Differential effects of prostaglandin synthetase stimulators on inhibition of cyclooxygenase

The different effects of prostaglandin synthetase stimulators on inhibition of the cyclooxygenase by structurally distinct classes of nonsteroidal antiinflammatory agents suggest that the enzyme is altered by interaction with these stimulators. Reversible stimulation of prostaglandin synthetase activity by phenols and some other compounds and the relative influence of these stimulators on inhibitors of the cyclooxygenase were determined quantitatively. Two distinct classes of inhibitors were established. The fenamates were relatively weak inhibitors alone but were much more potent in the presence of phenolic compounds. In contrast, ibuprofen, indomethacin, and flurbiprofen were more potent than the fenamates and were reduced in effectiveness by the stimulators, as expected on the basis of two opposing actions. The relative potency of the cyclooxygenase stimulators (phenol greater than norepinephrine greater than tryptophan greater than benzoquinone greater than anisole) paralleled their synergistic action on the fenamates and their antagonist action on the nonfenamates. This correlation suggests that an enzyme alteration which leads to cyclooxygenase stimulation may also result in increased sensitivity to fenamates and decreased sensitivity to the other inhibitors, possibly by altering their capacity to bind.