Systematic Reviews
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2015; 21(41): 11862-11876
Published online Nov 7, 2015. doi: 10.3748/wjg.v21.i41.11862
Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology
Vibeke Andersen, Katrine Svenningsen, Lina Almind Knudsen, Axel Kornerup Hansen, Uffe Holmskov, Allan Stensballe, Ulla Vogel
Vibeke Andersen, Katrine Svenningsen, Lina Almind Knudsen, Molecular Diagnostic and Clinical Health Research Unit, Hospital of Southern Jutland, 6200 Aabenraa, Denmark
Vibeke Andersen, Katrine Svenningsen, Lina Almind Knudsen, Institute of Regional Health Research-Centre Sønderjylland, University of Southern Denmark, 5000 Odense, Denmark
Vibeke Andersen, Medical Department, Regional Hospital Viborg, 8800 Viborg, Denmark
Axel Kornerup Hansen, Experimental Animal Models, University of Copenhagen, 1870 Frederiksberg, Denmark
Uffe Holmskov, Department of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark
Allan Stensballe, Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark
Ulla Vogel, National Research Centre for the Working Environment, 2100 Copenhagen, Denmark
Author contributions: Andersen V was the guarantor of the article, collected the material and wrote the manuscript; Vogel U critically commented the work; Svenningsen K, Knudsen LA, Hansen AK, Holmskov U, Stensballe A and Vogel U participated in the manuscript writing; all authors have accepted the final version.
Conflict-of-interest statement: Vibeke Andersen is receiving compensation as a consultant for MSD (Merck) and Janssen and advisory board member for MSD (Merck). Katrine Svenningsen, Lina A Knudsen, Axel Kornerup Hansen, Uffe Holmskov, Allan Stensballe, and Ulla Vogel declare no competing interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Vibeke Andersen, Molecular Diagnostic and Clinical Health Research Unit, Hospital of Southern Jutland, 6200 Aabenraa, Denmark. vandersen@health.sdu.dk
Telephone: +45-21157790 Fax: +45-88834488
Received: June 10, 2015
Peer-review started: June 14, 2015
First decision: July 14, 2015
Revised: August 7, 2015
Accepted: September 30, 2015
Article in press: September 30, 2015
Published online: November 7, 2015
Abstract

AIM: To evaluate ATP-binding cassette (ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer (CRC) development.

METHODS: Literature search was conducted on PubMed using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1/Mdr1a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function.

RESULTS: Recently, human studies reported that changes in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of host-microbiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogen-free Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells which were resistant to treatment with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak.

CONCLUSION: ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies.

Keywords: ATP-binding cassette transporters, Colorectal cancer, Intestinal, Inflammatory bowel disease, Inflammation, Adenoma-carcinoma sequence

Core tip: Recently, human studies reported that changes in the levels of ATP-binding cassette (ABC) transporters were early events in the adenoma-carcinoma sequence leading to colorectal cancer. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Such strategy may provide insight which can be translated into preventive and treatment strategies to benefit the patients.