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B Chantemargue, F Di Meo, K Berka, N Picard, H Arnion, M Essig, P Marquet, M Otyepka, P Trouillas
The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed atomistic model of the wild type (WT) MRP4 and the p...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Rebecca R Crawford, Praveen K Potukuchi, Erin G Schuetz, John D Schuetz
ATP-binding cassette (ABC) transporters are transmembrane efflux transporters mediating the extrusion of an array of substrates ranging from amino acids and lipids to xenobiotics, and many therapeutic compounds, including anticancer drugs. The ABC transporters are also recognized as important contributors to pharmacokinetics, especially in drug-drug interactions and adverse drug effects. Drugs and xenobiotics, as well as pathological conditions, can influence the transcription of ABC transporters, or modify their activity or intracellular localization...
March 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Katja Vogt, Shailaja Mahajan-Thakur, Robert Wolf, Susanne Bröderdorf, Conny Vogel, Andreas Böhm, Christoph A Ritter, Markus Gräler, Stefan Oswald, Andreas Greinacher, Heyo K Kroemer, Gabriele Jedlitschky, Bernhard H Rauch
Sphingosine-1-phosphate (S1P) is a potent lipid mediator released from activated platelets by an adenosine triphosphate (ATP)-dependent export mechanism. A candidate transport protein is the multidrug resistance protein 4 (MRP4/ABCC4), an ATP-dependent transporter highly expressed in platelets. Furthermore, several statins are known to affect platelet functions and exhibit antithrombotic properties. This study determines the involvement of MRP4 in the transport of S1P and a possible interference by statins...
January 2018: Thrombosis and Haemostasis
Agustín Yaneff, Ana Sahores, Natalia Gomez, Alejandro Carozzo, Carina Shayo, Carlos Davio
MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology...
December 29, 2017: Current Medicinal Chemistry
Liuqing Xu, Yingfeng Shi, Shougang Zhuang, Na Liu
Uric acid is the product of purine metabolism and its increased levels result in hyperuricemia. A number of epidemiological reports link hyperuricemia with multiple disorders, such as kidney diseases, cardiovascular diseases and diabetes. Recent studies also showed that expression and functional changes of urate transporters are associated with hyperuricemia. Uric acid transporters are divided into two categories: urate reabsorption transporters, including urate anion transporter 1 (URAT1), organic anion transporter 4 (OAT4) and glucose transporter 9 (GLUT9), and urate excretion transporetrs, including OAT1, OAT3, urate transporter (UAT), multidrug resistance protein 4 (MRP4/ABCC4), ABCG-2 and sodium-dependent phosphate transport protein...
November 21, 2017: Oncotarget
Tacy Santana Machado, Stéphane Poitevin, Pascale Paul, Nathalie McKay, Noémie Jourde-Chiche, Tristan Legris, Annick Mouly-Bandini, Françoise Dignat-George, Philippe Brunet, Rosalinde Masereeuw, Stéphane Burtey, Claire Cerini
In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1 , SLC22A1 , SLC22A7 , SLC47A1 , SLCO1B1 , SLCO1B3 , SLCO2B1 , ABCB1 , ABCB11 , ABCC2 , ABCC3 , ABCC4 , ABCC6 , and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters...
March 2018: Journal of the American Society of Nephrology: JASN
Aaron Pitre, Yubin Ge, Wenwei Lin, Yao Wang, Yu Fukuda, Jamshid Temirov, Aaron H Phillips, Jennifer L Peters, Yiping Fan, Jing Ma, Amanda Nourse, Chandrima Sinha, Hai Lin, Richard Kriwacki, James R Downing, Tanja A Gruber, Victoria E Centonze, Anjaparavanda P Naren, Taosheng Chen, John D Schuetz
The overall survival of patients with acute myeloid leukemia (AML) is poor and identification of new disease-related therapeutic targets remains a major goal for this disease. Here we show that expression of MPP1, a PDZ-domain-containing protein, highly correlated with ABCC4 in AML, is associated with worse overall survival in AML. Murine hematopoietic progenitor cells overexpressing MPP1 acquired the ability to serially replate in methylcellulose culture, a property crucially dependent upon ABCC4. The highly conserved PDZ-binding motif of ABCC4 is required for ABCC4 and MPP1 to form a protein complex, which increased ABCC4 membrane localization and retention, to enhance drug resistance...
