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https://www.readbyqxmd.com/read/27909713/age-associated-differences-in-transporter-gene-expression-in-kidneys-of-male-rats
#1
Yong-Ji Xu, Yang Wang, Yuan-Fu Lu, Shang-Fu Xu, Qin Wu, Jie Liu
Kidney transporters are involved in the secretion and reabsorption of endogenous and exogenous molecules. Numerous factors may influence their expression and affect drug disposition, efficacy and toxicity. The present study aimed to examine the development‑ and age‑associated variations in primary renal transporters in rats, including 6 uptake transporters: Organic anion transporter (OAT) 1 and 3, organic cation transporter (OCT) 1, 2 and 3 and organic anion‑transporting polypeptide (OATP) 4C1, and 6 efflux transporters: Multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance‑associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2‑K...
November 28, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27903597/impact-of-organic-cation-transporters-oct-slc22a-on-differential-diagnosis-of-intrahepatic-lesions
#2
Michele Visentin, Belle V van Rosmalen, Christian Hiller, Matthanja Bieze, Lia Hofstetter, Joanne Verheij, Gerd A Kullak-Ublick, Hermann Koepsell, Saffire Sks Phoa, Ikumi Tamai, Roelof J Bennink, Thomas M van Gulik, Bruno Stieger
Positron emission tomography (PET) using the cationic compound [(18)F]fluoromethylcholine (FCH) enhances the sensitivity for non-invasive classification of hepatic tumours due to peculiar patterns of accumulation. The underlying transporters are not known. We aim to identify the carriers mediating uptake of FCH in liver and to correlate their expression pattern with PET intrahepatic signal distribution to clarify the role of membrane transporters in FCH accumulation. FCH transport was characterized in cells overexpressing organic cation transporters (OCTs)...
November 30, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27903454/effects-of-frequently-used-pharmaceutical-excipients-on-the-organic-cation-transporters-1-3-and-peptide-transporters-1-2-stably-expressed-in-mdckii-cells
#3
Marcus Otter, Stefan Oswald, Werner Siegmund, Markus Keiser
There is ample evidence that pharmaceutical excipients, which are supposed to be pharmacologically inactive, have an impact on drug metabolism and efflux transport. So far, little is known whether they also modulate uptake transporter proteins. We have recently shown that commonly used solubilizing agents exert significant effects on the function of organic anion uptake transporting polypeptides. Therefore, we investigated in this study the influence of frequently used pharmaceutical excipients on the transport activity of organic cation transporters OCT1, OCT2 and OCT3 and the peptide transporters PEPT1 and PEPT2...
November 26, 2016: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/27862160/in-vitro-and-pbpk-based-assessment-of-drug-drug-interaction-potential-of-canagliflozin
#4
Rao N V S Mamidi, Shannon Dallas, Carlo Sensenhauser, Heng Keang Lim, Ellen Scheers, Peter Verboven, Filip Cuyckens, Laurent Leclercq, David C Evans, Michael F Kelley, Mark D Johnson, Jan Snoeys
AIMS: Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed. METHODS: DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interaction in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of CYP inhibition by canagliflozin...
November 11, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27859023/variants-in-pharmacokinetic-transporters-and-glycaemic-response-to-metformin-a-metgen-meta-analysis
#5
Tanja Dujic, Kaixin Zhou, Sook Wah Yee, Nienke van Leeuwen, Catherine E de Keyser, Martin Javorský, Srijib Goswami, Linda Zaharenko, Mette Marie, H Christensen, Mattijs Out, Roger Tavendale, Michiaki Kubo, Monique M Hedderson, Amber A van der Heijden, Lucia Klimčáková, Valdis Pirags, Adriaan Kooy, Kim Brøsen, Janis Klovins, Sabina Semiz, Ivan Tkáč, Bruno H Stricker, Colin N A Palmer, Leen M 't Hart, Kathleen M Giacomini, Ewan R Pearson
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporters genes, with inconsistent results. To clarify the significance of these variants in glycaemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (OCT1, OCT2, MATE1, MATE2-K and OCTN1) were analysed in up to 7,968 individuals...
