的目的是调查高剂量6MP对急性淋巴细胞白血病患儿甲基化能力的影响。5例患者接受4个疗程的高剂量静脉注射MTX（24小时内5 g.m-2），随后立即给予高剂量6MP（24小时内1300 mg.m-2）。5例对照患者接受高剂量MTX和口服6MP（每日25 mg.m -2，共8周）。两组均在36小时开始亚叶酸解救。在静脉注射6MP组中，血浆中可检测到6-甲基巯基嘌呤、其核苷和6-甲基巯基-8-羟基嘌呤，浓度为0.3 - 2.6 μM（6MP稳态水平：11.6 μM）。在红细胞中，甲硫基肌苷核苷酸的平均水平是ATP的三分之一（13.1 nmol/10(8)）。两组中AdoHcy水平（10 pmol/10(8)）保持恒定，且未检测到AdoMet（< 20 pmol/10(8)）。两组在给予MTX后血浆高半胱氨酸均升高，甲硫氨酸均降低。MTX输注后静脉注射6MP组中甲硫氨酸恢复延迟可能是6MP输注期间甲基需求增加的结果。
