Metabolism of non-steroidal anti-inflammatory drugs by peroxidase: Implication for gastrointestinal mucosal lesions

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory diseases including rheumatoid arthritis and gout. The anti-inflammatory action of NSAIDs is due to the inhibition of prostaglandin synthesis by preventing cyclooxygenase (COX) activity of prostaglandin H synthase (PGS). However, administration of NSAIDs causes gastrointestinal mucosal lesions and a decrease of granulocytes as side effects. PGS catalyzes two distinct enzyme reactions: (1) bis-dioxygenation of arachidonic acid catalyzed by COX activity of PGS to form PGG2; and (2) reduction of the hydroperoxide group in PGG2 by PGS hydroperoxidase. Most NSAID are oxidized by peroxidases to produce NSAID radicals that damage biological components such as lipids and enzymes. Indomethacin, phenylbutazone, and piroxicam are more toxic under aerobic conditions than anaerobic conditions during the interaction with peroxidase. We discuss the contribution of peroxidases in the formation of gastrointestinal mucosal lesions induced by NSAIDs. © 2007 The Pharmaceutical Society of Japan.