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International Journal of Molecular... Nov 2022Maintenance 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... (Review)
Review
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.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Endothelial Cells; ATP Binding Cassette Transporter, Subfamily B; Brain; Blood-Brain Barrier; Central Nervous System Agents
PubMed: 36498995
DOI: 10.3390/ijms232314667 -
FEBS Letters Dec 2020The levels of amyloid peptides in the brain are regulated by a clearance pathway from neurons to the blood-brain barrier. The first step is thought to involve diffusion... (Review)
Review
The levels of amyloid peptides in the brain are regulated by a clearance pathway from neurons to the blood-brain barrier. The first step is thought to involve diffusion from the plasma membrane to the interstitium. However, amyloid peptides are hydrophobic and avidly intercalate within membranes. The ABC transporter P-glycoprotein is implicated in the clearance of amyloid peptides across the blood-brain, but its role at neurons is undetermined. We here propose that P-glycoprotein mediates 'exit' of amyloid peptides from neurons. Indeed, amyloid peptides have physicochemical similarities to substrates of P-glycoprotein, but their larger size represents a conundrum. This review probes the plausibility of a mechanism for amyloid peptide transport by P-glycoprotein exploiting evolving biochemical and structural models.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Amyloid beta-Peptides; Animals; Endothelial Cells; Humans; Neurons
PubMed: 33022784
DOI: 10.1002/1873-3468.13951 -
The International Journal of... 2016Epilepsy is a serious neurological disorder that affects more than 60 million people worldwide. Intractable epilepsy (IE) refers to approximately 20%-30% of epileptic... (Review)
Review
Epilepsy is a serious neurological disorder that affects more than 60 million people worldwide. Intractable epilepsy (IE) refers to approximately 20%-30% of epileptic patients who fail to achieve seizure control with antiepileptic drug (AED) treatment. Although the mechanisms underlying IE are not well understood, it has been hypothesized that multidrug transporters such as P-glycoprotein (P-gp) play a major role in drug efflux at the blood-brain barrier, and may be the underlying factor in the variable responses of patients to AEDs. The main goal of the present review is to show evidence from different areas that support the idea that the overexpression of P-gp is associated with IE. We discuss here evidence from animal studies, pharmacology, clinical cases and genetic studies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Brain; Drug Resistant Epilepsy; Epilepsy; Humans
PubMed: 26000919
DOI: 10.3109/00207454.2015.1038710 -
Life Sciences Dec 2018P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity... (Review)
Review
P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity has been the subject of numerous attempts to develop P-gp inhibitors. The aim of this review is to present up-to-date information on the structural and functional aspects of P-gp and its known inhibitors. The data presented also provide some information on drug discovery approaches for candidate P-gp inhibitors. Nucleotide-binding domains (NBDs) and drug-binding domains (DBDs) have been extensively studied to gain more information about P-gp inhibition and it looks that the ATPase activity of this pump has been the most attractive target for designing inhibitors. Hydrophobic and π-π (aromatic) interactions between P-gp binding domains and inhibitors are dominant intermolecular forces that have been reported in many studies using different methods. Many synthetic and natural products have been found to possess inhibitory or modulatory effects on drug transporter proteins. Log P value is an important factor in studying these inhibitors and has a crucial role on absorption, distribution, metabolism, and excretion (ADME) properties of candidate P-gp inhibitors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Acridines; Antineoplastic Agents; Binding Sites; Biological Products; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lipid Bilayers; Molecular Targeted Therapy; Piperidines; Protein Conformation; Quinolines; Tetrahydroisoquinolines
PubMed: 30449449
DOI: 10.1016/j.lfs.2018.10.048 -
Biological & Pharmaceutical Bulletin 2018This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe... (Review)
Review
