In recent years, ellagic acid (EA), a naturally-occurring phenolic compound richly contained in some of the human food sources such as and , was reported to have a number of biological effects. Based on our earlier 3D-QSAR/CoMFA models for cyclooxygenase (COX) I and II, we hypothesize that EA may have the potential to modulate the catalytic activity of COX enzymes, and this hypothesis is examined in the present study. The results from both and experiments show that EA is an activator of COX enzyme-catalyzed production of prostaglandin E2, a representative prostaglandin tested. Mechanistically, EA can activate the peroxidase active site of COX enzymes by serving as a co-substrate, presumably for the reduction of protoporphorin IX with Fe inside. The effect of EA is abrogated by the co-presence of galangin, which is known to bind to COX's peroxidase active site and thereby blocks the effect of the reducing co-substrates. In view of the known physiological functions of COX enzymes in the body, it is suggested that some of the pharmacological and/or toxicological effects of EA may result from an increased production of certain prostaglandins and their related derivatives in the body.
