EFFECT OF INHIBITOR TIME-DEPENDENCY ON SELECTIVITY TOWARDS CYCLOOXYGENASE ISOFORMS

摘要: Cyclooxygenase (Cox) is a key enzyme in the biosynthesis of prostaglandins and, as such, target non-steroidal anti-inflammatory drugs (NSAIDs). Two isoforms exist, being expressed constitutively (Cox-1), or inducibly response to inflammatory mediators (Cox-2). Currently available NSAIDs inhibit both somewhat equipotently but selective Cox-2 inhibition may eliminate unwanted side effects. We have characterized kinetic mechanisms interactions purified recombinant human cyclooxygenase-1 and -2 (hCox-1, hCox-2) with inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulphonamide (NS-398) some classical non-selective NSAIDs. NS-398, flurbiprofen, meclofenamic acid indomethacin are time-dependent, irreversible inhibitors hCox-2. The consistent two-step process, involving an initial rapid equilibrium binding inhibitor, by Ki, followed slow formation tightly bound enzyme-inhibitor complex, first-order rate constant kon. NS-398 time-independent hCox-1, reversible complex. Flurbiprofen, also time-dependent hCox-1 hence show little selectivity for one isoform over other. Flufenamic time independent towards non-selective. high degree results therefore from difference nature time-dependency two isoforms.