4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor κB activation
4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor κB activation
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DOI：
10.1038/sj.bjp.0702441
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发表时间：
1999-03-01
影响因子：
7.3
通讯作者：
Crespo, MS
中科院分区：
文献类型：
--
作者：
Bayón, Y;Alonso, A;Crespo, MS
1水杨酸的两种衍生物2-羟基-4-三氟甲基苯甲酸（HTB）和2-乙酰氧基-4-三氟甲基苯甲酸（三氟柳），对肿瘤坏死因子-α引起的NF-κ B活化的影响2、血管细胞粘附分子-1（VCAM-1）mRNA的表达作为其表达受NF-κ B调节的基因的一个例子进行了研究。为了将这些发现扩展到其他系统，研究了大鼠粘附性腹腔巨噬细胞中一氧化氮合酶的诱导。3作为NF-κ B核转位的抑制剂，HT B和三氟柳醛均比阿司匹林或水杨酸更有效。IC 50值的计算显示HTB约为2 mM，4这些化合物对VCAM-1 mRNA表达的效力的比较显示，在4 mM的浓度下，三氟柳和HTB均完全抑制，而阿司匹林和水杨酸盐在相同浓度下仅产生36-43%的抑制。在大鼠腹腔巨噬细胞中也观察到κ B活化，所述巨噬细胞通过IgG/卵清蛋白免疫复合物对抗体分子的Fc部分的受体刺激。这是伴随着剂量依赖性的抑制亚硝酸盐的生产通过L-精氨酸途径通过iNOS。该效应的IC 50值为1.13+/-0.12 mM（三氟柳）、1.84+/-0.34（HTB）、6.08 +/- 1.53 mM（阿司匹林）和9.16 +/- 1.9 mM 6这些数据表明，将4-三氟甲基并入水杨酸酯分子强烈增强了其对NF-κ B活化的抑制作用，VCAM-1 mRNA的表达和诱导型一氧化氮合酶，无论是否存在的乙酰基部分参与抑制环氧合酶。
1 The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the activation of NF-kappa B elicited by tumour necrosis factor-alpha (TNF-alpha) on human umbilical vein endothelial cells (HUVEC) was tested.2 The expression of the mRNA of vascular cell adhesion molecule-1 (VCAM-1) was studied as an example of a gene the expression of which is regulated by NF-kappa B. To extend these findings to other systems, the induction of nitric oxide synthase in rat adherent peritoneal macrophages was studied.3 Both HTB and triflusal were more potent than aspirin or salicylate as inhibitors of the nuclear translocation of NF-kappa B. The calculation of the IC50 values showed approximate to 2 mM for HTB, 4 mM for aspirin and >4 mM for salicylate.4 Comparison of the potency of these compounds on VCAM-1 mRNA expression showed complete inhibition by both triflusal and HTB at a concentration of 4 mM whereas aspirin and salicylate produced only 36-43% inhibition at the same concentration.5 Inhibition of NF-kappa B activation was also observed in rat peritoneal macrophages stimulated via their receptors for the Fc portion of the antibody molecule with IgG/ovalbumin immune complexes. This was accompanied by a dose-dependent inhibition of nitrite production by the L-arginine pathway via iNOS. IC50 values for this effect were 1.13+/-0.12 mM (triflusal), 1.84+/-0.34 (HTB), 6.08 +/- 1.53 mM (aspirin) and 9.16 +/- 1.9 mM (salicylate).6 These data indicate that the incorporation of a 4-trifluoromethyl group to the salicylate molecule strongly enhances its inhibitory effect on NF-kappa B activation, VCAM-1 mRNA expression and iNOS induction, irrespective of the presence of the acetyl moiety involved in the inhibition of cyclooxygenase.