This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe findings demonstrating that the distribution of P-gp along the small intestine is heterogeneous, which explains why orally administered P-gp substrate drugs often show bimodal changes of plasma concentration. Secondly, we discuss the post-translational regulation of P-gp localization and function by the scaffold proteins ezrin, radixin and moesin (ERM proteins), together with recent reports indicating that tissue-specific differences in regulation by ERM proteins in normal tissues might be retained in corresponding cancerous tissues. Thirdly, we review evidence that P-gp activity is enhanced in the process of epithelial-to-mesenchymal transition (EMT), which is associated with cancer progression, without any increase in expression of P-gp mRNA. Finally, we describe two examples in which P-gp critically influences the brain distribution of drugs, i.e., oseltamivir, where low levels of P-gp associated with early development allow oseltamivir to enter the brain, potentially resulting in neuropsychiatric side effects in children, and cilnidipine, where impairment of P-gp function in ischemia allows cilnidipine to enter the ischemic brain, where it exerts a neuroprotective action.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Cell Membrane; Drug-Related Side Effects and Adverse Reactions; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Intestine, Small; Pharmaceutical Preparations; Protein Processing, Post-Translational; Substrate Specificity
PubMed: 29311472
DOI: 10.1248/bpb.b17-00725 -
Expert Opinion on Drug Metabolism &... Apr 2021: P-glycoprotein (P-gp) is an important efflux pump responsible for the extruding of many endogenous and exogenous substances out of the cells. P-gp can be modulated by... (Review)
Review
: P-glycoprotein (P-gp) is an important efflux pump responsible for the extruding of many endogenous and exogenous substances out of the cells. P-gp can be modulated by different molecules - including xanthone derivatives - to surpass the multidrug resistance (MDR) phenomenon through P-gp inhibition, or to serve as an antidotal strategy in intoxication scenarios through P-gp induction/activation.: This review provides a perspective on P-gp modulators, with particular focus on xanthonic derivatives, highlighting their ability to modulate P-gp expression and/or activity, and the potential impact of these effects on the pharmacokinetics, pharmacodynamics and toxicity of P-gp substrates.: Xanthones, of natural or synthetic origin, are able to modulate P-gp, interfering with its protein synthesis or with its mechanism of action, by decreasing or increasing its efflux capacity. These modulatory effects make the xanthonic scaffold a promising source of new derivatives with therapeutic potential. However, the mechanisms beyond the xanthones-mediated P-gp modulation and the chemical characteristics that make them more potent P-gp inhibitors or inducers/activators are still understudied. Furthermore, a new window of opportunity exists in the neuropathologies field, where xanthonic derivatives with potential to modulate P-gp should be further explored to optimize the prevention/treatment of brain pathologies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Brain Diseases; Drug Interactions; Humans; Pharmaceutical Preparations; Xanthones
PubMed: 33283552
DOI: 10.1080/17425255.2021.1861247 -
Journal of Veterinary Pharmacology and... Jan 2023In 2001 the molecular genetic basis of so-called "ivermectin sensitivity" in herding breed dogs was determined to be a P-glycoprotein deficiency caused by a genetic... (Review)
Review
In 2001 the molecular genetic basis of so-called "ivermectin sensitivity" in herding breed dogs was determined to be a P-glycoprotein deficiency caused by a genetic variant of the MDR1 (ABCB1) gene often called "the MDR1 mutation." We have learned a great deal about P-glycoprotein's role in drug disposition since that discovery, namely that P-glycoprotein transports many more drugs than just macrocyclic lactones that P-glycoprotein mediated drug transport is present in more places than just the blood brain barrier, that some cats have a genetic variant of MDR1 that results in P-glycoprotein deficiency, that P-glycoprotein dysfunction can occur as a result of drug-drug interactions in any dog or cat, and that the concept of P-glycoprotein "inhibitors" versus P-glycoprotein substrates is somewhat arbitrary and artificial. This paper will review these discoveries and discuss how they impact drug selection and dosing in dogs and cats with genetically mediated P-glycoprotein deficiency or P-glycoprotein dysfunction resulting from drug-drug interactions.
