TEPOXALIN, A NOVEL DUAL INHIBITOR OF THE PROSTAGLANDIN-H SYNTHASE CYCLOOXYGENASE AND PEROXIDASE-ACTIVITIES

Prostaglandin-H synthase-1, the rate-limiting enzyme in prostaglandin synthesis, has both cyclooxygenase (CO) and peroxidase (PO) activities . While most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit onl y the CO activity, we describe an inhibitor, tepoxalin, that inhibits both the CO (IC50 = 0.1 mu M) and the PO (IC50 = 4 mu M) activities. U nlike many NSAIDs which are competitive inhibitors of CO, tepoxalin is a noncompetitive inhibitor of CO and its inhibitory effect on PO but not CO is reversed by excess heme. Moreover, inhibition of the PO acti vity by tepoxalin is not dependent on the enzymatic turnover of the CO activity. The hydroxamic acid of tepoxalin is responsible for the PO inhibition since a carboxylic acid derivative of tepoxalin retains ful l CO but not PO inhibition. We postulated that the hydroxamic group mi ght confer the ability to inhibit PO on conventional CO inhibitors. Th is idea was supported by the observation that naproxen hydroxamic acid , but not naproxen showed PO inhibition. Furthermore, tepoxalin's carb oxylic acid analogue and naproxen each competitively relieved PO inhib ition by their respective hydroxamic acids. The intracellular activity of PO as monitored by the release of reactive oxygen species was also inhibited by both tepoxalin and naproxen hydroxamic acid. These obser vations suggest a strategy for design of novel compounds to inhibit pr ostaglandin synthase PO. The therapeutic implications of these novel P O inhibitors are discussed.