Cited by 152Drug Transport and Resistance MechanismsBarrier Structure and Function StudiesPharmacogenetics and Drug Metabolism

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Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders

Gil-Martins, Eva, Barbosa, Daniel José, Silva, Vera, Remião, Fernando, Silva, Renata·2020·Pharmacology & Therapeutics

DOI 10.1016/j.pharmthera.2020.107554

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Abstract

ABC (ATP-binding cassette) transporters represent one of the largest and most diverse superfamily of proteins in living species, playing an important role in many biological processes such as cell homeostasis, cell signaling, drug metabolism and nutrient uptake. Moreover, using the energy generated from ATP hydrolysis, they mediate the efflux of endogenous and exogenous substrates from inside the cells, thereby reducing their intracellular accumulation. At present, 48 ABC transporters have been identified in humans, which were classified into 7 different subfamilies (A to G) according to their phylogenetic analysis. Nevertheless, the most studied members with importance in drug therapeutic efficacy and toxicity include P-glycoprotein (P-gp), a member of the ABCB subfamily, the multidrug-associated proteins (MPRs), members of the ABCC subfamily, and breast cancer resistance protein (BCRP), a member of the ABCG subfamily. They exhibit ubiquitous expression throughout the human body, with a special relevance in barrier tissues like the blood-brain barrier (BBB). At this level, they play a physiological function in tissue protection by reducing or limiting the brain accumulation of neurotoxins. Furthermore, dysfunction of ABC transporters, at expression and/or activity level, has been associated with many neurological diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. Additionally, these transporters are strikingly associated with the pharmacoresistance to central nervous system (CNS) acting drugs, because they contribute to the decrease in drug bioavailability. This article reviews the signaling pathways that regulate the expression and activity of P-gp, BCRP and MRPs subfamilies of transporters, with particular attention at the BBB level, and their mis-regulation in neurological disorders.

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Authors: Gil-Martins, E., Barbosa, D. J., Silva, V., Remião, F., & Silva, R.
Affiliations: Universidade do Porto (PT)
Corresponding author: Remião, Fernando
Silva, Renata
ORCID: Gil-Martins, Eva
Barbosa, Daniel José
Silva, Vera
Remião, Fernando
Silva, Renata
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2020-09
Volume: 213
Pages: 107554
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2020.107554
OpenAlex: W3017050326
Cited by: 152
References: 379
Citations by year: 2026: 16 · 2025: 23 · 2024: 18 · 2023: 33 · 2022: 33 · 2021: 22 · 2020: 7
FWCI: 2.55
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Funders: Fundação para a Ciência e a Tecnologia
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: ABC transporters, blood-brain barrier, P-glycoprotein, ABCG2, multidrug resistance protein, neurological disorders, epilepsy, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, drug resistance, signaling pathways, transporter regulation, drug bioavailability
MeSH terms: Animals, Blood-Brain Barrier, Brain, Central Nervous System Agents, Drug Resistance, Humans, Nervous System Diseases, ATP-Binding Cassette Transporters

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Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders

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