Increased transport of resveratrol across monolayers of the human intestinal caco-2 cells is mediated by inhibition and saturation of metabolites

The study's aim was to investigate the dose-dependent effect of sulfation and glucuronidation on intestinal absorption of resveratrol, a dietary constituent found in grapes and various medical plants. The intestinal epithelial membrane transport kinetics and metabolism of resveratrol (10-200 mi...

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Published in:	Pharmaceutical research 2006-09, Vol.23 (9), p.2107-2115
Main Authors:	MAIER-SALAMON, Alexandra, HAGENAUER, Birgit, WIRTH, Michael, GABOR, Franz, SZEKERES, Thomas, JÄGER, Walter
Format:	Article
Language:	eng
Subjects:	Algorithms Animals Anticarcinogenic Agents - metabolism Bioavailability Biological and medical sciences Biological Transport, Active Biotransformation Caco-2 Cells Cell culture Cell Membrane Permeability Chromatography, High Pressure Liquid Data Interpretation, Statistical General pharmacology Glucuronides - metabolism Humans Inhibitor drugs Liver - metabolism Male Medical sciences Metabolism Pharmaceutical technology. Pharmaceutical industry Pharmacology Pharmacology. Drug treatments Rats Rats, Wistar Spectrophotometry, Ultraviolet Stilbenes - metabolism Sulfates - metabolism
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Summary:	The study's aim was to investigate the dose-dependent effect of sulfation and glucuronidation on intestinal absorption of resveratrol, a dietary constituent found in grapes and various medical plants. The intestinal epithelial membrane transport kinetics and metabolism of resveratrol (10-200 microM) was studied using Caco-2 monolayers cultured in Transwells. Along with resveratrol it was possible to identify three metabolites, namely, resveratrol-4'-O-glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate (M3) by LC/MS and NMR. Efflux of the glucuronides M1 and M2 followed Michaelis-Menten kinetics significantly favouring basolateral efflux. The predominant metabolite was the monosulfate M3, however, its formation was strongly inhibited at higher resveratrol concentrations. As biotransformation was either inhibited or saturated, total amount of resveratrol transported across the Caco-2 monolayers increased as much as 3.5-fold at 200 microM resveratrol. This value might be even higher when taking into account the high intracellular concentration of resveratrol, which accounted for up to 61% of the applied dose. Our data demonstrate a concentration-dependent biotransformation of resveratrol in Caco-2 cells, which may also apply to human enterocytes affecting oral bioavailability.
ISSN:	0724-8741 1573-904X