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1
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Suominen L, Rashidpour H, Sjöstedt N, Kidron H. In vitro identification of decreased function genetic variants of ABCB1. Eur J Pharm Sci 2025; 209:107078. [PMID: 40113104 DOI: 10.1016/j.ejps.2025.107078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/21/2025] [Accepted: 03/18/2025] [Indexed: 03/22/2025]
Abstract
The efflux transporter ABCB1 (P-glycoprotein, P-gp) has an important role in drug disposition, and thus, genetic variants that lead to decreased transport function might increase drug exposure. Complete loss of function of ABCB1 is rare but a few nonfunctional variants have been found. We studied the transport activity of the common S893A/T (c.2677T>G/A) variants and a set of 14 other naturally occurring non-synonymous single nucleotide variants to find new decreased function variants. The reference ABCB1 (c.1236T, c.2677T, c.3435T haplotype) and variants (N21D, H61Y, Y116C, N183S, I261V, L305P, R580P, C717Y, S795C, I836V, Y853N, S893A, S893T, V907F, Y928S, and A980P) were expressed in Sf9 cells. These cells were then used to prepare membrane vesicles, which were used to study N-methyl-quinidine (NMQ) and aliskiren transport. Aliskiren kinetics were characterised, as it has not previously been used in vesicle transport assays. Compared to the reference, C717Y caused a complete loss of NMQ and aliskiren transport, and L305P and V907F decreased transport to <25 % of the reference. In addition, R580P and A980P decreased the transport of both substrates to ≤50 %, while S795C affected only NMQ transport. Based on our results, carriers of the C717Y, L305P, or V907F variants may experience altered distribution and exposure of ABCB1 substrate drugs.
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Affiliation(s)
- Laura Suominen
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Hatam Rashidpour
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Noora Sjöstedt
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
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2
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Tia ST, Luo M, Fan W. Mapping the Role of P-gp in Multidrug Resistance: Insights from Recent Structural Studies. Int J Mol Sci 2025; 26:4179. [PMID: 40362415 PMCID: PMC12072085 DOI: 10.3390/ijms26094179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/22/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
P-glycoprotein (P-gp/ABCB1), a key ATP-binding cassette (ABC) transporter, plays a central role in multidrug resistance (MDR), one of the leading causes of chemotherapy failure in cancer treatment. P-gp actively pumps chemotherapeutic agents out of cancer cells, reducing intracellular drug concentration and compromising therapeutic efficacy. Recent advancements in structural biology, particularly cryogenic electron microscopy (cryo-EM), have revealed detailed conformational states of P-gp, providing unprecedented insights into its transport mechanisms. In parallel, studies have identified various P-gp mutants in cancer patients, many of which are linked to altered drug efflux activity and resistance phenotypes. This review systematically examines recent structural studies of P-gp, correlates known patient-derived mutations to their functional consequences, and explores their impact on MDR. We propose plausible mechanisms by which these mutations affect P-gp's activity based on structural evidence and discuss their implications for chemotherapy resistance. Additionally, we review current approaches for P-gp inhibition, a critical strategy to restore drug sensitivity in resistant cancers, and outline future research directions to combat P-gp-mediated MDR.
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MESH Headings
- Humans
- Drug Resistance, Multiple/genetics
- Drug Resistance, Neoplasm/genetics
- Mutation
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Neoplasms/drug therapy
- Neoplasms/genetics
- Neoplasms/metabolism
- Animals
- Antineoplastic Agents/pharmacology
- Protein Conformation
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/chemistry
- ATP Binding Cassette Transporter, Subfamily B/metabolism
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Affiliation(s)
- Shi Ting Tia
- Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore;
| | - Min Luo
- Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore;
- Center for Bioimaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
| | - Wenjie Fan
- Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore;
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3
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Shchulkin AV, Abalenikhina YV, Kosmachevskaya OV, Topunov AF, Yakusheva EN. Regulation of P-Glycoprotein during Oxidative Stress. Antioxidants (Basel) 2024; 13:215. [PMID: 38397813 PMCID: PMC10885963 DOI: 10.3390/antiox13020215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/02/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
P-glycoprotein (Pgp, ABCB1, MDR1) is an efflux transporter protein that removes molecules from the cells (outflow) into the extracellular space. Pgp plays an important role in pharmacokinetics, ensuring the absorption, distribution, and excretion of drugs and its substrates, as well as in the transport of endogenous molecules (steroid and thyroid hormones). It also contributes to tumor cell resistance to chemotherapy. In this review, we summarize the mechanisms of Pgp regulation during oxidative stress. The currently available data suggest that Pgp has a complex variety of regulatory mechanisms under oxidative stress, involving many transcription factors, the main ones being Nrf2 and Nf-kB. These factors often overlap, and some can be activated under certain conditions, such as the deposition of oxidation products, depending on the severity of oxidative stress. In most cases, the expression of Pgp increases due to increased transcription and translation, but under severe oxidative stress, it can also decrease due to the oxidation of amino acids in its molecule. At the same time, Pgp acts as a protector against oxidative stress, eliminating the causative factors and removing its by-products, as well as participating in signaling pathways.
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Affiliation(s)
- Aleksey V. Shchulkin
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
| | - Yulia V. Abalenikhina
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
| | - Olga V. Kosmachevskaya
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (A.F.T.)
| | - Alexey F. Topunov
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (A.F.T.)
| | - Elena N. Yakusheva
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
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4
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Sito H, Tan SC. Genetic polymorphisms as potential pharmacogenetic biomarkers for platinum-based chemotherapy in non-small cell lung cancer. Mol Biol Rep 2024; 51:102. [PMID: 38217759 DOI: 10.1007/s11033-023-08915-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/08/2023] [Indexed: 01/15/2024]
Abstract
Platinum-based chemotherapy (PBC) is a widely used treatment for various solid tumors, including non-small cell lung cancer (NSCLC). However, its efficacy is often compromised by the emergence of drug resistance in patients. There is growing evidence that genetic variations may influence the susceptibility of NSCLC patients to develop resistance to PBC. Here, we provide a comprehensive overview of the mechanisms underlying platinum drug resistance and highlight the important role that genetic polymorphisms play in this process. This paper discussed the genetic variants that regulate DNA repair, cellular movement, drug transport, metabolic processing, and immune response, with a focus on their effects on response to PBC. The potential applications of these genetic polymorphisms as predictive indicators in clinical practice are explored, as are the challenges associated with their implementation.
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Affiliation(s)
- Hilary Sito
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
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5
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Polano M, Bedon L, Dal Bo M, Sorio R, Bartoletti M, De Mattia E, Cecchin E, Pisano C, Lorusso D, Lissoni AA, De Censi A, Cecere SC, Scollo P, Marchini S, Arenare L, De Giorgi U, Califano D, Biagioli E, Chiodini P, Perrone F, Pignata S, Toffoli G. Machine Learning Application Identifies Germline Markers of Hypertension in Patients With Ovarian Cancer Treated With Carboplatin, Taxane, and Bevacizumab. Clin Pharmacol Ther 2023; 114:652-663. [PMID: 37243926 DOI: 10.1002/cpt.2960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/22/2023] [Indexed: 05/29/2023]
Abstract
Pharmacogenomics studies how genes influence a person's response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential - namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-induced, taxane-induced, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single-nucleotide variation (SNV, formerly SNP) profiles were examined using ML to find and prioritize those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, nonhematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNVs in predicting toxicities. Important SNVs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNVs critical for predicting toxicity were identified. For each toxicity, key SNVs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28-fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for patients with ovarian cancer, which may be useful for reducing toxicities and improving toxicity management.
