Svardal A M, Ueland P M, Berge R K, Aarsland A, Aarsaether N, Lønning P E, Refsum H
Department of Pharmacology, University of Bergen, Norway.
Cancer Chemother Pharmacol. 1988;21(4):313-8. doi: 10.1007/BF00264197.
Methotrexate (MTX) affects homocysteine (Hcy) metabolism in both cultured cells and patients, and this may be explained by a lack of the 5-methyltetrahydrofolate required for salvage of Hcy to methionine. We here report the effect of MTX on Hcy in serum and Hcy, S-adenosylhomocysteine (AdoHcy), S-adenosylmethionine (AdoMet) and reduced glutathione (GSH) in tissues of rats fed either a normal or a defined, choline-deficient (CD) diet. The CD diet alone did not affect the amounts of Hcy in serum and tissues, but decreased the amount of AdoMet in most tissues and increased the GSH content in the liver. MTX increased the amount of Hcy about 2-fold in serum, liver and kidney, and decreased the amount of AdoMet in liver and kidney, whereas the AdoHcy content in these tissues was essentially unaffected. Accordingly, both choline deficiency and MTX treatment reduced the AdoMet to AdoHcy ratio. The increased GSH in the liver induced by CD diet seemed to be abolished by MTX. In the spleen MTX had only a marginal effect on the Hcy and AdoMet content and decreased the GSH content. It is concluded that the increase in serum Hcy during MTX exposure probably reflects a disturbance of the Hcy metabolism in some tissues, and especially in the liver. Altered metabolism of other sulfur-containing metabolites may only partly be related to the inhibition of Hcy salvage, and some metabolic effects of MTX may be modulated by tissue-specific metabolic pathways as well as by the diet.
甲氨蝶呤（MTX）在培养细胞和患者体内均会影响同型半胱氨酸（Hcy）的代谢，这可能是由于缺乏将Hcy挽救为蛋氨酸所需的5-甲基四氢叶酸所致。我们在此报告MTX对正常饮食或特定胆碱缺乏（CD）饮食喂养的大鼠血清中的Hcy以及组织中的Hcy、S-腺苷同型半胱氨酸（AdoHcy）、S-腺苷甲硫氨酸（AdoMet）和还原型谷胱甘肽（GSH）的影响。单独的CD饮食不影响血清和组织中Hcy的含量，但会降低大多数组织中AdoMet的含量，并增加肝脏中GSH的含量。MTX使血清、肝脏和肾脏中的Hcy含量增加约2倍，并降低肝脏和肾脏中AdoMet的含量，而这些组织中AdoHcy的含量基本未受影响。因此，胆碱缺乏和MTX治疗均降低了AdoMet与AdoHcy的比值。CD饮食诱导的肝脏中GSH的增加似乎被MTX消除了。在脾脏中，MTX对Hcy和AdoMet含量的影响很小，并降低了GSH的含量。得出的结论是，MTX暴露期间血清Hcy的增加可能反映了某些组织，尤其是肝脏中Hcy代谢的紊乱。其他含硫代谢物代谢的改变可能仅部分与Hcy挽救的抑制有关，MTX的一些代谢作用可能受组织特异性代谢途径以及饮食的调节。
