Baggott J E, Morgan S L, Ha T, Vaughn W H, Hine R J
Department of Nutrition Sciences, University of Alabama, Birmingham 35294.
Biochem J. 1992 Feb 15;282 ( Pt 1)(Pt 1):197-202. doi: 10.1042/bj2820197.
Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 2.1.2.3) and bovine liver dihydrofolate reductase (EC 1.5.1.3). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound.
许多非甾体抗炎药（NSAIDs）（包括柳氮磺吡啶、舒林酸、吲哚美辛、萘普生、水杨酸、布洛芬、吡罗昔康和甲芬那酸）被发现是禽肝磷酸核糖氨基咪唑甲酰胺甲酰基转移酶（AICAR转甲酰酶，EC 2.1.2.3）和牛肝二氢叶酸还原酶（EC 1.5.1.3）的竞争性抑制剂（相对于叶酸）。相比之下，阿司匹林以及解热镇痛药对乙酰氨基酚和安替比林是这些酶的弱抑制剂。构效关系表明，带有含羧酸侧链的芳环是竞争性抑制转甲酰酶的必要条件。在将上述NSAIDs添加到人血单核细胞（BMC）培养物的实验中，这些NSAIDs还抑制了BMC中由甘氨酸和甲酸通过叶酸辅酶介导的丝氨酸生物合成（即C1指数）。对乙酰氨基酚对C1指数有较弱的抑制作用。与体外实验结果一致的是，用抗叶酸活性较弱的药物（如对乙酰氨基酚）治疗的类风湿性关节炎患者的BMC的C1指数高于用抗叶酸活性较强的NSAIDs（如舒林酸、柳氮磺吡啶、萘普生和布洛芬）治疗的类风湿性关节炎患者的BMC的C1指数。取自健康人的BMC中转甲酰酶的平均活性为每10(6)个细胞每小时1.98 nmol产物，且该活性与BMC叶酸水平呈正相关。这些结果与以下假设一致：（1）NSAIDs的抗叶酸活性以及由此产生的细胞生长抑制后果是产生抗炎活性的重要因素；（2）阿司匹林在转化为水杨酸后发挥其抗炎作用，水杨酸比其母体化合物具有更强的抗叶酸活性。