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Affiliation(s)
- Maurizio Polano
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Luca Bedon
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Roberto Sorio
- Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Michele Bartoletti
- Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Elena De Mattia
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Erika Cecchin
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Carmela Pisano
- Uro-Gynecologic Oncology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy
| | - Domenica Lorusso
- Department of Women and Child Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
- Department of Life Science and Public Health, Catholic University of Sacred Heart Largo Agostino Gemelli, Rome, Italy
| | - Andrea Alberto Lissoni
- Clinica Ostetrica e Ginecologica, Istituto di Ricovero e Cura a Carattere Scientifico S. Gerardo Monza, Università di Milano Bicocca, Milano, Italy
| | | | - Sabrina Chiara Cecere
- Uro-Gynecologic Oncology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy
| | - Paolo Scollo
- Unità Operativa Ostetricia e Ginecologia, Dipartimento Materno-Infantile, Ospedale Cannizzaro, Catania, Italy
| | - Sergio Marchini
- Molecular Pharmacology laboratory, Group of Cancer Pharmacology Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Italy
| | - Laura Arenare
- Clinical Trial Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione G. Pascale, Naples, Italy
| | - Ugo De Giorgi
- Istituto di Ricovero e Cura a Carattere Scientifico Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy
| | - Daniela Califano
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Elena Biagioli
- Department Of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milano, Milano, Italy
| | - Paolo Chiodini
- Department of Mental Health and Public Medicine, Section of Statistics, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Francesco Perrone
- Clinical Trial Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione G. Pascale, Naples, Italy
| | - Sandro Pignata
- Uro-Gynecologic Oncology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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6
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Özvegy-Laczka C, Ungvári O, Bakos É. Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochem Pharmacol 2023; 209:115448. [PMID: 36758706 DOI: 10.1016/j.bcp.2023.115448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
In humans, approximately 70% of drugs are eliminated through the liver. This process is governed by the concerted action of membrane transporters and metabolic enzymes. Transporters mediating hepatocellular uptake of drugs belong to the SLC (Solute carrier) superfamily of transporters. Drug efflux either toward the portal vein or into the bile is mainly mediated by active transporters of the ABC (ATP Binding Cassette) family. Alteration in the function and/or expression of liver transporters due to mutations, disease conditions, or co-administration of drugs or food components can result in altered pharmacokinetics. On the other hand, drugs or food components interacting with liver transporters may also interfere with liver function (e.g., bile acid homeostasis) and may even cause liver toxicity. Accordingly, certain transporters of the liver should be investigated already at an early stage of drug development. Most frequently radioactive probes are applied in these drug-transporter interaction tests. However, fluorescent probes are cost-effective and sensitive alternatives to radioligands, and are gaining wider application in drug-transporter interaction tests. In our review, we summarize our current understanding about hepatocyte ABC and SLC transporters affected by drug interactions. We provide an update of the available fluorescent and fluorogenic/activable probes applicable in in vitro or in vivo testing of these ABC and SLC transporters, including near-infrared transporter probes especially suitable for in vivo imaging. Furthermore, our review gives a comprehensive overview of the available fluorescence-based methods, not directly relying on the transport of the probe, suitable for the investigation of hepatic ABC or SLC-type drug transporters.
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Affiliation(s)
- Csilla Özvegy-Laczka
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
| | - Orsolya Ungvári
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
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7
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Xiao Q, Zhou Y, Lauschke VM. Ethnogeographic and inter-individual variability of human ABC transporters. Hum Genet 2020; 139:623-646. [PMID: 32206879 PMCID: PMC7170817 DOI: 10.1007/s00439-020-02150-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 03/16/2020] [Indexed: 12/19/2022]
Abstract
ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health.
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Affiliation(s)
- Qingyang Xiao
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden
| | - Yitian Zhou
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden
| | - Volker M Lauschke
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden.
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8
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Yap C, Short JL, Nicolazzo JA. A Combination of Clioquinol, Zinc and Copper Increases the Abundance and Function of Breast Cancer Resistance Protein in Human Brain Microvascular Endothelial Cells. J Pharm Sci 2020; 110:338-346. [PMID: 32339529 DOI: 10.1016/j.xphs.2020.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/17/2020] [Accepted: 04/17/2020] [Indexed: 10/24/2022]
Abstract
Modulating the abundance of the blood-brain barrier (BBB) efflux transporter breast cancer resistance protein (BCRP) has the potential to impact brain levels of drugs and endogenous substrates. Studies have demonstrated that the metal ionophore clioquinol (CQ) increases BBB abundance of P-glycoprotein (P-gp), an effect associated with increased endothelial cell levels of Cu2+. This study therefore assessed whether human brain endothelial (hCMEC/D3) cell abundance and function of BCRP is modulated by CQ. hCMEC/D3 cells were treated with CQ, Zn2+ and Cu2+ (CZC) (0.5 μM, 0.5 μM, 0.1 μM, respectively) for 24 h and BCRP mRNA and protein abundance was determined by Western blot and qPCR, respectively. After a series of optimisation studies assessing specificity of bodipy prazosin (BP) and Ko143 as a substrate and inhibitor of BCRP, respectively, the impact of CZC on BP uptake was assessed. While CZC did not increase mRNA expression of BCRP, BCRP abundance was increased 1.8 ± 0.1-fold; this was associated with a 68.1 ± 3.3% reduction in accumulation of BP in hCMEC/D3 cells. This is the first study to demonstrate that augmenting metal ion availability enhances protein abundance and function of BCRP at the BBB, which may be exploited to modulate CNS access of therapeutics and endogenous substrates.
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Affiliation(s)
- Chris Yap
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Jennifer L Short
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Joseph A Nicolazzo
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
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9
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Saiz-Rodríguez M, Belmonte C, Román M, Ochoa D, Jiang-Zheng C, Koller D, Mejía G, Zubiaur P, Wojnicz A, Abad-Santos F. Effect of ABCB1 C3435T Polymorphism on Pharmacokinetics of Antipsychotics and Antidepressants. Basic Clin Pharmacol Toxicol 2018; 123:474-485. [PMID: 29723928 DOI: 10.1111/bcpt.13031] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 04/18/2018] [Indexed: 12/15/2022]
Abstract
P-glycoprotein, encoded by ABCB1, is an ATP-dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P-glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real-time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T1/2 of 9-OH-risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro-aripiprazole and trazodone area under the concentration-time curve, along with lower half-life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro-aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P-glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants.
