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Am J Physiol Cell Physiol 286: C931-C939, 2004; doi:10.1152/ajpcell.00351.2003
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VASCULAR BIOLOGY

CYP450 dietary inhibitors attenuate TNF-{alpha}-stimulated endothelial molecule expression and leukocyte adhesion

Makoto Sasaki,1 John W. Elrod,1 Paul Jordan,2 Makoto Itoh,3 Takashi Joh,3 Alireza Minagar,1 and J. Steven Alexander1

Department of 1Molecular and Cellular Physiology and 2Gastroenterology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932; and 3Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Submitted 15 August 2003 ; accepted in final form 26 November 2003

Enhanced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and other endothelial cell adhesion molecules (ECAMs) are associated with the onset and progression of inflammatory bowel disease (IBD). We show in this study that two cytochrome P-450 (CYP450) inhibitors from Citrus paradis (grapefruit), bergamottin, and 6',7'-dihydroxybergamottin (DHB) block tumor necrosis factor (TNF)-{alpha}-stimulated expression of MAdCAM-1 in cultured endothelial cells and also reduce {alpha}4{beta}7-dependent lymphocyte adhesion. Bergamottin (20–50 µM) or DHB (10–30 µM) pretreatment dose-dependently reduced TNF-{alpha}-mediated expression of MAdCAM-1 and lymphocyte adhesion. Bergamottin and DHB also prevented expression of two other ECAMs, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (but not E-selectin). SKF-525a, a specific CYP450 inhibitor, also blocked the expression of MAdCAM-1 mediated by TNF-{alpha}. Similar to SKF-525a (20 µM), bergamottin (20 µM) and DHB (20 µM) directly inhibited the activity of CYP450 3A4. These results suggest that natural CYP450 inhibitors may be effective in reducing ECAM expression and leukocyte adhesion and therefore be useful in the clinical treatment of inflammatory states like IBD.

cytochrome P-450; inflammatory bowel disease; lymphocytes; mucosal adhesion cell adhesion molecule-1


Address for reprint requests and other correspondence: J. S. Alexander, Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932 (E-mail: jalexa{at}lsuhsc.edu).






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