Baggott J E, Morgan S L, Ha T S, Alarcón G S, Koopman W J, Krumdieck C L
Nutritional Biochemistry and Metabolism Division, University of Alabama, Birmingham 35294-3360.
Clin Exp Rheumatol. 1993 Mar-Apr;11 Suppl 8:S101-5.
The antifolates, methotrexate, aminopterin, 10-deazaaminopterin and sulfasalazine are clinically useful in the treatment of rheumatoid arthritis. Toxicity, rather than efficacy, appears to the the major factor limiting the usefulness of the classical antifolates (i.e., methotrexate and 10-deazaaminopterin). The fact that folate supplementation of methotrexate-treated rheumatoid arthritis patients reduces toxicity without altering efficacy also suggests that inhibition of the drug's target enzyme, dihydrofolate reductase, is not complete and not essential for efficacy. Since polyglutamates of methotrexate are direct inhibitors of thymidylate synthase and folate dependent enzymes of purine biosynthesis, the efficacy of this agent may involve blockade of these pathways. We hypothesize that blockage of aminoimidazole carboxamide ribotide transformylase, the folate dependent enzyme responsible for the insertion of carbon 2 into the purine ring, produces an immunosuppression mediated by secondary inhibition of adenosine deaminase, and S-adenosyl homocystein hydrolase by aminoimidazolecarboxamide metabolites. This mechanism of immunosuppression may explain the clinical effect of methotrexate, 10-deazaaminopterin, and possibly sulfasalazine. Since purine biosynthesis is a fundamental process, blockading this pathway may also decrease leukotriene production and interleukin-1 expression, which also could contribute to the efficacy of methotrexate.
抗叶酸药、甲氨蝶呤、氨基蝶呤、10-脱氮氨基蝶呤和柳氮磺胺吡啶在类风湿性关节炎的治疗中具有临床应用价值。毒性而非疗效似乎是限制经典抗叶酸药（即甲氨蝶呤和10-脱氮氨基蝶呤）应用的主要因素。对接受甲氨蝶呤治疗的类风湿性关节炎患者补充叶酸可降低毒性而不改变疗效，这一事实也表明抑制该药物的靶酶二氢叶酸还原酶并不完全，且对疗效并非必不可少。由于甲氨蝶呤的聚谷氨酸盐是胸苷酸合成酶和嘌呤生物合成中叶酸依赖性酶的直接抑制剂，该药物的疗效可能涉及对这些途径的阻断。我们推测，阻断氨基咪唑甲酰胺核糖核苷酸转甲酰酶（负责将碳2插入嘌呤环的叶酸依赖性酶）会产生免疫抑制作用，这种作用由氨基咪唑甲酰胺代谢产物对腺苷脱氨酶和S-腺苷同型半胱氨酸水解酶的继发性抑制介导。这种免疫抑制机制可能解释了甲氨蝶呤、10-脱氮氨基蝶呤以及可能的柳氮磺胺吡啶的临床效果。由于嘌呤生物合成是一个基本过程，阻断该途径也可能减少白三烯的产生和白细胞介素-1的表达，这也可能有助于甲氨蝶呤发挥疗效。
