Fernández de Arriba A, Cavalcanti F, Miralles A, Bayón Y, Alonso A, Merlos M, García-Rafanell J, Forn J
Department of Pharmacology, Uriach Research Center, Barcelona, Spain.
Mol Pharmacol. 1999 Apr;55(4):753-60.
The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated.
阻断环氧化酶 -2 诱导的药物的治疗潜力已得到强调。当将两种 4 - 三氟甲基水杨酸酯衍生物 [2 - 乙酰氧基 -4 - 三氟甲基苯甲酸（曲氟柳）及其脱乙酰代谢物 2 - 羟基 -4 - 三氟甲基苯甲酸（HTB）] 与阿司匹林和水杨酸钠作为环氧化酶 -2（COX -2）抑制剂进行比较时，我们观察到在细菌脂多糖激活的人血液中，曲氟柳、阿司匹林和 HTB 能抑制 COX -2 介导的前列腺素 E2（PGE2）生成（IC50 分别为 0.16、0.18、0.39 和 >10 mM），但水杨酸钠不能。然而，只有曲氟柳和阿司匹林能抑制纯化的 COX -2 酶。为了检验这一明显差异，我们发现 HTB 和曲氟柳（但阿司匹林和水杨酸盐均不能）对外周血人单核细胞中 COX -2 蛋白表达产生浓度依赖性抑制。这一观察结果在大鼠气袋体内模型中得到进一步证实，在该模型中阿司匹林和曲氟柳均抑制 PGE2 生成（口服 ID50 分别为 18.9 和 11.4 mg/kg），但只有经曲氟柳处理的动物显示 COX -2 表达下降。这种不同的行为可能至少部分归因于 HTB 和曲氟柳比阿司匹林和水杨酸钠更能阻断转录因子核因子 -κB 的激活。因此，除了在治疗浓度下抑制 COX -2 活性外，曲氟柳还能够通过其代谢物 HTB 阻断新酶的表达，从而恢复 PGE2 的合成。曲氟柳和 HTB 可能在涉及 COX -2 从头表达的过程中发挥有益作用，从更广泛的意义上讲，在核因子 -κB 控制下的基因上调的病理情况下也可能发挥有益作用。
