Editorial

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4 pages, 185 KiB

Open AccessEditorial

ABC Transporters 45 Years On

by Anthony M. George

Int. J. Mol. Sci. 2023, 24(23), 16789; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242316789 - 27 Nov 2023

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Abstract

ABC transporters constitute one of the largest gene families among all species [...] Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

Research

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24 pages, 4827 KiB

Open AccessArticle

Synergistic Inhibitory Effect of Quercetin and Cyanidin-3O-Sophoroside on ABCB1

by Kuljeet Singh, Rajesh B. Patil, Vikas Patel, Judit Remenyik, Tamás Hegedűs and Katalin Goda

Int. J. Mol. Sci. 2023, 24(14), 11341; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411341 - 12 Jul 2023

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Abstract

The human ABCB1 (P-glycoprotein, Pgp) protein is an active exporter expressed in the plasma membrane of cells forming biological barriers. In accordance with its broad substrate spectrum and tissue expression pattern, it affects the pharmacokinetics of numerous chemotherapeutic drugs and it is involved [...] Read more.

The human ABCB1 (P-glycoprotein, Pgp) protein is an active exporter expressed in the plasma membrane of cells forming biological barriers. In accordance with its broad substrate spectrum and tissue expression pattern, it affects the pharmacokinetics of numerous chemotherapeutic drugs and it is involved in unwanted drug–drug interactions leading to side effects or toxicities. When expressed in tumor tissues, it contributes to the development of chemotherapy resistance in malignancies. Therefore, the understanding of the molecular details of the ligand–ABCB1 interactions is of crucial importance. In a previous study, we found that quercetin (QUR) hampers both the transport and ATPase activity of ABCB1, while cyandin-3O-sophroside (C3S) stimulates the ATPase activity and causes only a weak inhibition of substrate transport. In the current study, when QUR and C3S were applied together, both a stronger ATPase inhibition and a robust decrease in substrate transport were observed, supporting their synergistic ABCB1 inhibitory effect. Similar to cyclosporine A, a potent ABCB1 inhibitor, co-treatment with QUR and C3S shifted the conformational equilibrium to the “inward-facing” conformer of ABCB1, as it was detected by the conformation-selective UIC2 mAb. To gain deeper insight into the molecular details of ligand–ABCB1 interactions, molecular docking experiments and MD simulations were also carried out. Our in silico studies support that QUR and C3S can bind simultaneously to ABCB1. The most favourable ligand–ABCB1 interaction is obtained when C3S binds to the central substrate binding site and QUR occupies the “access tunnel”. Our results also highlight that the strong ABCB1 inhibitory effect of the combined treatment with QUR and C3S may be exploited in chemotherapy protocols for the treatment of multidrug-resistant tumors or for improving drug delivery through pharmacological barriers. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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15 pages, 3969 KiB

Open AccessArticle

Role of the ABCA4 Gene Expression in the Clearance of Toxic Vitamin A Derivatives in Human Hair Follicle Stem Cells and Keratinocytes

by Aneta Ścieżyńska, Krzysztof Łuszczyński, Marcin Radziszewski, Michał Komorowski, Marta Soszyńska, Natalia Krześniak, Kateryna Shevchenko, Anna Lutyńska and Jacek Malejczyk

Int. J. Mol. Sci. 2023, 24(9), 8275; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098275 - 05 May 2023

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Abstract

The ABCA4 gene encodes an ATP-binding cassette transporter that is expressed specifically in the disc of photoreceptor outer segments. Mutations in the ABCA4 gene are the main cause of retinal degenerations known as “ABCA4-retinopathies.” Recent research has revealed that ABCA4 is [...] Read more.

The ABCA4 gene encodes an ATP-binding cassette transporter that is expressed specifically in the disc of photoreceptor outer segments. Mutations in the ABCA4 gene are the main cause of retinal degenerations known as “ABCA4-retinopathies.” Recent research has revealed that ABCA4 is expressed in other cells as well, such as hair follicles and keratinocytes, although no information on its significance has been evidenced so far. In this study, we investigated the role of the ABCA4 gene in human keratinocytes and hair follicle stem cells for the first time. We have shown that silencing the ABCA4 gene increases the deleterious effect of all-trans-retinal on human hair follicle stem cells. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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18 pages, 3152 KiB

Open AccessArticle

ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression

by Kelli Monteiro da Costa, Leonardo Freire-de-Lima, Leonardo Marques da Fonseca, José Osvaldo Previato, Lucia Mendonça-Previato and Raphael do Carmo Valente

Int. J. Mol. Sci. 2023, 24(7), 6046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076046 - 23 Mar 2023

Cited by 4 | Viewed by 1599

Abstract

Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory [...] Read more.

Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters’ role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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10 pages, 510 KiB

Open AccessArticle

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients

by Hironobu Yagishita, Hideaki Kagaya, Mitsuru Saito, Kazuyuki Numakura, Ryohei Yamamoto, Ryuichiro Sagehashi, Tomonori Habuchi, Shigeru Satoh and Masatomo Miura

Int. J. Mol. Sci. 2022, 23(19), 11742; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911742 - 03 Oct 2022

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Abstract

The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just [...] Read more.

The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration–time curve (AUC_0-12) of everolimus was significantly lower in patients with the NR1I2 8055C/C genotype than in those with other genotypes (p = 0.022) and was significantly higher in male patients than female patients (p = 0.045). Significant correlations between the dose-adjusted AUC_0-12 of everolimus and age (p = 0.001), aspartate transaminase (p = 0.001), and alanine transaminase (p = 0.005) were found. In multivariate analysis, aging (p = 0.008) and higher alanine transaminase levels (p = 0.032) were independently predictive of a higher dose-adjusted everolimus AUC_0-12. Aging and hepatic dysfunction in patients may need to be considered when evaluating dose reductions in everolimus. In renal transplant patients, management using everolimus blood concentrations after administration may be more important than analysis of NR1I2 8055C>T polymorphism before administration. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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Review

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29 pages, 5100 KiB

Open AccessReview

ABC Transporters in Bacterial Nanomachineries

by Florestan L. Bilsing, Manuel T. Anlauf, Eymen Hachani, Sakshi Khosa and Lutz Schmitt

Int. J. Mol. Sci. 2023, 24(7), 6227; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076227 - 25 Mar 2023

Cited by 4 | Viewed by 2072

Abstract

Members of the superfamily of ABC transporters are found in all domains of life. Most of these primary active transporters act as isolated entities and export or import their substrates in an ATP-dependent manner across biological membranes. However, some ABC transporters are also [...] Read more.

Members of the superfamily of ABC transporters are found in all domains of life. Most of these primary active transporters act as isolated entities and export or import their substrates in an ATP-dependent manner across biological membranes. However, some ABC transporters are also part of larger protein complexes, so-called nanomachineries that catalyze the vectorial transport of their substrates. Here, we will focus on four bacterial examples of such nanomachineries: the Mac system providing drug resistance, the Lpt system catalyzing vectorial LPS transport, the Mla system responsible for phospholipid transport, and the Lol system, which is required for lipoprotein transport to the outer membrane of Gram-negative bacteria. For all four systems, we tried to summarize the existing data and provide a structure-function analysis highlighting the mechanistical aspect of the coupling of ATP hydrolysis to substrate translocation. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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12 pages, 3077 KiB

Open AccessReview

The Switch and Reciprocating Models for the Function of ABC Multidrug Exporters: Perspectives on Recent Research

by Peter M. Jones and Anthony M. George

Int. J. Mol. Sci. 2023, 24(3), 2624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032624 - 30 Jan 2023

Cited by 6 | Viewed by 1571

Abstract

ATP-binding cassette (ABC) transporters comprise a large superfamily of primary active transporters, which are integral membrane proteins that couple energy to the uphill vectorial transport of substrates across cellular membranes, with concomitant hydrolysis of ATP. ABC transporters are found in all living organisms, [...] Read more.

