Mechanism-based inactivation of COX-1 by red wine m-hydroquinones: a structure-activity relationship study.
Resveratrol (1) is a m-hydroquinone found in red wine, which has antiinflammatory, cardiovascular protective (antiplatelet), and cancer chemopreventive properties. It is a potent peroxidase-dependent mechanism-based inactivator of COX-1, a desired target for antiplatelet agents, and has no similar effect on COX-2. Much attention has focused on resveratrol (1) as being the sole agent responsible for the cardioprotective effects associated with red wine consumption (commonly known as the "French paradox"). In this study we show that other red wine constituents, namely, the catechins (2, 3) and epicatechins (4, 5), act as peroxidase mediated mechanism-based inactivators of COX-1 but not of COX-2. Structure-activity relationships identify these agents as being as effective as resveratrol with respect to their ability to specifically inactivate COX-1. We show that resorcinol (6) is the minimum structure necessary for mechanism-based inactivation of COX-1. These findings imply that resveratrol is not the sole agent responsible for the antiplatelet activity of red wine and suggest that all dietary m-hydroquinones should be examined for cardioprotective effects.
Szewczuk
Lawrence M
LM
Department of Biochemistry & Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Penning
Trevor M
TM
D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006873:Hydroquinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000187:drug effects; D015394:Molecular Structure; D009195:Peroxidase / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014920:Wine / Q000032:analysis*
D002316:Cardiotonic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006873:Hydroquinones; D007527:Isoenzymes; D010975:Platelet Aggregation Inhibitors; D013267:Stilbenes; D002392:Catechin; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077185:Resveratrol