title: Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy.
abstract: P-glycoprotein (P-gp) is an ATP-dependent efflux pump encoded by the MDR1 gene in humans, known to mediate multidrug resistance of neoplastic cells to cancer therapy. For several decades, P-gp inhibition has drawn many significant research efforts in an attempt to overcome this phenomenon. However, P-gp is also constitutively expressed in normal human epithelial tissues and, due to its broad substrate specificity, to its cellular polarized expression in many excretory and barrier tissues, and to its great efflux capacity, it can play a crucial role in limiting the absorption and distribution of harmful xenobiotics, by decreasing their intracellular accumulation. Such a defense mechanism can be of particular relevance at the intestinal level, by significantly reducing the intestinal absorption of the xenobiotic and, consequently, avoiding its access to the target organs. In this review, the current knowledge on this important efflux pump is summarized, and a new focus is brought on the therapeutic interest of inducing and/or activating P-gp for limiting the toxicity caused by its substrates. Several in vivo and in vitro studies validating the use of such a therapeutic strategy are discussed. An extensive literature search for reported P-gp inducers/activators and for the experimental models used in their characterization was conducted. Those studies demonstrate that effective antidotal pathways can be achieved by efficiently promoting the P-gp-mediated efflux of deleterious xenobiotics, resulting in a significant reduction in their intracellular levels and, consequently, in a significant reduction of their toxicity.
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: rsilva@ff.up.pt.
authors.forename: Renata
authors.initials: R
authors.lastname: Silva
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: vvilasboas@ff.up.pt.
authors.forename: Vânia
authors.initials: V
authors.lastname: Vilas-Boas
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: helenacarmo@ff.up.pt.
authors.forename: Helena
authors.initials: H
authors.lastname: Carmo
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; INFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences - North (ISCS-N), CESPU, CRL, Gandra, Portugal; Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal. Electronic address: ricardinis@med.up.pt.
authors.forename: Ricardo Jorge
authors.initials: RJ
authors.lastname: Dinis-Oliveira
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: felixdc@ff.up.pt.
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: mlbastos@ff.up.pt.
authors.forename: Maria
authors.initials: M
authors.lastname: de Lourdes Bastos
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: remiao@ff.up.pt.
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D000931:Antidotes / Q000494:pharmacology* / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D015398:Signal Transduction; D013312:Stress, Physiological; D015262:Xenobiotics / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000931:Antidotes; D015262:Xenobiotics
keywords: Activation; Induction; P-glycoprotein; Paraquat; Toxicity