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Affiliation(s)
- Miriam Saiz-Rodríguez
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain
| | - Carmen Belmonte
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.,UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain
| | - Manuel Román
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.,UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain
| | - Dolores Ochoa
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.,UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain
| | - Carolina Jiang-Zheng
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain
| | - Dora Koller
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain
| | - Gina Mejía
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.,UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain
| | - Pablo Zubiaur
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain
| | - Aneta Wojnicz
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain
| | - Francisco Abad-Santos
- Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.,UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain.,Center for Biomedical Research Network Hepatic and Liver diseases (CIBERedh) - Instituto de Salud Carlos III, Madrid, Spain
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10
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Hu R, Barratt DT, Coller JK, Sallustio BC, Somogyi AA. CYP3A5*3
and ABCB1
61A>G Significantly Influence Dose-adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post-Kidney Transplantation. Basic Clin Pharmacol Toxicol 2018; 123:320-326. [DOI: 10.1111/bcpt.13016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Rong Hu
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
| | - Daniel T. Barratt
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
| | - Janet K. Coller
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
| | - Benedetta C. Sallustio
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
- Department of Pharmacology; Queen Elizabeth Hospital; Adelaide SA Australia
| | - Andrew A. Somogyi
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
- Department of Clinical Pharmacology; Royal Adelaide Hospital; Adelaide SA Australia
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11
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Mijac D, Vukovic-Petrovic I, Mijac V, Perovic V, Milic N, Djuranovic S, Bojic D, Popovic D, Culafic D, Krstic M, Jankovic G, Pravica V, Markovic M. MDR1 gene polymorphisms are associated with ulcerative colitis in a cohort of Serbian patients with inflammatory bowel disease. PLoS One 2018; 13:e0194536. [PMID: 29543864 PMCID: PMC5854418 DOI: 10.1371/journal.pone.0194536] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 03/05/2018] [Indexed: 12/12/2022] Open
Abstract
Background Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology in which genetic factors contribute to development of disease. Single nucleotide polymorphisms (SNPs) in multidrug resistance 1 (MDR1) gene encoding transporter P-glycoprotein have been associated with IBD, but their role in disease susceptibility remains unclear. Therefore, the aim of this study was to investigate the association of three MDR1 polymorphisms, C1236T (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642), with Serbian IBD patients. Methods A total of 206 IBD patients, 107 Crohn's disease (CD) and 99 ulcerative colitis (UC), and 255 healthy controls were included in the study. All subjects were genotyped using TaqMan SNP genotyping assays. Comparisons between the groups were performed using the Pearson Chi-square test. False discovery rate according to Benjamini-Hochberg procedure was applied to adjust for multiple comparisons. Results Carriers of T allele of all three MDR1 SNPs were more common in UC patients compared to healthy controls, suggesting predisposing role of T allele of these SNPs in UC pathogenesis. Consistently, TT genotype of C1236T and TTT haplotype were also found more frequently in UC patients. On the other hand, C allele and CC genotype of C1236T and C3435T, as well as G allele and GG genotype of G2677T/A were more frequent in healthy subjects, implying protective role of these variants in UC. Likewise, CGC haplotype and CGC/CGC diplotype were more frequent in controls. Contrary to UC, no statistical difference was observed between CD patients and controls in any of the SNPs analyzed. Conclusion MDR1 gene variants and haplotypes were associated with UC in Serbian IBD patients, further supporting their potential role in susceptibility to UC.
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Affiliation(s)
- Dragana Mijac
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
- * E-mail:
| | - Irena Vukovic-Petrovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vera Mijac
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladimir Perovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Natasa Milic
- Department for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Srdjan Djuranovic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Daniela Bojic
- Department of Gastroenterology, University Hospital Zvezdara, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragan Popovic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Djordje Culafic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Miodrag Krstic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Goran Jankovic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Vera Pravica
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milos Markovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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12
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Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma. Oncotarget 2018; 8:9388-9398. [PMID: 27566582 PMCID: PMC5354739 DOI: 10.18632/oncotarget.11543] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 08/09/2016] [Indexed: 01/08/2023] Open
Abstract
Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.
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Ben Cheikh Y, Xuereb B, Boulangé-Lecomte C, Le Foll F. Multixenobiotic resistance in Mytilus edulis: Molecular and functional characterization of an ABCG2- type transporter in hemocytes and gills. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2018; 195:88-96. [PMID: 29304406 DOI: 10.1016/j.aquatox.2017.12.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/12/2017] [Accepted: 12/24/2017] [Indexed: 06/07/2023]
Abstract
Among the cellular protection arsenal, ABC transporters play an important role in xenobiotic efflux in marine organisms. Two pumps belonging to B and C subfamily has been identified in Mytilus edulis. In this study, we investigated the presence of the third major subtype ABCG2/BCRP protein in mussel tissues. Transcript was expressed in hemocytes and with higher level in gills. Molecular characterization revealed that mussel ABCG2 transporter shares the sequence and organizational structure with mammalian and molluscan orthologs. Overall identity of the predicted amino acid sequence with corresponding homologs from other organisms was between 49% and 98%. Moreover, protein efflux activity was demonstrated using a combination of fluorescent allocrites and specific inhibitors. The accumulation of bodipy prazosin and pheophorbide A was heterogeneous in gills and hemocytes. Most of the used blockers enhanced probe accumulation at different levels, most significantly for bodipy prazosin. Moreover, Mrp classical blocker MK571 showed a polyspecificity. In conclusion, our data demonstrate that several ABC transporters contribute to MXR phenotype in the blue mussel including ABCG2 that forms an active pump in hemocytes and gills. Efforts are needed to distinguish between the different members and to explore their single function and specificity towards allocrites and chemosensitizers.
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Affiliation(s)
- Yosra Ben Cheikh
- University of Le Havre Normandy, Environmental Stress and Aquatic Biomonitoring, UMR-I 02 SEBIO, 25 rue Philippe Lebon, F-76063, Le Havre, France.
| | - Benoit Xuereb
- University of Le Havre Normandy, Environmental Stress and Aquatic Biomonitoring, UMR-I 02 SEBIO, 25 rue Philippe Lebon, F-76063, Le Havre, France
| | - Céline Boulangé-Lecomte
- University of Le Havre Normandy, Environmental Stress and Aquatic Biomonitoring, UMR-I 02 SEBIO, 25 rue Philippe Lebon, F-76063, Le Havre, France
| | - Frank Le Foll
- University of Le Havre Normandy, Environmental Stress and Aquatic Biomonitoring, UMR-I 02 SEBIO, 25 rue Philippe Lebon, F-76063, Le Havre, France
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Zhai Y, He H, Ma X, Xie J, Meng T, Dong Y, Lu J. Meta-analysis of effects of ABCB1 polymorphisms on clopidogrel response among patients with coronary artery disease. Eur J Clin Pharmacol 2017; 73:843-854. [PMID: 28378058 DOI: 10.1007/s00228-017-2235-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 03/07/2017] [Indexed: 11/30/2022]
Abstract
PURPOSE The substantial variability in the antiplatelet efficacy of clopidogrel has raised major concerns. Molecular epidemiological research suggests that ABCB1 C3435T polymorphism may be associated with clopidogrel response, but results remain controversial. To derive a more precise evaluation of the associations between ABCB1 C3435T polymorphism and the clinical efficacy of clopidogrel, we have conducted a PRISMA-compliant meta-analysis. METHODS The PubMed and EMBASE databases were searched for eligible studies up to 25 October 2016. The odds ratio (OR), the standard mean difference (SMD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS Overall, 28 related studies involving 23,243 patients were analyzed. No association was found between the ABCB1 polymorphisms and the primary outcome. In the subgroup analysis, the C3435T mutation significantly reduced platelet activity as tested by the LTA assay in the dominant (SMD -0.140, 95% CI -0.272 to -0.009, P = 0.036) and heterozygous (SMD -0.154, 95% CI -0.290 to -0.017, P = 0.027) models, but the result lacked robustness in the sensitivity analysis. A significant association between the C3435T polymorphism and bleeding risk was also observed with low heterogeneity in the dominant (OR 1.805, 95% CI1.124-2.900, P =0.015, I 2 = 0%), homozygous (OR 1.952, 95% CI 1.055-3.611, P = 0.033, I 2 = 13.2%) and heterozygous (OR 1.793, 95% CI 1.091-2.946, P = 0.021, I 2 = 0%) models in Asian patients. CONCLUSIONS The results of the meta-analysis suggest that ABCB1 C3435T polymorphism may increase the risk of bleeding in Asian patients treated with clopidogrel. The implied relationship needs to be verified in future basic genetic pharmacology studies.
