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Review
.2012 Apr 15;83(8):1073-83.
doi: 10.1016/j.bcp.2011.12.042. Epub 2012 Jan 20.

ABC transporters and their role in nucleoside and nucleotide drug resistance

Affiliations
Review

ABC transporters and their role in nucleoside and nucleotide drug resistance

Yu Fukuda et al. Biochem Pharmacol..

Abstract

ATP-binding cassette (ABC) transporters confer drug resistance against a wide range of chemotherapeutic agents, including nucleoside and nucleotide based drugs. While nucleoside based drugs have been used for many years in the treatment of solid and hematological malignancies as well as viral and autoimmune diseases, the potential contribution of ABC transporters has only recently been recognized. This neglect is likely because activation of nucleoside derivatives require an initial carrier-mediated uptake step followed by phosphorylation by nucleoside kinases, and defects in uptake or kinase activation were considered the primary mechanisms of nucleoside drug resistance. However, recent studies demonstrate that members of the ABCC transporter subfamily reduce the intracellular concentration of monophosphorylated nucleoside drugs. In addition to the ABCC subfamily members, ABCG2 has been shown to transport nucleoside drugs and nucleoside-monophosphate derivatives of clinically relevant nucleoside drugs such as cytarabine, cladribine, and clofarabine to name a few. This review will discuss ABC transporters and how they interact with other processes affecting the efficacy of nucleoside based drugs.

Copyright © 2012 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1
Predicted two-dimensional topology of ABC transporters and Model of ABC transporter mechanism. A) The two membrane spanning domains (MSDs) and nucleotide binding domains (NBDs) are represented by P-gp and some MRP (ABCC) family members with some MRPs containing an additional N-terminal extension (MSD0), while some ABC transporters have only one MSD and NBD; B) A structure of P-gp in the inward facing conformation showing the transmembrane domains (TMs) and the NBDs; C) Transporter mechanism showing a large conformational change as a result of ATP binding. Substrates can enter by either the cytoplasmic face or extracellular face of an ABC transporter. Adopted from [43].
Figure 2
Figure 2
ABC transporters can confer resistance to nucleosides and single-nucleotide polymorphisms (SNP’s) can modify ABC transporter function. A) The pathway of nucleoside uptake and activation by a nucleoside kinase can be disrupted by an ABC transporter. B) Single-nucleotide polymorphisms (SNP’s) can result in loss of function through mechanisms affecting protein targeting, stability etc. resulting in “loss of function” but SNP’s can also result in enhanced transport activity: “gain of function.” The arrow size indicates transport activity.
Figure 2
Figure 2
ABC transporters can confer resistance to nucleosides and single-nucleotide polymorphisms (SNP’s) can modify ABC transporter function. A) The pathway of nucleoside uptake and activation by a nucleoside kinase can be disrupted by an ABC transporter. B) Single-nucleotide polymorphisms (SNP’s) can result in loss of function through mechanisms affecting protein targeting, stability etc. resulting in “loss of function” but SNP’s can also result in enhanced transport activity: “gain of function.” The arrow size indicates transport activity.
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