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 K1 of 26 +/- 2 microM 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 microM) better than that of PGHS-2 (IC50 = > 200 microM). Inhibition of the perxidase activity but not the cyclooxygenase activity of PGHS-2 resulted in the production of PGG2 from arachidonic acid. A plausible relationship between these observation and the anticarcinogenic activity of resveratrol is discussed.
Division of Bioorganic Chemistry, Cayman Chemical Company, Ann Arbor, Michigan 48108, USA.
J L
JL
Johnson
K R
KR
Maddipati
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D010084:Oxidation-Reduction; D019800:Phenol / Q000494:pharmacology; D044262:Prostaglandin H2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011462:Prostaglandins G / Q000096:biosynthesis; D011463:Prostaglandins H / Q000096:biosynthesis; D000077185:Resveratrol; D012756:Sheep; D013267:Stilbenes / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011462:Prostaglandins G; D011463:Prostaglandins H; D013267:Stilbenes; D016718:Arachidonic Acid; D019800:Phenol; D044262:Prostaglandin H2; C038291:prostaglandin G2; D011451:Prostaglandin-Endoperoxide Synthases; D000077185:Resveratrol; D007213:Indomethacin