Paradoxical effects of resveratrol on the two prostaglandin H synthases

Prostaglandin H synthase (PGHS) is the primary enzyme responsible for the biosynthesis of prostaglandins and thromboxanes. Of the two isoenzymes of PGHS, PGHS-1 is constitutively expressed and PGHS-2 is inducible by mitogens or other inflammatory stimuli. Constitutive expression of PGHS-2 in neoplastic tissues has been implicated in carcinogenesis. Resveratrol, a lignan, was recently shown to be an anticarcinogen that selectively inhibits PGHS-1. In vitro experiments to resolve these seemingly paradoxical observations revealed that resveratrol is not only an inhibitor of PGHS-1 but also is an activator of PGHS-2. Resveratrol non-competitively inhibited PGHS-1 with a K-I of 26 +/- 2 mu M but enhanced the PGHS-2 activity nearly twofold. Additionally, resveratrol did not serve as a reducing co-substrate for the peroxidase activities of either enzyme despite being an easily oxidizable phenolic compound. Resveratrol inhibited the peroxidase activity of PGHS-1 (IC50 = 15 mu M) better than that of PGHS-2 (IC50 = >200 mu M) Inhibition of the peroxidase activity but not the cyclooxygenase activity of PGHS-2 resulted in the production of PGG(2) from arachidonic acid. A plausible relationship between these observations and the anticarcinogenic activity of resveratrol is discussed.