Topics: Dogs; Cats; Animals; Cat Diseases; Dog Diseases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Ivermectin; ATP Binding Cassette Transporter, Subfamily B
PubMed: 36326478
DOI: 10.1111/jvp.13102 -
Phytomedicine : International Journal... Jul 2019Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated...
BACKGROUND
Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated that artemisinin and its derivatives exhibit considerable anticancer activity both in vitro, in vivo, and even in clinical Phase I/II trials. P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) is one of the most serious causes of chemotherapy failure in cancer treatment. Interestingly, many artemisinin derivatives exhibit excellent ability to overcome P-gp mediated MDR and even show collateral sensitivity against MDR cancer cells. Furthermore, some artemisinin derivatives show P-gp-mediated MDR reversal activity. Therefore, the interaction between P-gp and artemisinin derivatives is important to develop novel combination treatment protocols with artemisinin derivatives and established anticancer drugs that are P-gp substrates.
PURPOSE
This systematic review provides an updated overview on the interaction between artemisinin derivatives and P-gp and the effect of artemisinin derivatives on the P-gp expression level.
RESULTS
Artemisinin derivatives exhibit multi-specific interactions with P-gp. The currently used artemisinin derivatives are not transported by P-gp. However, some of novel synthetized artemisinin derivatives exhibit P-gp substrate properties. Furthermore, many artemisinin derivatives act as P-gp inhibitors, which exhibit the potential to reverse MDR towards clinically used anticancer drugs.
CONCLUSION
Therefore, studies on the interaction between artemisinin derivatives and P-gp provide important information for the development of novel anti-cancer artemisinin derivatives to reverse P-gp mediated MDR and for the design of rational artemisinin-based combination therapies against cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Artemisinins; Drug Resistance, Multiple; Humans; Neoplasms
PubMed: 31301971
DOI: 10.1016/j.phymed.2019.152998 -
International Journal of Cancer Jul 2014Overexpression of P-glycoprotein (P-gp) contributes to the multidrug resistance (MDR) phenotype found in many cancer cells. P-gp has been identified as a promising... (Review)
Review
Overexpression of P-glycoprotein (P-gp) contributes to the multidrug resistance (MDR) phenotype found in many cancer cells. P-gp has been identified as a promising molecular target, although attempts to find successful therapies to counteract its function as a drug efflux pump have largely failed to date. Apart from its role in drug efflux, P-gp may have other cellular functions such as being involved in apoptosis, and is found in various locations in the cell. Its expression is highly regulated, namely by microRNAs (miRNAs or miRs). In addition, P-gp may regulate the expression of miRs in the cell. Furthermore, both P-gp and miRs may be found in microvesicles or exosomes and may be transported to neighboring, drug-sensitive cells. Here, we review this current issue together with recent evidence of this network of interactions between P-gp and miRs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation; Humans; MicroRNAs; Signal Transduction
PubMed: 24122334
DOI: 10.1002/ijc.28500 -
Food and Chemical Toxicology : An... Dec 2020The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including...
The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including drugs, herbal products, and food components. In this study, we tested six common arylsulfonate food dyes-allura red, carmoisine, ponceau 4R, quinolone yellow, sunset yellow, and tartrazine-as activators and inhibitors of P-gp activity in vitro. The dyes were studied as P-gp activators by measuring ATPase activity in P-gp-expressing membranes. Compared to verapamil, a known activator of P-gp, the six food dyes showed no stimulatory activity. The potential for these six food dyes to act as P-gp inhibitors was tested in an intracellular efflux assay with P-gp-expressing cells. Compared to GF120918, a known P-gp inhibitor, there was no inhibitory activity for these six food dyes. The six food dyes tested do not interact with P-gp in vitro and, therefore, are unlikely cause clinical drug-food dye interactions. Further investigation is necessary to determine whether these food dyes could interact with other drug transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphatases; Biological Transport; Drug Interactions; Food Coloring Agents; Food-Drug Interactions; Humans; Verapamil
PubMed: 33011351
DOI: 10.1016/j.fct.2020.111785