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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 -
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 -
Journal of Veterinary Science Sep 2021Hepatocellular carcinoma is the most common primary hepatic malignancy in humans and dogs. Several differentially expressed molecules have been studied and reported in...
BACKGROUND
Hepatocellular carcinoma is the most common primary hepatic malignancy in humans and dogs. Several differentially expressed molecules have been studied and reported in human hepatocellular carcinoma and non-neoplastic liver lesions. However, studies on the features of canine hepatocellular carcinoma are limited, especially related to the differential characteristics of neoplastic and non-neoplastic lesions.
OBJECTIVES
The study's objective was 1) to examine and evaluate the expression of arginase-1, P-glycoprotein, and cytokeratin 19 in canine liver tissues and 2) to investigate the differential features of hepatocellular carcinomas, liver tissue with non-neoplastic lesions, and paracancerous liver tissues in dogs.
METHODS
The expression levels of three markers underwent immunohistochemical analysis in 40 non-neoplastic liver tissues, 32 hepatocellular carcinoma tissues, and 11 paracancerous liver tissues. Scoring of each marker was performed semi-quantitatively.
RESULTS
Arginase-1 and P-glycoprotein were significantly downregulated in hepatocellular carcinoma, compared with hepatic tissues with non-neoplastic diseases ( < 0.001). Expression levels of arginase-1 and P-glycoprotein were also significantly lower in hepatocellular carcinoma than in paracancerous liver tissues (arginase-1, 0.0195; P-glycoprotein, 0.047). Few cytokeratin 19-positive hepatocytes were detected and only in one hepatocellular carcinoma and one cirrhotic liver sample.
CONCLUSIONS
The results of this study suggest that downregulation of arginase-1 and P-glycoprotein is a feature of canine hepatocellular carcinoma; thus, those markers are potential candidates for use in differentiating hepatocellular carcinomas from non-neoplastic liver lesions in dogs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Arginase; Carcinoma, Hepatocellular; Dog Diseases; Dogs; Down-Regulation
PubMed: 34423599
DOI: 10.4142/jvs.2021.22.e61 -
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 -
Molecules (Basel, Switzerland) Feb 2018Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)-a drug efflux pump (ABCB1... (Review)
Review
Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)-a drug efflux pump (ABCB1 member of the ABC transporter gene family)-is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein -glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR). UPR is responsible for modification of protein folding pathways, removal of misfolded proteins by ER associated protein degradation (ERAD) and inhibition of proteosynthesis. However, sustained ERS may result in UPR-mediated cell death. Neoplastic cells could escape from the death pathway induced by ERS by switching UPR into pro survival mechanisms instead of apoptosis. Here, we aimed to present state of the art information about consequences of P-gp expression on mechanisms associated with ERS development and regulation of the ERAD system, particularly focused on advances in ERS-associated therapy of drug resistant malignancies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Multiple; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; Glycosylation; Humans; Neoplasms; Signal Transduction; Unfolded Protein Response
PubMed: 29415493
DOI: 10.3390/molecules23020337 -
Journal of the American College of... Jun 2013Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule,... (Review)
Review
Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule, serving a protective function for the body against foreign substances. Intestinal absorption, biliary excretion, and urinary excretion of P-gp substrates can therefore be altered by either the inhibition or induction of P-gp. A wide spectrum of drugs, such as anticancer agents and steroids, are known P-gp substrates and/or inhibitors, and many cardiovascular drugs have recently been observed to have clinically relevant interactions as well. We review the interactions among commonly prescribed cardiovascular drugs that are P-gp substrates and observe interactions involving P-gp that may be relevant to clinical practice. Cardiovascular drugs with narrow therapeutic indexes (e.g., antiarrhythmic agents, anticoagulant agents) have demonstrated large increases in concentrations when coadministered with potent P-gp inhibitors, thus increasing the risk for drug toxicity. Therefore, dose adjustment or use of alternative agents should be considered when strong P-gp-mediated drug-drug interactions are present. Finally, interactions between novel drugs and known P-gp inhibitors are now being systematically evaluated during drug development, and recommended guidelines for the administration of P-gp substrate drugs will be expanded.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Protein Structure, Tertiary; Protein Transport
PubMed: 23563132
DOI: 10.1016/j.jacc.2013.02.058 -
Journal of Veterinary Internal Medicine Jan 2015Drug-drug interactions can cause unanticipated patient morbidity and mortality. The consequences of drug-drug interactions can be especially severe when anticancer drugs... (Review)
Review
Drug-drug interactions can cause unanticipated patient morbidity and mortality. The consequences of drug-drug interactions can be especially severe when anticancer drugs are involved because of their narrow therapeutic index. Veterinary clinicians have traditionally been taught that drug-drug interactions result from alterations in drug metabolism, renal excretion or protein binding. More recently, drug-drug interactions resulting from inhibition of P-glycoprotein-mediated drug transport have been identified in both human and veterinary patients. Many drugs commonly used in veterinary patients are capable of inhibiting P-glycoprotein function and thereby causing an interaction that results in severe chemotherapeutic drug toxicity. The intent of this review is to describe the mechanism and clinical implications of drug-drug interactions involving P-glycoprotein and anticancer drugs. Equipped with this information, veterinarians can prevent serious drug-drug interactions by selecting alternate drugs or adjusting the dose of interacting drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Drug Interactions; Humans; Neoplasms
PubMed: 25619511
DOI: 10.1111/jvim.12525 -
Proceedings. Biological Sciences May 2022Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach...
Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach their targets. Specifically, the role of ABC transporters in pesticide absorption and excretion is poorly understood, especially compared to the detailed knowledge about mammalian systems. Here, we present a comprehensive characterization of pesticide transporters in the model insect . An RNAi screen was performed, which knocked down individual ABCs in specific epithelial tissues and examined the subsequent changes in sensitivity to the pesticides spinosad and fipronil. This implicated a novel ABC drug transporter, in spinosad transport, but also highlighted the P-glycoprotein orthologue as the most impactful ABC in terms of chemoprotection. Further characterization of the P-glycoprotein family was performed via transgenic overexpression and immunolocalization, finding that and play enigmatic roles in pesticide toxicology perhaps determined by their different subcellular localizations within the midgut. Lastly, transgenic lines expressing P-glycoprotein from the major malaria vector were used to establish a system for characterization of this transporter in non-model insects. This study provides the basis for establishing as a model for toxicology research on drug transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Animals; Animals, Genetically Modified; Anopheles; Drosophila melanogaster; Insecticide Resistance; Insecticides; Malaria; Mammals; Mosquito Vectors; Pesticides
PubMed: 35582794
DOI: 10.1098/rspb.2022.0625 -
The International Journal of... Mar 2012Overexpression of P-glycoprotein (P-gp) is a major cause of multidrug resistance in cancer. P-gp is mainly localized in the plasma membrane and can efflux structurally... (Review)
Review
Overexpression of P-glycoprotein (P-gp) is a major cause of multidrug resistance in cancer. P-gp is mainly localized in the plasma membrane and can efflux structurally and chemically unrelated substrates, including anticancer drugs. P-gp is also localized in intracellular compartments, such as endoplasmic reticulum (ER), Golgi, endosomes and lysosomes, and cycles between endosomal compartments and the plasma membrane in a microtubular-actin dependent manner. Intracellular trafficking pathways for P-gp and participation of different Rab proteins depend on cellular polarization and choice of primary culture, cell line or neoplasm. Interruption of P-gp trafficking to the plasma membrane increases intracellular P-gp accumulation and anticancer drug levels, suggesting a potential approach to overcome P-gp-mediated multidrug resistance in cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Golgi Apparatus; Humans; Lysosomes; Protein Transport
PubMed: 22212176
DOI: 10.1016/j.biocel.2011.12.009 -
Molecules (Basel, Switzerland) May 2019P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with...
P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by eliminating compounds from cells, thereby preventing intracellular accumulation. Therefore, in the drug discovery and toxicological assessment process it is advisable to pay attention to whether a compound under development could be transported by P-gp or not. In this study, an in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp was developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds). The model provided a good classification performance, producing non error rate (NER) values of 0.93 for the training set and 0.85 for the test set, while the average precision (AvPr) was 0.93 for the training set and 0.87 for the test set. An external validation set of 385 compounds was used to challenge the model's performance. On the external validation set the NER and AvPr values were 0.70 for both indices. We believe that this in silico classifier could be effectively used as a reliable virtual screening tool for identifying potential P-gp ligands.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Discovery; Humans; Mice; Models, Molecular; Models, Theoretical; Neural Networks, Computer
PubMed: 31130601
DOI: 10.3390/molecules24102006