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Affiliation(s)
- Yajing Zhai
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Hairong He
- Clinical Research Center, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Xiancang Ma
- Clinical Research Center, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Jiao Xie
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Ti Meng
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yalin Dong
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.
| | - Jun Lu
- Clinical Research Center, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.
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15
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Serra M, Hattinger CM. Polymorphisms of genes related to metotrexate response and toxicity in high-grade osteosarcoma. Expert Opin Drug Metab Toxicol 2016; 13:123. [DOI: 10.1080/17425255.2017.1260300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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16
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Ruiz J, Herrero MJ, Bosó V, Megías JE, Hervás D, Poveda JL, Escrivá J, Pastor A, Solé A, Aliño SF. Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation. Int J Mol Sci 2015; 16:20168-82. [PMID: 26307985 PMCID: PMC4613195 DOI: 10.3390/ijms160920168] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/13/2015] [Accepted: 08/13/2015] [Indexed: 01/08/2023] Open
Abstract
Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation.
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Affiliation(s)
- Jesus Ruiz
- Unidad de Farmacogenética, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
- Servicio de Farmacia, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - María José Herrero
- Unidad de Farmacogenética, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
- Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.
| | - Virginia Bosó
- Unidad de Farmacogenética, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
- Servicio de Farmacia, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - Juan Eduardo Megías
- Unidad de Farmacogenética, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
- Servicio de Farmacia, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - David Hervás
- Unidad de Bioestadística, Instituto Investigación Sanitaria La Fe. Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - Jose Luis Poveda
- Servicio de Farmacia, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - Juan Escrivá
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - Amparo Pastor
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - Amparo Solé
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
| | - Salvador Francisco Aliño
- Unidad de Farmacogenética, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
- Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.
- Unidad de Farmacología Clínica, Área Clínica del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell 106, 46010 Valencia, Spain.
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17
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Sánchez-Lázaro I, Herrero MJ, Jordán-De Luna C, Bosó V, Almenar L, Rojas L, Martínez-Dolz L, Megías-Vericat JE, Sendra L, Miguel A, Poveda JL, Aliño SF. Association of SNPs with the efficacy and safety of immunosuppressant therapy after heart transplantation. Pharmacogenomics 2015; 16:971-9. [DOI: 10.2217/pgs.15.39] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Studying the possible influence of SNPs on efficacy and safety of calcineurin inhibitors upon heart transplantation. Materials & methods: In 60 heart transplant patients treated with tacrolimus or cyclosporine, we studied a panel of 36 SNPs correlated with a series of clinical parameters during the first post-transplantation year. Results: The presence of serious infections was correlated to ABCB1 rs1128503 (p = 0.012), CC genotype reduced the probability of infections being also associated with lower blood cyclosporine concentrations. Lower renal function levels were found in patients with rs9282564 AG (p = 0.003), related to higher blood cyclosporine blood levels. A tendency toward increased graft rejection (p = 0.05) was correlated to rs2066844 CC in NOD2/CARD15, a gene related to lymphocyte activation. Conclusion: Pharmacogenetics can help identify patients at increased risk of clinical complications. Original submitted 30 January 2015; revision submitted 27 March 2015
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Affiliation(s)
- Ignacio Sánchez-Lázaro
- Unidad de Insuficiencia Cardiaca y Transplante, Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - María José Herrero
- Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe & Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
- Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
| | - Consuelo Jordán-De Luna
- Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe & Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
- Servicio de Farmacia, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - Virginia Bosó
- Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe & Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
- Servicio de Farmacia, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - Luis Almenar
- Unidad de Insuficiencia Cardiaca y Transplante, Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - Luis Rojas
- Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe & Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
- Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O Higgins 340, Santiago, Chile
| | - Luis Martínez-Dolz
- Unidad de Insuficiencia Cardiaca y Transplante, Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - Juan E Megías-Vericat
- Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe & Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
- Servicio de Farmacia, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - Luis Sendra
- Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
| | - Antonio Miguel
- Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
| | - José L Poveda
- Servicio de Farmacia, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
| | - Salvador F Aliño
- Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe & Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
- Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
- Unidad de Farmacología Clínica, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
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Gökirmak T, Shipp LE, Campanale JP, Nicklisch SCT, Hamdoun A. Transport in technicolor: mapping ATP-binding cassette transporters in sea urchin embryos. Mol Reprod Dev 2014; 81:778-93. [PMID: 25156004 DOI: 10.1002/mrd.22357] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 06/27/2014] [Indexed: 12/15/2022]
Abstract
One quarter of eukaryotic genes encode membrane proteins. These include nearly 1,000 transporters that translocate nutrients, signaling molecules, and xenobiotics across membranes. While it is well appreciated that membrane transport is critical for development, the specific roles of many transporters have remained cryptic, in part because of their abundance and the diversity of their substrates. Multidrug resistance ATP-binding cassette (ABC) efflux transporters are one example of cryptic membrane proteins. Although most organisms utilize these ABC transporters during embryonic development, many of these transporters have broad substrate specificity, and their developmental functions remain incompletely understood. Here, we review advances in our understanding of ABC transporters in sea urchin embryos, and methods developed to spatially and temporally map these proteins. These studies reveal that multifunctional transporters are required for signaling, homeostasis, and protection of the embryo, and shed light on how they are integrated into ancestral developmental pathways recapitulated in disease.
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Affiliation(s)
- Tufan Gökirmak
- Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California
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19
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Somogyi AA, Barratt DT, Ali RL, Coller JK. Pharmacogenomics of methadone maintenance treatment. Pharmacogenomics 2014; 15:1007-27. [DOI: 10.2217/pgs.14.56] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Methadone is the major opioid substitution therapy for opioid dependence. Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines. Nevertheless many genetic factors have been investigated including those affecting its metabolism (CYP2B6-consistent results), efflux transport (P-gp-inconsistent results), target μ-opioid receptor (μ-opioid receptor-inconsistent results) and a host of other receptors (DRD2) and signaling elements (GIRK2 and ARRB2; not replicated). None by themselves have been able to substantially explain dosage variation (the major but not sole end point). When multiple genes have been combined such as ABCB1, CYP2B6, OPRM1 and DRD2 a greater contribution to dosage variation was found but not as yet replicated. As stabilization of dosage needs to be made rapidly, it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed, which may or may not tailor to different ethnic groups and each country’s policy towards an outcome that benefits all.
