Transport of nucleoside analogs across the plasma membrane: a clue to understanding drug-induced cytotoxicity.
Nucleoside analogs are widely used in the treatment of cancer and viral-induced diseases. Efficacy of treatments relies upon a variety of events, including transport across tissue and target barriers, which determine drug pharmacokinetics and target cell bioavailability. To exert their action, nucleosides have to be chemically modified, thus compromising cellular uptake by those routes which are responsible for the uptake of natural nucleosides and nucleobases. In this review we will focus on established knowledge and recent advances in the understanding of nucleoside- and nucleobase-derived drug uptake mechanisms. Basically, these drug uptake processes involve the gene families SLC22, SLC28 and SLC29. These gene families encode Organic Anion Transporter (OAT)/Organic Cation Transporter (OCT), Concentrative Nucleoside Transporter (CNT) and Equilibrative Nucleoside Transporter (ENT) proteins, respectively. The pharmacological profiles of these plasma membrane carriers as well as their basic physiological and regulatory properties, including their tissue and subcellular distribution will be reviewed. This knowledge is crucial for the understanding of nucleoside- and nucleobase-derived drug bioavailability and therapeutic action. Moreover, changes in both transporter expression and/or transporter function (for instance as a consequence of gene variability) might also modulate response to treatment, thereby anticipating a putative diagnostic and predictive added value to the analysis of transporter expression and their corresponding genetic variants.
Huber-Ruano
I
I
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona and CIBER EHD, Barcelona, Spain.
Pastor-Anglada
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M
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers / Q000493:pharmacokinetics; D033705:Equilibrative Nucleoside Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D033703:Nucleoside Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009705:Nucleosides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D027361:Organic Anion Transporters / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004337:Drug Carriers; D033705:Equilibrative Nucleoside Transport Proteins; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C065171:cif nucleoside transporter