title: Intestinal multidrug resistance-associated protein 2 is down-regulated in fructose-fed rats.
abstract: Expression and activity of jejunal multidrug resistance-associated protein 2 (Mrp2) and glutathione-S-transferase (GST) were examined in fructose fed Wistar rats, an experimental model of metabolic syndrome. Animals were fed on (a) control diet or (b) control diet plus 10% w/vol fructose in the drinking water. Mrp2 and the α class of GST proteins as well as their corresponding mRNAs were decreased, suggesting a transcriptional regulation by fructose. Confocal microscopy studies reaffirmed down-regulation of Mrp2. Everted intestinal sacs were incubated with 1-chloro-2,4-dinitrobenzene in the mucosal compartment, and the glutathione-conjugated derivative, dinitrophenyl- S-glutathione (DNP-SG; model Mrp2 substrate), was measured in the same compartment to estimate Mrp2 activity. Excretion of DNP-SG was substantially decreased by fructose treatment, consistent with simultaneous down-regulation of Mrp2 and GST. In addition, the effect of fructose on intestinal barrier function exerted by Mrp2 was evaluated in vivo using valsartan, a recognized Mrp2 substrate of therapeutic use. After intraduodenal administration as a bolus, intestinal absorption of valsartan was increased in fructose-drinking animals. Fructose administration also induced oxidative stress in intestinal tissue as demonstrated by significant increases of intestinal lipid peroxidation end products and activity of the antioxidant enzyme superoxide dismutase, by a decreased GSH/GSSG ratio. Moreover, fructose treatment conduced to increased intestinal levels of the proinflammatory cytokines IL-β1 and IL-6. Collectively, our results demonstrate that metabolic syndrome-like conditions, induced by a fructose-rich diet, result in down-regulation of intestinal Mrp2 expression and activity and consequently in an impairment of its barrier function.
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: Ana Sofía
authors.initials: AS
authors.lastname: Londero
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: Maite Rocío
authors.initials: MR
authors.lastname: Arana
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: Virginia Gabriela
authors.initials: VG
authors.lastname: Perdomo
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: Guillermo Nicolás
authors.initials: GN
authors.lastname: Tocchetti
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: Felipe
authors.initials: F
authors.lastname: Zecchinati
authors.affiliation: Instituto de Investigaciones Farmacológicas (ININFA-CONICET)-Facultad de Farmacia y Bioquímica-Universidad de Buenos Aires. Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Carolina Inés
authors.initials: CI
authors.lastname: Ghanem
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Ruiz
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Universität Heidelberg. Heidelberg, Germany.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rigalli
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.
authors.forename: Aldo Domingo
authors.initials: AD
authors.lastname: Mottino
authors.affiliation: Facultad de Ciencias Médicas-Universidad Nacional de Rosario-CONICET-Cátedra Fisiología Humana. Rosario, Santa Fe, Argentina.
authors.forename: Fabiana
authors.initials: F
authors.lastname: García
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina. Electronic address: villanueva@ifise-conicet.gov.ar.
authors.forename: Silvina Stella Maris
authors.initials: SSM
authors.lastname: Villanueva
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005632:Fructose / Q000009:adverse effects*; D005982:Glutathione Transferase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000975:Antioxidants; D016207:Cytokines; D005632:Fructose; D013482:Superoxide Dismutase; D005982:Glutathione Transferase
keywords: Fructose-rich diet; GST; Insulin resistance; Intestine; Metabolic syndrome; Mrp2