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Affiliation(s)
- Andrew A Somogyi
- Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia
- Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, 5005, Australia
| | - Daniel T Barratt
- Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia
| | - Robert L Ali
- Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia
- DASSA World Health Organization Collaborating Centre for Research in the Treatment of Drug & Alcohol Problems, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia
| | - Janet K Coller
- Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia
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20
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Keers R, Aitchison KJ. Pharmacogenetics of antidepressant response. Expert Rev Neurother 2014; 11:101-25. [DOI: 10.1586/ern.10.186] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Abstract
This chapter provides a review of the pharmacogenetics of membrane transporters, including ABC transporters and OATPs. Membrane transporters are heavily involved in drug disposition, by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have a significant effect on the absorption, distribution, metabolism, excretion, and activity of compounds. Although few drug transporter polymorphisms have transitioned from the bench to the bedside, this chapter discusses clinical development of transporter pharmacogenetic markers. Finally, development of SLCO1B1 genotyping to avoid statin induced adverse drug reactions is discussed as a model case for transporter pharmacogenetics clinical development.
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22
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Bircsak KM, Gibson CJ, Robey RW, Aleksunes LM. Assessment of drug transporter function using fluorescent cell imaging. ACTA ACUST UNITED AC 2013; 57:Unit 23.6.. [PMID: 24510579 DOI: 10.1002/0471140856.tx2306s57] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
ATP-binding cassette (ABC) proteins, including the breast cancer resistance protein (BCRP) and multidrug resistance proteins (MDRs), actively transport structurally diverse chemicals from a number of tissues and are being increasingly cited as mediators of clinically relevant drug-drug interactions. The potential outcomes of concomitantly administering two drugs that interact at the same transporter include altered disposition and toxicity and/or efficacy of one or both of the drugs. Research demonstrating the role of transporters in clinical pharmacokinetics has shed light on the need for in vitro screening methods that detect drug-transporter interactions during preclinical development. This unit describes cell-based procedures for detecting functional inhibitors of BCRP and MDR1 by measuring fluorescent substrate accumulation in suspended cells using an automated cell counter, which offers convenience, sensitivity, and speed in measuring intracellular fluorescence and identifying new inhibitors. An alternative method is provided for making similar measurements using a spectrophotometer with fluorescence detection capabilities.
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Affiliation(s)
- Kristin M Bircsak
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey
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Kim HJ, Um JY, Kim YK. Association of a multidrug resistance 1 gene polymorphism and colorectal cancer in the Korean population. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s13596-013-0136-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Skoglund K, Moreno SB, Baytar M, Jönsson JI, Gréen H. ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2013; 6:63-72. [PMID: 24019750 PMCID: PMC3760445 DOI: 10.2147/pgpm.s45522] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Single-nucleotide polymorphisms (SNPs) in the gene coding for the efflux-transport protein ABCB1 (P-glycoprotein) are commonly inherited as haplotypes. ABCB1 SNPs and haplotypes have been suggested to influence the pharmacokinetics and therapeutic outcome of the tyrosine kinase inhibitor (TKI) imatinib, used for treatment of chronic myeloid leukemia (CML). However, no consensus has yet been reached with respect to the significance of variant ABCB1 in CML treatment. Functional studies of variant ABCB1 transport of imatinib as well as other TKIs might aid the interpretation of results from in vivo association studies, but are currently lacking. The aim of this study was to investigate the consequences of ABCB1 variant haplotypes for transport and efficacy of TKIs (imatinib, its major metabolite N-desmethyl imatinib [CGP74588], dasatinib, nilotinib, and bosutinib) in CML cells. Variant haplotypes – including the 61A>G, 1199G>A, 1236C>T, 1795G>A, 2677G>T/A, and 3435T>C SNPs – were constructed in ABCB1 complementary DNA and transduced to K562 cells using retroviral gene transfer. The ability of variant cells to express ABCB1 protein and protect against TKI cytotoxicity was investigated. It was found that dasatinib and the imatinib metabolite CGP74588 are effectively transported by ABCB1, while imatinib, nilotinib, and bosutinib are comparatively weaker ABCB1 substrates. None of the investigated haplotypes altered the protective effect of ABCB1 expression against TKI cytotoxicity. These findings imply that the ABCB1 haplotypes investigated here are not likely to influence TKI pharmacokinetics or therapeutic efficacy in vivo.
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Affiliation(s)
- Karin Skoglund
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
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Jabir RS, Naidu R, Annuar MABA, Ho GF, Munisamy M, Stanslas J. Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity. Pharmacogenomics 2013; 13:1979-88. [PMID: 23215890 DOI: 10.2217/pgs.12.165] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.
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Affiliation(s)
- Rafid Salim Jabir
- Pharmacotherapeutics Unit, Department of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
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Brinar M, Cukovic-Cavka S, Bozina N, Ravic KG, Markos P, Ladic A, Cota M, Krznaric Z, Vucelic B. MDR1 polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients. BMC Gastroenterol 2013; 13:57. [PMID: 23537364 PMCID: PMC3616873 DOI: 10.1186/1471-230x-13-57] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 03/18/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic diseases of unknown etiology and pathogenesis in which genetic factors contribute to development of disease. MDR1/ABCB1 is an interesting candidate gene for IBD. The role of two single nucleotide polymorphisms, C3435T and G2677T remains unclear due to contradictory results of current studies. Thus, the aims of this research were to investigate the association of MDR1 polymorphisms, C3435T and G2677T, and IBD. METHODS A total of 310 IBD patients, 199 Crohn's disease (CD) patients and 109 ulcerative colitis (UC) patients, and 120 healthy controls were included in the study. All subjects were genotyped for G2677T/A and C3435T polymorphism using RT-PCR. In IBD patients, review of medical records was performed and patients were phenotyped according to the Montreal classification. RESULTS Significantly higher frequency of 2677T allele (p=0.05; OR 1.46, 95% CI (1.0-2.14)) and of the 3435TT genotype was observed among UC patients compared to controls (p=0.02; OR 2.12; 95% CI (1.11-4.03). Heterozygous carriers for C3435T were significantly less likely to have CD (p=0.02; OR 0.58, 95% CI (0.36-0.91)). Haplotype analysis revealed that carriers of 3435T/2677T haplotype had a significantly higher risk of having UC (p=0.02; OR 1.55; 95% CI (1.06-2.28)). CONCLUSION MDR1 polymorphisms are associated with both CD and UC with a stronger association with UC.
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Affiliation(s)
- Marko Brinar
- Division of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb, 10000, Croatia.
