Fructose-induced metabolic syndrome decreases protein expression and activity of intestinal P-glycoprotein

Abstract

Objectves: Metabolic syndrome (MetS) is a health disorder that increases the risk for cardiovascular complications such as heart disease and type 2 diabetes. Some drugs used in patients with MetS are substrates of intestinal P-glycoprotein (P-gp), one of the most important efflux pumps that limit the absorption of xenobiotics. Thus, their bioavailability could be affected by changes in this transporter. Because one of the major causes of MetS in humans is excessive sugar intake, the aim of this study was to evaluate the effect of a fructose-rich diet on intestinal P-gp activity and protein expression in male Sprague-Dawley rats. Methods: Fructose-drinking animals received standard chow and 15% (w/v) fructose in the drinking water over 8 wk; control rats were fed on standard chow and tap water. Results: Ileal protein expression of P-gp was 50% lower in fructose-drinking rats than in control animals. This reduction was confirmed by immunofluorescence microscopy. These results correlated well with the decrease of about 50% in the transport rate of the substrate rhodamine 123 in everted intestinal sacs. Finally, an increase of 62% in the intestinal absorption of digoxin, a P-gp substrate used as therapeutic drug, was observed in vivo, in fructose-drinking animals. Conclusion: The present study demonstrated that MetS-like conditions generated by enhanced fructose intake in rats decreased the protein expression and activity of ileal P-gp, thus increasing the bioavailability of P-gp substrates.