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Drug Transporter in Pathological Conditions

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 7318

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Special Issue Editor

Dr. Atsushi Kawase

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Guest Editor

Department of Pharmacy, Kindai University, Higashiosaka 579-8064, Japan
Interests: scaffold protein; inflammatory transporter liver disorder

Special Issue Information

Dear Colleagues,

Transporters such as P-glycoprotein and organic-anion-transporting polypeptide govern the organ disposition of various drugs. The plasma membrane localization and transport activity of transporters are regulated by transporter-associated proteins. Transporter activity varies depending on factors such as age, gender, concomitant drugs, and pathological conditions. In particular, pathological conditions cause complicated effects on transporter regulation. However, the effects of pathological conditions on the expression and activity of transporters are undetermined, although those under normal conditions have been well understood. Therefore, it is important to summarize the recent findings on transporter regulation in pathological conditions.

This Special Issue attempts to explore the recent advances in transporter regulation in pathological conditions. We welcome original research or review papers demonstrating the mechanisms of transporter regulation in pathological conditions, and the changes in expression and activity in pathological conditions using in vivo or in vitro models of animals as well as clinical settings.

Dr. Atsushi Kawase
Guest Editor

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Keywords

drug disposition
efflux
uptake
inflammation
liver
kidney
cancer
cytokine
pharmacokinetics
scaffold protein

Published Papers (4 papers)

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Research

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23 pages, 3106 KiB

Open AccessArticle

Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications

by Zsuzsanna Gutay-Tóth, Gabriella Gellen, Minh Doan, James F. Eliason, János Vincze, Lajos Szente, Ferenc Fenyvesi, Katalin Goda, Miklós Vecsernyés, Gábor Szabó and Zsolt Bacso

Int. J. Mol. Sci. 2023, 24(15), 12335; https://doi.org/10.3390/ijms241512335 - 2 Aug 2023

Viewed by 1418

Abstract

The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane’s raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations. Full article

(This article belongs to the Special Issue Drug Transporter in Pathological Conditions)

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14 pages, 3409 KiB

Open AccessArticle

Lipopolysaccharide-Induced Functional Alteration of P-glycoprotein in the Ex Vivo Rat Inner Blood–Retinal Barrier

by Kiyotaka Daikohara, Shin-ichi Akanuma, Yoshiyuki Kubo and Ken-ichi Hosoya

Int. J. Mol. Sci. 2022, 23(24), 15504; https://doi.org/10.3390/ijms232415504 - 7 Dec 2022

Cited by 1 | Viewed by 1694

Abstract

At the inner blood–retinal barrier (BRB), P-glycoprotein (P-gp) contributes to maintaining the homeostasis of substance concentration in the retina by transporting drugs and exogenous toxins from the retina to the circulating blood. Under inflammatory conditions, P-gp activities have been reported to be altered in various tissues. The purpose of this study was to clarify the alterations in P-gp activity at the inner BRB due to lipopolysaccharide (LPS), an inflammatory agent, and the molecular mechanisms of the alterations induced by LPS. Ex vivo P-gp activity was evaluated as luminal accumulation of 7-nitro-2,1,3-benzoxadiazole-cyclosporin A (NBD-CSA), a fluorescent P-gp substrate, in freshly prepared rat retinal capillaries. The luminal NBD-CSA accumulation was significantly decreased in the presence of LPS, indicating that P-gp activity at the inner BRB is reduced by LPS. This LPS-induced attenuation of the luminal NBD-CSA accumulation was abolished by inhibiting toll-like receptor 4 (TLR4), a receptor for LPS. Furthermore, an inhibitor/antagonist of tumor necrosis factor receptor 1, endothelin B receptor, nitric oxide synthase, or protein kinase C (PKC) significantly restored the LPS-induced decrease in the luminal NBD-CSA accumulation. Consequently, it is suggested that the TLR4/PKC pathway is involved in the reduction in P-gp function in the inner BRB by LPS. Full article

(This article belongs to the Special Issue Drug Transporter in Pathological Conditions)

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Review

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19 pages, 1034 KiB

Open AccessReview

ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives

by Daniela Damiani and Mario Tiribelli

Int. J. Mol. Sci. 2023, 24(8), 7147; https://doi.org/10.3390/ijms24087147 - 12 Apr 2023

Cited by 4 | Viewed by 1885

Abstract

Despite recent advances, prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to poor response to therapy or relapse. Among causes of resistance, over-expression of multidrug resistance (MDR) proteins represents a pivotal mechanism. ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML resistance and/or relapse, even if conflicting data have been reported to date. Moreover, ABCG2 may be co-expressed with other MDR-related proteins and is finely regulated by epigenetic mechanisms. Here, we review the main issues regarding ABCG2 activity and regulation in the AML clinical scenario, focusing on its expression and the role of polymorphisms, as well as on the potential ways to inhibit its function to counteract drug resistance to, eventually, improve outcomes in AML patients. Full article

(This article belongs to the Special Issue Drug Transporter in Pathological Conditions)

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12 pages, 1944 KiB

Open AccessReview

The Role of ABC Transporters in Skin Cells Exposed to UV Radiation

by Agnieszka Gęgotek and Elżbieta Skrzydlewska

Int. J. Mol. Sci. 2023, 24(1), 115; https://doi.org/10.3390/ijms24010115 - 21 Dec 2022

Cited by 4 | Viewed by 1835

Abstract

ABC transporters are expressed in skin cells to protect them against harmful xenobiotics. Moreover, these transmembrane proteins have a number of additional functions that ensure skin homeostasis. This review summarizes the current knowledge about the role of specific ABC proteins in the skin, including multi-drug resistance transporters (MDR1/3), the transporter associated with antigen processing 1/2 (TAP1/2), the cystic fibrosis transmembrane conductance regulator (CFTR), sulfonylurea receptors (SUR1/2), and the breast cancer resistance protein (BCRP). Additionally, the effect of UV radiation on ABC transporters is shown. The exposure of skin cells to UV radiation often leads to increased activity of ABC transporters—as has been observed in the case of MDRs, TAPs, CFTR, and BCRP. A different effect of oxidative stress has been observed in the case of mitochondrial SURs. However, the limited data in the literature—as indicated in this article—highlights the limited number of experimental studies dealing with the role of ABC transporters in the physiology and pathophysiology of skin cells and the skin as a whole. At the same time, the importance of such knowledge in relation to the possibility of daily exposure to UV radiation and xenobiotics, used for both skin care and the treatment of its diseases, is emphasized. Full article

(This article belongs to the Special Issue Drug Transporter in Pathological Conditions)

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