Interaction of non-steroidal anti-inflammatory drugs on platelet cyclo-oxygenase and lipoxygenase activity.

Non-steroidal anti-inflammatory drugs inhibit platelet cyclo-oxygenase activity. This study shows that salicylate, diflunisal, sulphinpyrazone and indomethacin prevent the in vivo inhibitory effect of aspirin on cyclo-oxygenase activity as measured by the formation of malondialdehyde and thromboxane B2, two products of platelet arachidonic acid metabolism. Salicylate also prevents the inhibitory effect of indomethacin. All these drugs therefore appear to interact with the same site on platelet cyclo-oxygenase. Since salicylate is inactive by itself on this platelet enzyme and diflunisal and sulphinpyrazone were used at ineffective doses, it is suggested that they interact with aspirin (or indomethacin) at a supplementary binding site, rather than directly on the substrate active site. Interaction with this putative supplementary site is necessary but not sufficient for the efficacy of these drugs as cyclo-oxygenase inhibitors. Acetylation by aspirin of the active site appears to be secondary to binding of the salicylate moiety to the supplementary site. Sodium salicylate is also inactive on platelet lipoxygenase. It prevents the inhibition of cyclo-oxygenase induced by aspirin, but does not counteract the inhibitory effect of 5, 8, 11, 14-eicosatetraynoic acid on both enzymes. It also fails to interfere with the inhibitory activity of nordihydroguaiaretic acid on lipoxygenase. These data confirm that, unlike eicosatetraynoic acid, nonsteroidal anti-inflammatory drugs interact with a site on cyclo-oxygenase distinct from the catalytic site, although related to it. Such a supplementary binding site is lacking on lipoxygenase.