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Cascorbi I. P‐glycoprotein (MDR1/ABCB1). PHARMACOGENOMICS OF HUMAN DRUG TRANSPORTERS 2013:271-293. [DOI: 10.1002/9781118353240.ch12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Gökirmak T, Campanale JP, Shipp LE, Moy GW, Tao H, Hamdoun A. Localization and substrate selectivity of sea urchin multidrug (MDR) efflux transporters. J Biol Chem 2012; 287:43876-83. [PMID: 23124201 DOI: 10.1074/jbc.m112.424879] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In this study, we cloned, expressed and functionally characterized Stronglycentrotus purpuratus (Sp) ATP-binding cassette (ABC) transporters. This screen identified three multidrug resistance (MDR) transporters with functional homology to the major types of MDR transporters found in humans. When overexpressed in embryos, the apical transporters Sp-ABCB1a, ABCB4a, and ABCG2a can account for as much as 87% of the observed efflux activity, providing a robust assay for their substrate selectivity. Using this assay, we found that sea urchin MDR transporters export canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine, and mitoxantrone. In addition, we characterized the impact of nonconservative substitutions in the primary sequences of drug binding domains of sea urchin versus murine ABCB1 by mutation of Sp-ABCB1a and treatment of embryos with stereoisomeric cyclic peptide inhibitors (QZ59 compounds). The results indicated that two substitutions in transmembrane helix 6 reverse stereoselectivity of Sp-ABCB1a for QZ59 enantiomers compared with mouse ABCB1a. This suggests that subtle changes in the primary sequence of transporter drug binding domains could fine-tune substrate specificity through evolution.
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Affiliation(s)
- Tufan Gökirmak
- Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, USA
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van Assema DM, Lubberink M, Rizzu P, van Swieten JC, Schuit RC, Eriksson J, Scheltens P, Koepp M, Lammertsma AA, van Berckel BN. Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene. EJNMMI Res 2012; 2:57. [PMID: 23067778 PMCID: PMC3483228 DOI: 10.1186/2191-219x-2-57] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 10/05/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND P-glycoprotein is a blood-brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood-brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood-brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease. METHODS Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction. RESULTS In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T. CONCLUSIONS In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood-brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.
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Affiliation(s)
- Daniëlle Me van Assema
- Department of Neurology and Alzheimer Center, VU University Medical Center, P,O, Box 7057, Amsterdam, 1007 MB, The Netherlands.
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Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes. Arch Pharm Res 2011; 34:1817-28. [DOI: 10.1007/s12272-011-1104-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2011] [Revised: 08/28/2011] [Accepted: 09/05/2011] [Indexed: 01/11/2023]
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Moons T, de Roo M, Claes S, Dom G. Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics 2011; 12:1193-211. [PMID: 21843066 DOI: 10.2217/pgs.11.55] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The membrane transport protein P-glycoprotein (P-gp) is an interesting candidate for individual differences in response to antipsychotics. To present an overview of the current knowledge of P-gp and its interaction with second-generation antipsychotics (SGAs), an internet search for all relevant English original research articles concerning P-gp and SGAs was conducted. Several SGAs are substrates for P-gp in therapeutic concentrations. These include amisulpride, aripiprazole, olanzapine, perospirone, risperidone and paliperidone. Clozapine and quetiapine are not likely to be substrates of P-gp. However, most antipsychotics act as inhibitors of P-gp, and can therefore influence plasma and brain concentrations of other substrates. No information was available for sertindole, ziprasidone or zotepine. Research in animal models demonstrated significant differences in antipsychotic brain concentration and behavior owing to both P-gp knockout and inhibition. Results in patients are less clear, as several external factors have to be accounted for. Patients with polymorphisms which decrease P-gp functionality tend to perform better in clinical settings. There is some variability in the findings concerning adverse effects, and no definitive conclusions can be drawn at this point.
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Affiliation(s)
- Tim Moons
- University Psychiatric Centre, Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium.
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Jamieson D, Boddy AV. Pharmacogenetics of genes across the doxorubicin pathway. Expert Opin Drug Metab Toxicol 2011; 7:1201-10. [DOI: 10.1517/17425255.2011.610180] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Wolf SJ, Bachtiar M, Wang J, Sim TS, Chong SS, Lee CGL. An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics. THE PHARMACOGENOMICS JOURNAL 2011; 11:315-25. [PMID: 21625253 DOI: 10.1038/tpj.2011.16] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The human ABCB1 protein, (P-glycoprotein or MDR1) is a membrane-bound glycoprotein that harnesses the energy of ATP hydrolysis to drive the unidirectional transport of substrates from the cytoplasm to the extracellular space. As a large range of therapeutic agents are known substrates of ABCB1 protein, its role in the onset of multidrug resistance has been the focus of much research. This role has been of particular interest in the field of pharmacogenomics where genetic variation within the ABCB1 gene, particularly in the form of single nucleotide polymorphisms (SNPs), is believed to contribute to inter-individual variation in ABCB1 function and drug response. In this review we provide an update on the influence of coding region SNPs within the ABCB1 gene on drug pharmacokinetics. By utilizing the crystal structure of the mouse ABCB1 homolog (Abcb1a), which is 87% homologous to the human sequence, we accompany this discussion with a graphical representation of residue location for amino acids corresponding to human ABCB1 coding region SNPs. Also, an assessment of residue conservation, which is calculated following multiple sequence alignment of 11 confirmed sequences of ABCB1 homologs, is presented and discussed. Superimposing a 'heat map' of residue homology to the Abcb1a crystal structure has permitted additional insights into both the conservation of individual residues and the conservation of their immediate surroundings. Such graphical representation of residue location and conservation supplements this update of ABCB1 pharmacogenetics to help clarify the often confounding reports on the influence of ABCB1 polymorphisms on drug pharmacokinetics and response.
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Affiliation(s)
- S J Wolf
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Robey RW, Lin B, Qiu J, Chan LLY, Bates SE. Rapid detection of ABC transporter interaction: potential utility in pharmacology. J Pharmacol Toxicol Methods 2011; 63:217-22. [PMID: 21112407 PMCID: PMC3086650 DOI: 10.1016/j.vascn.2010.11.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2010] [Revised: 11/16/2010] [Accepted: 11/16/2010] [Indexed: 11/16/2022]
Abstract
INTRODUCTION The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are known to transport a wide range of structurally diverse compounds. Their high level of expression at the blood-brain, maternal-fetal, and blood-testis barriers as well as their purported roles in oral absorption suggests that ABC transporters play important pharmacologic roles. METHODS We have developed a method to characterize the function and inhibition of ABC transporters using an automated cell counter with fluorescence detection capability. The assay was performed using stably-transfected HEK293 cells expressing P-gp, MRP1, or ABCG2 and examining transport of fluorescent substrates in the presence or absence of known inhibitors and compared to results obtained with a flow cytometer. Fold increase in intracellular fluorescence was then calculated for cells incubated with fluorescent substrate in the absence of inhibitor versus in the presence of inhibitor. RESULTS Fold increase values obtained either with the cell counter or flow cytometer were comparable for cells expressing either MRP1 or ABCG2; slightly higher fold increase values were observed when cells expressing P-gp were read on a flow cytometer compared to the cell counter. DISCUSSION The assay described provides an inexpensive detection method to aid in the development of novel ABC transporter inhibitors or to characterize potential drug-drug interactions.
