Resveratrol is a Peroxidase-mediated Inactivator of COX-1 but Not COX-2

Abstract

Resveratrol (3,4 ,5-trihydroxy-trans-stilbene) is a phytoalexin found in grapes that has anti-inflammatory, cardiovascular protective, and cancer chemopreventive properties. It has been shown to target prostaglandin H 2 synthase (COX)-1 and COX-2, which catalyze the first committed step in the synthesis of prostaglandins via sequential cyclooxygenase and peroxidase reactions. Resveratrol discriminates between both COX isoforms. It is a potent inhibitor of both catalytic activities of COX-1, the desired drug target for the prevention of cardiovascular disease, but only a weak inhibitor of the peroxidase activity of COX-2, the isoform target for nonsteroidal anti-inflammatory drugs. We have investigated the unique inhibitory properties of resveratrol. We find that it is a potent peroxidase-mediated mechanism-based inactivator of COX-1 only (k inact ‫؍‬ 0.069 ؎ 0.004 s ؊1 , K i(inact) ‫؍‬ 1.52 ؎ 0.15 M), with a calculated partition ratio of 22. Inactivation of COX-1 was time-and concentration-dependent, it had an absolute requirement for a peroxide substrate, and it was accompanied by a concomitant oxidation of resveratrol. Resveratrolinactivated COX-1 was devoid of both the cyclooxygenase and peroxidase activities, neither of which could be restored upon gel-filtration chromatography. Inactivation of COX-1 by [ 3 H]resveratrol was not accompanied by stable covalent modification as evident by both SDS-PAGE and reverse phase-high performance liquid chromatography analysis. Structure activity relationships on methoxy-resveratrol analogs showed that the m-hydroquinone moiety was essential for irreversible inactivation of COX-1. We propose that resveratrol inactivates COX-1 by a "hit-and-run" mechanism, and offers a basis for the design of selective COX-1 inactivators that work through a mechanism-based event at the peroxidase active site.

Resveratrol as a Chemopreventive Agent: A Promising Molecule for Fighting Cancer

“…In fact, resveratrol noncompetitively inhibits the cyclooxygenase activity of COX-1 [100]. A recent study has shown that resveratrol-inactivated COX-1 was devoid of both cyclooxygenase and peroxidase activities, this inactivation being accompanied by a concomitant oxidation of resveratrol [101]. Moreover, docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes [102].…”

Vascular Dysfunction in Aging: Potential Effects of Resveratrol, an Anti- Inflammatory Phytoestrogen

“…Importantly, recent studies revealed that resveratrol effectively inhibits aggregation of platelets from patients with aspirin resistance (Stef and Veress, unpublished data, 2005). Structure-activity relationships on methoxy-resveratrol analogs showed that the m-hydroquinone moiety is essential for irreversible inactivation of cyclooxygenase-1 [38]. These findings encourage the search for structurally related compounds with better bioavailability for cardiovascular protection in elderly patients with aspirin resistance.…”

“…2) and it has been suggested that this action may be responsible for its protection against coronary heart disease [ [33][34][35][36][37]. Resveratrol was shown to inhibit cyclooxygenase-1 [38], which likely contributes to its aspirin-like effects. Other potential mechanisms of the antiplatelet action of resveratrol involves inhibition of signal transduction pathways including MAP kinases [33] and polyphosphoinositide signaling [37].…”

Myeloperoxidase-induced Genomic DNA-centered Radicals

“…In addition, resveratrol inhibits O 2 . production by NADPH oxidase-2 (15), blocks cyclooxygenase activity (42), and thus, might protect DNA against mutations induced by reactive oxygen species (see Scheme 1). To test whether resveratrol inhibits HOCl-triggered DNA oxidation, we measured the ability of resveratrol to block DNA-DMPO nitrone adduct formation and luminol oxidation by HOCl.…”