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J. Biol. Chem., Vol. 281, Issue 48, 37102-37110, December 1, 2006

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Dietary Flavonoids Attenuate Tumor Necrosis Factor -induced Adhesion Molecule Expression in Human Aortic Endothelial Cells

STRUCTURE-FUNCTION RELATIONSHIPS AND ACTIVITY AFTER FIRST PASS METABOLISM^*

From the Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331

Flavonoids have been suggested to exert human health benefits by anti-oxidant and anti-inflammatory mechanisms. In this study, we investigated whether and by what mechanisms dietary flavonoids inhibit expression of cellular adhesion molecules, which is relevant to inflammation and atherosclerosis. We found that the capacity of flavonoids to inhibit tumor necrosis factor -induced adhesion molecule expression in human aortic endothelial cells was dependent on specific structural features of the flavonoids. The 5,7-dihydroxyl substitution of a flavonoid A-ring and 2,3-double bond and 4-keto group of the C-ring were the main structural requirements for inhibition of adhesion molecule expression. In striking contrast, hydroxyl substitutions of the B- and C-rings but not the A-ring were essential for antioxidant activity. Hence, only hydroxyl flavones, such as apigenin and chrysin, and flavonols, such as galangin, kaempferol, and quercetin, were able to inhibit endothelial adhesion molecule expression, whereas flavone, chromone, the flavanone, naringenin, and the flavanol, (-)-epicatechin, were ineffectual. At low concentrations, the active flavonoids significantly attenuated expression of E-selectin and intercellular adhesion molecule 1 but not vascular cell adhesion molecule 1. In addition, exposure of apigenin and kaempferol to cultured hepatocytes, mimicking first pass metabolism, greatly diminished the inhibitory effect of flavonoids on endothelial intercellular adhesion molecule 1 expression. We conclude that the effect of dietary flavonoids on endothelial adhesion molecule expression depends on their molecular structure, concentration, and metabolic transformation but not their antioxidant activity.

Received for publication, July 17, 2006 , and in revised form, September 14, 2006.

^* This work was supported by National Center for Complementary and Alternative Medicine (National Institutes of Health) Center of Excellence Grant AT002034 and a research grant from USANA Health Sciences (Salt Lake City, UT). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Linus Pauling Inst., Oregon State University, 571 Weniger Hall, Corvallis, OR 97331. Tel.: 541-737-5075; Fax: 541-737-5077; E-mail: balz.frei{at}oregonstate.edu.

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