ATP-binding cassette (ABC) transporters comprise a large superfamily of primary active transporters, which are integral membrane proteins that couple energy to the uphill vectorial transport of substrates across cellular membranes, with concomitant hydrolysis of ATP. ABC transporters are found in all living organisms, coordinating mostly import in prokaryotes and export in eukaryotes. Unlike the highly conserved nucleotide binding domains (NBDs), sequence conservation in the transmembrane domains (TMDs) is low, with their divergent nature likely reflecting a need to accommodate a wide range of substrate types in terms of mass and polarity. An explosion in high resolution structural analysis over the past decade and a half has produced a wealth of structural information for ABCs. Based on the structures, a general mechanism for ABC transporters has been proposed, known as the Switch or Alternating Access Model, which holds that the NBDs are widely separated, with the TMDs and NBDs together forming an intracellular-facing inverted “V” shape. Binding of two ATPs and the substrate to the inward-facing conformation induces a transition to an outward conformation. Despite this apparent progress, certainty around the transport mechanism for any given ABC remains elusive. How substrate binding and transport is coupled to ATP binding and hydrolysis is not known, and there is a large body of biochemical and biophysical data that is at odds with the widely separated NBDs being a functional physiological state. An alternative Constant Contact model has been proposed in which the two NBSs operate 180 degrees out of phase with respect to ATP hydrolysis, with the NBDs remaining in close proximity throughout the transport cycle and operating in an asymmetric allosteric manner. The two models are discussed in the light of recent nuclear magnetic resonance and hydrogen-deuterium exchange mass spectrometry analyses of three ABC exporters. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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17 pages, 5880 KiB

Open AccessReview

Recent Advances on P-Glycoprotein (ABCB1) Transporter Modelling with In Silico Methods

by Liadys Mora Lagares and Marjana Novič

Int. J. Mol. Sci. 2022, 23(23), 14804; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314804 - 26 Nov 2022

Cited by 12 | Viewed by 1879

Abstract

ABC transporters play a critical role in both drug bioavailability and toxicity, and with the discovery of the P-glycoprotein (P-gp), this became even more evident, as it plays an important role in preventing intracellular accumulation of toxic compounds. Over the past 30 years, [...] Read more.

ABC transporters play a critical role in both drug bioavailability and toxicity, and with the discovery of the P-glycoprotein (P-gp), this became even more evident, as it plays an important role in preventing intracellular accumulation of toxic compounds. Over the past 30 years, intensive studies have been conducted to find new therapeutic molecules to reverse the phenomenon of multidrug resistance (MDR) ), that research has found is often associated with overexpression of P-gp, the most extensively studied drug efflux transporter; in MDR, therapeutic drugs are prevented from reaching their targets due to active efflux from the cell. The development of P-gp inhibitors is recognized as a good way to reverse this type of MDR, which has been the subject of extensive studies over the past few decades. Despite the progress made, no effective P-gp inhibitors to reverse multidrug resistance are yet on the market, mainly because of their toxic effects. Computational studies can accelerate this process, and in silico models such as QSAR models that predict the activity of compounds associated with P-gp (or analogous transporters) are of great value in the early stages of drug development, along with molecular modelling methods, which provide a way to explain how these molecules interact with the ABC transporter. This review highlights recent advances in computational P-gp research, spanning the last five years to 2022. Particular attention is given to the use of machine-learning approaches, drug–transporter interactions, and recent discoveries of potential P-gp inhibitors that could act as modulators of multidrug resistance. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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16 pages, 1066 KiB

Open AccessReview

Regulation of P-Glycoprotein in the Brain

by Amanda B. Chai, Richard Callaghan and Ingrid C. Gelissen

Int. J. Mol. Sci. 2022, 23(23), 14667; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314667 - 24 Nov 2022

Cited by 8 | Viewed by 3858

Abstract

Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood–brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of [...] Read more.

Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood–brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of substrates to limit exposure of the vulnerable brain environment to waste buildup and neurotoxic compounds. Downregulation of P-gp expression and activity at the BBB have been reported with ageing and in neurodegenerative diseases. Upregulation of P-gp at the BBB contributes to poor therapeutic outcomes due to altered pharmacokinetics of CNS-acting drugs. The regulation of P-gp is highly complex, but unravelling the mechanisms involved may help the development of novel and nuanced strategies to modulate P-gp expression for therapeutic benefit. This review summarises the current understanding of P-gp regulation in the brain, encompassing the transcriptional, post-transcriptional and post-translational mechanisms that have been identified to affect P-gp expression and transport activity. Full article

(This article belongs to the Special Issue ABC Transporters: Where Are We 45 Years On?)

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