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Affiliation(s)
- Robert W Robey
- Medical Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
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Kim JH, Kim SR, Song IS, Shin HJ, Kim HS, Lee JH, Ko SG, Shin YC. Different Transport Activity of Human Triallelic MDR1
893Ala/Ser/Thr Variant and its Association with Herb Extracts. Phytother Res 2011; 25:1141-7. [DOI: 10.1002/ptr.3405] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 12/09/2010] [Accepted: 12/20/2010] [Indexed: 11/11/2022]
Affiliation(s)
- Jeong-Hyun Kim
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
| | - Soon Re Kim
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
| | - Im-Sook Song
- Department of Pharmacology and Pharmacogenomics Research Center; Inje University College of Medicine; Busan Republic of Korea
| | - Ho-Jung Shin
- Department of Pharmacology and Pharmacogenomics Research Center; Inje University College of Medicine; Busan Republic of Korea
| | - Han-Seop Kim
- Department of Life Science and Basic Science Institute for Cell Damage Control; Sogang University; Seoul Republic of Korea
| | - Jung-Ha Lee
- Department of Life Science and Basic Science Institute for Cell Damage Control; Sogang University; Seoul Republic of Korea
| | - Seong-Gyu Ko
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
| | - Yong-Cheol Shin
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
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Cascorbi I. P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol 2011:261-283. [PMID: 21103972 DOI: 10.1007/978-3-642-14541-4_6] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
P-glycoprotein (ABCB1, MDR1) belongs to the ABC transporter family transporting a wide range of drugs and xenobiotics from intra- to extracellular at many biological interfaces such as the intestine, liver, blood-brain barrier, and kidney. The ABCB1 gene is highly polymorphic. Starting with the observation of lower duodenal protein expression and elevated digoxin bioavailability in relation to the 3435C>T single nucleotide polymorphism, hundreds of pharmacokinetic and outcome studies have been performed, mostly genotyping 1236C>T, 2677G>T/A, and 3435C>T. Though some studies pointed out that intracellular concentrations of anticancer drugs, for example, within lymphocytes, might be affected by ABCB1 variants resulting in differential outcome, current knowledge of the functional significance genetic variants of ABC membrane transporters does not allow selection of a particular SNP to predict an individual's pharmacokinetics.
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Affiliation(s)
- Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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Cytotoxicity and topoisomerase I/II inhibition of glycosylated 2-phenyl-indoles, 2-phenyl-benzo[b]thiophenes and 2-phenyl-benzo[b]furans. Bioorg Med Chem 2011; 19:603-12. [DOI: 10.1016/j.bmc.2010.10.054] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Revised: 10/21/2010] [Accepted: 10/26/2010] [Indexed: 11/21/2022]
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Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects. Dig Dis Sci 2011; 56:115-24. [PMID: 21063774 DOI: 10.1007/s10620-010-1472-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2010] [Accepted: 10/20/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND Domperidone is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability. Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and domperidone targets. AIMS The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects. METHODS Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted. Fourteen single-nucleotide polymorphisms (SNPs) in seven candidate genes (ABCB1, CYP2D6, DRD2, KCNE1, KCNE2, KCNH2, KCNQ1) were used for genotyping. SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA1A, ADRA1B, and ADRA1D loci. RESULTS Forty-eight patients treated with domperidone participated in the study. DNA was successfully obtained from each patient. Age was associated with effectiveness of domperidone (p=0.0088). Genetic polymorphism in KCNH2 was associated with effectiveness of domperidone (p=0.041). The efficacious dose was associated with polymorphism in ABCB1 gene (p=0.0277). The side-effects of domperidone were significantly associated with the SNPs in the promoter region of ADRA1D gene. CONCLUSIONS Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene ABCB1, the potassium channel KCNH2 gene, and α1D--adrenoceptor ADRA1D gene. Age was associated with a beneficial response to domperidone. If verified in a larger population, this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects.
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Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype. THE PHARMACOGENOMICS JOURNAL 2010; 12:111-8. [PMID: 20938465 DOI: 10.1038/tpj.2010.79] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Errasti-Murugarren E, Pastor-Anglada M. Drug transporter pharmacogenetics in nucleoside-based therapies. Pharmacogenomics 2010; 11:809-41. [PMID: 20504255 DOI: 10.2217/pgs.10.70] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
This article focuses on the different types of transporter proteins that have been implicated in the influx and efflux of nucleoside-derived drugs currently used in the treatment of cancer, viral infections (i.e., AIDS) and other conditions, including autoimmune and inflammatory diseases. Genetic variations in nucleoside-derived drug transporter proteins encoded by the gene families SLC15, SLC22, SLC28, SLC29, ABCB, ABCC and ABCG will be specifically considered. Variants known to affect biological function are summarized, with a particular emphasis on those for which clinical correlations have already been established. Given that relatively little is known regarding the genetic variability of the players involved in determining nucleoside-derived drug bioavailability, it is anticipated that major challenges will be faced in this area of research.
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Affiliation(s)
- Ekaitz Errasti-Murugarren
- The Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, Diagonal 645, 08028 Barcelona, Spain
- Center for Biomedical Research Network in the Subject Area of Liver and Digestive Diseases (CIBERehd), Barcelona 08071, Spain
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Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 2010; 62:1-96. [PMID: 20103563 PMCID: PMC2835398 DOI: 10.1124/pr.109.002014] [Citation(s) in RCA: 581] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.
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Affiliation(s)
- Curtis D Klaassen
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
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Yang G, Tran H, Fan E, Shi W, Lowary TL, Xu Y. Determination of the absolute configurations of synthetic daunorubicin analogues using vibrational circular dichroism spectroscopy and density functional theory. Chirality 2010; 22:734-43. [PMID: 20143415 DOI: 10.1002/chir.20825] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The absolute configurations of three synthesized anthracycline analogues have been determined using vibrational circular dichroism (VCD) spectroscopy and the density functional theory (DFT) calculations. The experimental VCD spectra of the three compounds have been measured for the first time in the film state, prepared from their CDCl(3) solutions. Conformational searches for the monomers and some dimers of the three compounds have been performed at the DFT level using the B3LYP functional and the 6-311G** and 6-311++G** basis sets. The corresponding vibrational absorption and VCD spectra have been calculated. The good agreement between the experimental and the calculated spectra allows one to assign the absolute configurations of the three compounds with high confidence. In addition, the dominant conformers of the three compounds have also been identified.
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Affiliation(s)
- Guochun Yang
- Department of Chemistry and Alberta Ingenuity Centre for Carbohydrate Science, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
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Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD. Pharmacogenetics of membrane transporters: an update on current approaches. Mol Biotechnol 2010; 44:152-67. [PMID: 19950006 PMCID: PMC6362991 DOI: 10.1007/s12033-009-9220-6] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.
