Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins
Abstract
Multidrug Resistance Proteins (MRPs), together with the cystic fibrosis conductance regulator (CFTR/ABCC7) and the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) comprise the 13 members of the human "C" branch of the ATP binding cassette (ABC) superfamily. All C branch proteins share conserved structural features in their nucleotide binding domains (NBDs) that distinguish them from other ABC proteins. The MRPs can be further divided into two subfamilies "long" (MRP1, -2, -3, -6, and -7) and "short" (MRP4, -5, -8, -9, and -10). The short MRPs have a typical ABC transporter structure with two polytropic membrane spanning domains (MSDs) and two NBDs, while the long MRPs have an additional NH2-terminal MSD. In vitro, the MRPs can collectively confer resistance to natural product drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and, under certain circumstances, alkylating agents. The MRPs are also primary active transporters of other structurally diverse compounds, including glutathione, glucuronide, and sulfate conjugates of a large number of xeno- and endobiotics. In vivo, several MRPs are major contributors to the distribution and elimination of a wide range of both anticancer and non-anticancer drugs and metabolites. In this review, we describe what is known of the structure of the MRPs and the mechanisms by which they recognize and transport their diverse substrates. We also summarize knowledge of their possible physiological functions and evidence that they may be involved in the clinical drug resistance of various forms of cancer.
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OATPs belong to the SLCO transporter gene superfamily and are the primary transporters for the influx of conjugated steroids, while MDR proteins belonging to the ABC transporters are the primary transporters for the efflux of conjugated steroids.
“Organic anion-transporting polypeptides (OATPs) belong to the solute carrier organic anion (SLCO) transporter gene superfamily and are the primary transporters for the influx of conjugated steroids, while multi drug resistant (MDR) proteins belonging to the ATP-binding cassette (ABC) transporters are the primary transporters for the efflux of conjugated steroids (Deeley et al., 2006, Mueller et al”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Deeley et al., 2006
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Membrane Topology and Glycosylation of the Human Multidrug Resistance-associated Protein
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Rad50/SMC proteins and ABC transporters: unifying concepts from high-resolution structures
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Cited by
Sorted by citations
Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837 · see citing works
Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases
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Intracrine androgen biosynthesis, metabolism and action revisited
Schiffer, L., Arlt, W., & Storbeck, K.-H. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.08.016 · Cited by 217 · see citing works
“Organic anion-transporting polypeptides (OATPs) belong to the solute carrier organic anion (SLCO) transporter gene superfamily and are the primary transporters for the influx of conjugated steroids, while multi drug resistant (MDR) proteins belonging to the ATP-binding cassette (ABC) transporters are the primary trans…”
Nixon, M., Mackenzie, S. D., Taylor, A. I., Homer, N. Z. M., Livingstone, D. E., Mouras, R., Morgan, R. A., Mole, D. J., Stimson, R. H., Reynolds, R. M., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf9074 · Cited by 59 · see citing works
Conseil, G., & Cole, S. P. C. (2013) · Drug Metabolism and Disposition · doi:10.1124/dmd.113.054213 · Cited by 28 · see citing works
Self-citation
- Authors
- Deeley, R. G., Westlake, C., & Cole, S. P. C.
- Affiliations
- Queen's University (CA)
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2006-07
- Volume
- 86
- Issue
- 3
- Pages
- 849-899
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W2151625463
- Cited by
- 761
- References
- 584
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 17 · 2023: 19 · 2022: 26 · 2021: 33 · 2020: 21 · 2019: 20 · 2018: 26 · 2017: 42 · 2016: 40 · 2015: 42 · 2014: 55 · 2013: 51 · 2012: 54
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- multidrug resistance protein, ABC transporters, ABCB subfamily, drug efflux, xenobiotic transport, substrate recognition, nucleotide-binding domain, transmembrane domain, drug resistance, cancer chemotherapy resistance, glutathione conjugates, glucuronide conjugates, sulfate conjugates, CFTR, sulfonylurea receptor
- MeSH terms
- Amino Acid Sequence, Animals, Biological Transport, Humans, Mammals, Molecular Sequence Data, Xenobiotics, Protein Structure, Tertiary, ATP-Binding Cassette Transporters
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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