November 16, 2017: Nature Communications
Ryan D Huff, Christopher F Rider, Dong Yan, Robert Newton, Mark A Giembycz, Chris Carlsten, Jeremy A Hirota
No abstract text is available yet for this article.
March 2018: Journal of Allergy and Clinical Immunology
Peng-Cheng Li, Mei-Juan Tu, Pui Yan Ho, Joseph L Jilek, Zhijian Duan, Qian-Yu Zhang, Ai-Xi Yu, Ai-Ming Yu
The nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor in the regulation of many oxidative enzymes and efflux transporters critical for oxidative stress and cellular defense against xenobiotics. NRF2 is dysregulated in patient osteosarcoma (OS) tissues and correlates with therapeutic outcomes. Nevertheless, research on the NRF2 regulatory pathways and its potential as a therapeutic target is limited to the use of synthetic small interfering RNA (siRNA) carrying extensive artificial modifications...
January 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Kanokrat Rungtivasuwan, Anchalee Avihingsanon, Narukjaporn Thammajaruk, Siwaporn Mitruk, David M Burger, Kiat Ruxrungtham, Chonlaphat Sukasem, Baralee Punyawudho
AIM: To develop a population pharmacokinetic model and identify sources of variability, genetic and nongenetic factors, of tenofovir. METHODS: The ABCC2 and ABCC4 polymorphisms were genotyped in 342 patients. A nonlinear mixed effects model was used to develop the population pharmacokinetic model and investigate the influence of these polymorphisms and other patient specific covariates on the pharmacokinetics of tenofovir. RESULTS: The estimated glomerular filtration rate calculated by the Cockcroft and Gault equation, concomitant use of lopinavir/ritonavir and ABCC4 3463A>G polymorphism were associated with tenofovir apparent oral clearance (CL/F)...
October 24, 2017: Pharmacogenomics
Vinicius A Sortica, Juliana D Lindenau, Maristela G Cunha, Maria Deise O Ohnishi, Ana Maria R Ventura, Ândrea Kc Ribeiro-Dos-Santos, Sidney Eb Santos, Luciano Sp Guimarães, Mara H Hutz
AIM: The association of transporters gene polymorphisms with chloroquine/primaquine malaria treatment response was investigated in a Brazilian population. PATIENTS & METHODS: Totally, 164 Plasmodium vivax malaria infected patients were included. Generalized estimating equations were performed to determine gene influences on parasitemia and/or gametocytemia clearance over treatment time. RESULTS: Significant interaction between SLCO2B1 genotypes and treatment over time for parasitemia clearance rate on day 2 were observed (p FDR = 0...
October 4, 2017: Pharmacogenomics
J H Kim, K J Gellatly, B Lueke, M Kohler, R Nauen, E Murenzi, K S Yoon, J M Clark
We previously observed that ivermectin-induced detoxification genes, including ATP binding cassette transporter C4 (PhABCC4) and cytochrome P450 6CJ1 (CYP6CJ1) were identified from body lice following a brief exposure to a sublethal dose of ivermectin using a non-invasive induction assay. In this current study, the functional properties of PhABCC4 and CYP6CJ1 were investigated after expression in either X. laevis oocytes or using a baculovirus expression system, respectively. Efflux of [(3) H]-9-(2-phosphonomethoxyethyl) adenine ([(3) H]-PMEA), a known ABCC4 substrate in humans, was detected from PhABCC4 cRNA-injected oocytes by liquid scintillation spectrophotometric analysis and PhABCC4 expression in oocytes was confirmed using ABC transporter inhibitors...
September 27, 2017: Insect Molecular Biology
Fusako Usuki, Masatake Fujimura, Akio Yamashita
Endoplasmic reticulum (ER) stress preconditioning protects cells against methylmercury (MeHg) cytotoxicity by inducing integrated stress responses such as eIF2α phosphorylation, ATF4 accumulation, and nonsense-mediated mRNA decay (NMD) suppression. Here we demonstrated that ER stress preconditioning results in the upregulation of membrane transporters, leading to a decrease in intracellular mercury content. Our analyses showed that ER stress preconditioning upregulated the expression of methionine transporters that affect the cellular influx of MeHg, LAT1, LAT3, and SNAT2; and a membrane transporter that affects the efflux of MeHg, ABCC4, in MeHg-susceptible myogenic cells...