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Affiliation(s)
- Tristan M. Sissung
- Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA,
| | - Caitlin E. Baum
- Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA,
| | - C. Tyler Kirkland
- Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA,
| | - Rui Gao
- Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA,
| | - Erin R. Gardner
- Clinical Pharmacology Program, SAIC-Frederick, NCI-Frederick, Frederick, MD 21702, USA,
| | - William D. Figg
- Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA; Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA
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Cascorbi I, Haenisch S. Pharmacogenetics of ATP-binding cassette transporters and clinical implications. Methods Mol Biol 2010; 596:95-121. [PMID: 19949922 DOI: 10.1007/978-1-60761-416-6_6] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Drug resistance is a severe limitation of chemotherapy of various malignancies. In particular efflux transporters of the ATP-binding cassette family such as ABCB1 (P-glycoprotein), the ABCC (multidrug resistance-associated protein) family, and ABCG2 (breast cancer resistance protein) have been identified as major determinants of chemoresistance in tumor cells. Bioavailability depends not only on the activity of drug metabolizing enzymes but also to a major extent on the activity of drug transport across biomembranes. They are expressed in the apical membranes of many barrier tissues such as the intestine, liver, blood-brain barrier, kidney, placenta, testis, and in lymphocytes, thus contributing to plasma, liquor, but also intracellular drug disposition. Since expression and function exhibit a broad variability, it was hypothesized that hereditary variances in the genes of membrane transporters could explain at least in part interindividual differences of pharmacokinetics of a variety of anticancer drugs and many others contributing to the clinical outcome of certain leukemias and further malignancies.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Animals
- Antineoplastic Agents/metabolism
- Antineoplastic Agents/therapeutic use
- Cell Line
- Drug Resistance, Multiple/physiology
- Drug Resistance, Neoplasm/physiology
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins/genetics
- Multidrug Resistance-Associated Proteins/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Neoplasms/drug therapy
- Neoplasms/genetics
- Neoplasms/metabolism
- Neoplasms/pathology
- Polymorphism, Genetic
- Treatment Outcome
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Affiliation(s)
- Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University of Kiel, Kiel, Germany.
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Fujita KI, Ando Y, Yamamoto W, Miya T, Endo H, Sunakawa Y, Araki K, Kodama K, Nagashima F, Ichikawa W, Narabayashi M, Akiyama Y, Kawara K, Shiomi M, Ogata H, Iwasa H, Okazaki Y, Hirose T, Sasaki Y. Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer. Cancer Chemother Pharmacol 2010; 65:251-258. [PMID: 19466410 DOI: 10.1007/s00280-009-1029-2] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Accepted: 05/04/2009] [Indexed: 01/11/2023]
Abstract
PURPOSE To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients. METHODS We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. RESULTS The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1-3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1-3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1-3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting. CONCLUSION Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.
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Affiliation(s)
- Ken-ichi Fujita
- Department of Medical Oncology, Saitama International Medical Center-Comprehensive Cancer Center, Saitama Medical University, Yamane, Hidaka, Japan.
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Cygalova LH, Hofman J, Ceckova M, Staud F. Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility. J Pharmacol Exp Ther 2009; 331:1118-25. [PMID: 19779128 DOI: 10.1124/jpet.109.160564] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2025] Open
Abstract
Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentration-dependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited.
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Affiliation(s)
- Lenka Hahnova Cygalova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Prague, Czech Republic
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Shi W, Coleman RS, Lowary TL. Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics. Org Biomol Chem 2009; 7:3709-22. [PMID: 19707675 PMCID: PMC4669219 DOI: 10.1039/b909153j] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Anthracycline antibiotics such as daunomycin (Dauno) and doxorubicin (Dox) are well-known clinically used cancer chemotherapeutics, which, among other mechanisms, bind to DNA, thereby triggering a cascade of biological responses leading to cell death. However, anthracyclines are cardiotoxic, and drug resistance develops rapidly, thus limiting their clinical use. We report here the synthesis and DNA-binding affinity of a novel class of functional anthracycline mimetics consisting of an aromatic moiety linked to a carbohydrate (1-12). In the targets, the aromatic core consists of a 2-phenylbenzo[b]furan-3-yl, 2-phenylbenzo[b]thiophen-3-yl, 1-tosyl-2-phenylindol-3-yl, or 2-phenylindol-3-yl group that is bound to one of three aminosugars (daunosamine, acosamine, or 4-amino-2,3,4,6-tetradeoxy-alpha-l-hexopyranoside) via a propargyl linker. The DNA binding affinity of these twelve compounds has been evaluated by using both direct and indirect fluorescence measurements. Compared to Dauno and Dox, the DNA binding affinity of these analogues is weaker. However, both aromatic and aminosugar motifs are critical to DNA binding, with more influence coming from the structural features of the aromatic portion.
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Affiliation(s)
- Wei Shi
- Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada
| | - Robert S. Coleman
- Department of Chemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA
| | - Todd L. Lowary
- Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada
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Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. BIOCHIMICA ET BIOPHYSICA ACTA 2009; 1794:860-71. [PMID: 19285158 PMCID: PMC2810319 DOI: 10.1016/j.bbapap.2009.02.014] [Citation(s) in RCA: 259] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 02/23/2009] [Accepted: 02/26/2009] [Indexed: 12/30/2022]
Abstract
The MDR1 (ABCB1) gene encodes a membrane-bound transporter that actively effluxes a wide range of compounds from cells. The overexpression of MDR1 by multidrug-resistant cancer cells is a serious impediment to chemotherapy. MDR1 is expressed in various tissues to protect them from the adverse effect of toxins. The pharmacokinetics of drugs that are also MDR1 substrates also influence disease outcome and treatment efficacy. Although MDR1 is a well-conserved gene, there is increasing evidence that its polymorphisms affect substrate specificity. Three single nucleotide polymorphisms (SNPs) occur frequently and have strong linkage, creating a common haplotype at positions 1236C>T (G412G), 2677G>T (A893S) and 3435C>T (I1145I). The frequency of the synonymous 3435C>T polymorphism has been shown to vary significantly according to ethnicity. Existing literature suggests that the haplotype plays a role in response to drugs and disease susceptibility. This review summarizes recent findings on the 3435C>T polymorphism of MDR1 and the haplotype to which it belongs. A possible molecular mechanism of action by ribosome stalling that can change protein structure and function by altering protein folding is discussed.
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Affiliation(s)
- King Leung Fung
- Laboratory of Cell Biology, Center of Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 2108, Bethesda, Maryland 20892-4254 USA
| | - Michael M. Gottesman
- Laboratory of Cell Biology, Center of Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 2108, Bethesda, Maryland 20892-4254 USA
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Abstract
In vivo and in vitro studies have demonstrated that P-glycoprotein (P-gp) plays a very significant role in the ADME processes (absorption, distribution, metabolism, excretion) and drug-drug interaction (DDI) of drugs in humans. P-gp is the product of multidrug resistance gene (MDR1/ABCB1). Pharmacogenomics and pharmacogenetics studies have revealed that genetic polymorphisms of MDR1 are associated with alteration in P-gp expression and function in different ethnicities and subjects. By now, 50 single nucleotide polymorphisms (SNPs) and 3 insertion/deletion polymorphisms have been found in the MDR1 gene. Some of them, such as C3435T, have been identified to be a risk factor for numerous diseases. It is believed that further understanding of the physiology and biochemistry of P-gp with respect to its genetic variations may be important for individualized pharmacotherapy. Therefore, based on the latest public information and our studies, this review focuses on the following four aspects: 1) the impact of P-gp on pharmacokinetics; 2) MDR1 genetic polymorphisms and their impacts on pharmacogenetics; 3) relationship between altered P-gp expression and function and the MDR1(C3435T) SNP, and 4) relevance of MDR1 polymorphisms to certain human diseases.
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Affiliation(s)
- Yan-Hong Li
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
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Gréen H, Söderkvist P, Rosenberg P, Mirghani RA, Rymark P, Lundqvist EA, Peterson C. Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol Toxicol 2008; 104:130-7. [PMID: 19143748 DOI: 10.1111/j.1742-7843.2008.00351.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.
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Affiliation(s)
- Henrik Gréen
- Division of Drug Research, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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