Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivativesof salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid

The therapeutic potential of drugs that block the induction of cyclooxygena se-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethylbenzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared wit h aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflu sal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E-2 (PGE(2)) 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 trifl usal (but neither aspirin nor salicylate) produced a concentration-dependen t inhibition of COX-2 protein expression in peripheral human mononuclear ce lls. This observation was further confirmed in a rat air pouch model in viv o, in which both aspirin and triflusal inhibited PGE(2) 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 l east in part, due to the ability of HTB and triflusal to block the activati on of the transcription factor nuclear factor-kappa B to a higher extent th an 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 PGE(2) synthesis. Triflusal and HTB may exert beneficial effects in proc esses in which de novo COX-2 expression is involved and, in a broader sense , in pathological situations in which genes under nuclear factor-kappa B co ntrol are up-regulated.