September 28, 2017: Scientific Reports
Jarline Encarnación-Medina, Rosa I Rodríguez-Cotto, Joseph Bloom-Oquendo, Mario G Ortiz-Martínez, Jorge Duconge, Braulio Jiménez-Vélez
ATP-binding cassette subfamily C (ABCC) genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5)) and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1-4 gene expression changes and proinflammatory cytokine (IL-6, IL-8) release in human bronchial epithelial cells (BEAS-2B) exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients), and a cotreatment (Co-T: PM2...
2017: Mediators of Inflammation
Jinhua Li, Madlen Bauer, Birget Moe, Elaine M Leslie, Xing-Fang Li
Halobenzoquinones (HBQs) are frequently detected disinfection byproducts (DBPs) in treated water. Recent studies have demonstrated that HBQs are highly cytotoxic and capable of inducing the generation of reactive oxygen species (ROS) and depleting cellular glutathione (GSH). Multidrug resistance proteins (MRPs/ABCCs) are known to play a critical role in the elimination of numerous drugs, carcinogens, toxicants, and their conjugated metabolites. In general, little is known about the roles of transporters in DBP toxicity...
October 16, 2017: Chemical Research in Toxicology
Yoichi Tanaka
6-Mercaptopurine (6-MP) is one of the main components for the treatment of childhood acute lymphoblastic leukemia (ALL). However, many patients require a dose reduction of 6-MP due to its severe toxicities. NUDT15 variants are one of the factors that cause 6-MP intolerability in Asians. In each patient with heterozygous variants of NUDT15, 6-MP intolerability differs. Therefore, we hypothesized that the combination of NUDT15 genotype with ABCC4 genotype, which is associated with 6-MP efflux, might enable to accurately predict 6-MP intolerability...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Hyery Kim, Heewon Seo, Yoomi Park, Byung-Joo Min, Myung-Eui Seo, Kyung Duk Park, Hee Young Shin, Ju Han Kim, Hyoung Jin Kang
Purpose: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients. Materials and Methods: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients...
September 4, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Ryan D Huff, Alan C-Y Hsu, Kristy S Nichol, Bernadette Jones, Darryl A Knight, Peter A B Wark, Philip M Hansbro, Jeremy A Hirota
INTRODUCTION: The airway epithelium is a physical and immunological barrier that protects the pulmonary system from inhaled environmental insults. Uric acid has been detected in the respiratory tract and can function as an antioxidant or damage associated molecular pattern. We have demonstrated that human airway epithelial cells are a source of uric acid. Our hypothesis is that uric acid production by airway epithelial cells is induced by environmental stimuli associated with chronic respiratory diseases...
2017: PloS One
Qi Chen, Fanyi Meng, Lei Wang, Yong Mao, Huan Zhou, Dong Hua, Hongjian Zhang, Weipeng Wang
To investigate the association of microRNA (miRNA) binding-site polymorphisms in the drug transporter genes with the efficacy of 5-Fluorouracil (5-FU)/capecitabine-based chemotherapy in colorectal cancer (CRC), 6 polymorphisms were determined in 432 CRC patients by using DNA sequencing method. The impacts of the polymorphisms on the miRNA-mediated regulation of gene expression were evaluated by using the methods including quantitative real-time PCR, western blotting, and luciferase reporter assays. The effects of miRNA on the intracellular concentration and cytotoxicity of 5-FU in CRC cells were measured by high performance liquid chromatography conjected tandem mass spectrometry (HPLC-MS/MS) and MTT methods, respectively...
August 1, 2017: Scientific Reports
Marta Pellicer, Xandra García-González, María I García, Carolina Blanco, Pilar García-Alfonso, Luis Robles, Cristina Grávalos, Daniel Rueda, Joaquín Martínez, Vanessa Pachón, Federico Longo, Virginia Martínez, Irene Iglesias, Sara Salvador, María Sanjurjo, Luis A López-Fernández
AIM: To identify genetic variants associated with capecitabine toxicity in fluoropyrimidine pathway genes using exome sequencing. PATIENTS & METHODS: Exomes from eight capecitabine-treated patients with severe adverse reactions (grade >2), among a population of 319, were sequenced (Ion Proton). SNPs in genes classified as potentially damaging (Sorting Intolerant from Tolerant and Polymorphism Phenotyping v2) were tested for association with toxicity in a validation cohort of 319 capecitabine-treated patients...
August 2017: Pharmacogenomics
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