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Journal of Lipid Research, Vol. 49, 2557-2570, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Strong activation of cyclooxygenase I and II catalytic activity by dietary bioflavonoids^*

Hyoung-Woo Bai and Bao Ting Zhu¹

Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160

^* This study was supported, in part, by a grant from the NIH (ES 015242).

Published, JLR Papers in Press, July 26, 2008.

¹ To whom correspondence should be addressed. e-mail: BTZhu{at}kumc.edu

Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to prostaglandins (PGs), thromboxanes, and hydroxyeicosatetraenoic acids. In the present study, we investigated several dietary bioflavonoids for their ability to modulate the catalytic activity of COX I and II in vitro and also in cultured cells. We found that some of them are the most powerful direct stimulators of the catalytic activity of COX I and II known to date, increasing the formation of prostaglandin products in vitro by up to 11-fold over the controls. This stimulatory effect of bioflavonoids is enzyme specific because none of them stimulates the catalytic activity of a number of lipooxygenases tested. Compared with phenol, a prototypical COX stimulator commonly used in vitro, the naturally occurring bioflavonoids are up to 29 times more efficacious in stimulating the COX activity. Additional studies using intact cells in culture showed that some of the dietary compounds that were active in the biochemical assays also activated the formation of PGE₂ (a representative PG) when they were present at 0.01 to 1 µM concentrations. The stimulatory effect of dietary compounds on COX-mediated PG formation is far more potent in intact cells than in the in vitro assays. Mechanistically, bioflavonoids mainly acted to slow down the suicidal inactivation of the COX enzymes, but they did not appear to reactivate the inactivated enzymes. The finding of this study suggests that some of the bioflavonoids likely will serve as the naturally occurring cofactors for the COX enzymes in humans.

Supplementary key words Cyclooxygenase activation • prostaglandins

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; EDTA, ethylenediaminetetraacetic acid; HETE, hydroxyeicosatetraenoic acid; HHT, heptadecatrienoic acid; LC-MS/MS, liquid chromatography-mass spectrometry; LOX, lipoxygenase; LPS, lipopolysaccharide; PG, prostaglandin; TX, thromboxane

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