title: Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics.
abstract: The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs.
authors.affiliation: Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Guillermo Nicolás
authors.initials: GN
authors.lastname: Tocchetti
authors.affiliation: Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario, Argentina; Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rigalli
authors.affiliation: Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Maite Rocío
authors.initials: MR
authors.lastname: Arana
authors.affiliation: Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Silvina Stella Maris
authors.initials: SSM
authors.lastname: Villanueva
authors.affiliation: Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario, Argentina. Electronic address: amottino@unr.edu.ar.
authors.forename: Aldo Domingo
authors.initials: AD
authors.lastname: Mottino
mesh_terms: D000818:Animals; D000090702:Constitutive Androstane Receptor; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000378:metabolism*; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015262:Xenobiotics; C000715087:ABCC2 protein, human; C000716327:NR1I3 protein, human
keywords: Drug transport; Drug-drug interactions; Intestinal chemical barrier; Multidrug resistance-associated protein 2; Nutrient-drug interaction; Pregnane-X-receptor