November 10, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27825374/low-heritability-in-pharmacokinetics-of-talinolol-a-pharmacogenetic-twin-study-on-the-heritability-of-the-pharmacokinetics-of-talinolol-a-putative-probe-drug-of-mdr1-and-other-membrane-transporters
#6
Johannes Matthaei, Mladen V Tzvetkov, Valerie Gal, Cordula Sachse-Seeboth, Daniel Sehrt, Jakob B Hjelmborg, Ute Hofmann, Matthias Schwab, Reinhold Kerb, Jürgen Brockmöller
BACKGROUND: Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors. In this study we assessed the heritability of the pharmacokinetics of talinolol as a putative probe drug for MDR1 and possibly other membrane transporters. METHODS: Talinolol pharmacokinetics were investigated in a repeated dose study in 42 monozygotic and 13 same-sex dizygotic twin pairs...
November 8, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27819678/tet2-binds-the-androgen-receptor-and-loss-is-associated-with-prostate-cancer
#7
M L Nickerson, S Das, K M Im, S Turan, S I Berndt, H Li, H Lou, S A Brodie, J N Billaud, T Zhang, A J Bouk, D Butcher, Z Wang, L Sun, K Misner, W Tan, A Esnakula, D Esposito, W Y Huang, R N Hoover, M A Tucker, J R Keller, J Boland, K Brown, S K Anderson, L E Moore, W B Isaacs, S J Chanock, M Yeager, M Dean, T Andresson
Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2...
November 7, 2016: Oncogene
https://www.readbyqxmd.com/read/27817866/hla-c-level-is-regulated-by-a-polymorphic-oct1-binding-site-in-the-hla-c-promoter-region
#8
Nicolas Vince, Hongchuan Li, Veron Ramsuran, Vivek Naranbhai, Fuh-Mei Duh, Benjamin P Fairfax, Bahara Saleh, Julian C Knight, Stephen K Anderson, Mary Carrington
Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 × 10(-66)). This imputed expression quantitative trait locus, termed impeQTL, was also shown to associate with HLA-C expression in a genome-wide association study of 273 donors in which HLA-C mRNA expression levels were determined by quantitative PCR (qPCR) (p = 1...
October 25, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27817253/multidrug-and-toxin-extrusion-protein-1-mediated-interaction-of-metformin-and-scutellariae-radix-in-rats
#9
Sreymom Yim, Byoung Hoon You, Hee-Sung Chae, Young-Won Chin, Hojun Kim, Han Seok Choi, Young Hee Choi
The metformin and Scutellariae Radix extract (SB) combination has been previously reported to enhance anti-diabetic activity. Considering that organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) in the liver and kidney are determinant factors on hepatic distribution and renal clearance of metformin, the effects of SB on OCT or MATE-mediated systemic exposure of metformin as well as on glucose tolerance and hypoglycemia were examined. Although SB inhibited metformin uptake through human transporters OCT1 and MATE1 in vitro, the systemic exposures of metformin in vivo rats were not altered after metformin treatment with and without SB due to unchanged renal excretion of metformin...
November 7, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27812757/counter-flow-suggests-transport-of-dantrolene-and-5-oh-dantrolene-by-the-organic-anion-transporters-2-oat2-and-3-oat3
#10
Birgitta C Burckhardt, Maja Henjakovic, Yohannes Hagos, Gerhard Burckhardt
Dantrolene is the only available drug for the treatment of malignant hyperthermia, a life-threatening inborn sensitivity of the ryanodine receptor (RyR1) in skeletal muscles to volatile anesthetics. Dantrolene is metabolized in the liver to 5-OH dantrolene. Both compounds are zwitterions or net negatively charged. Here, we investigated interactions of dantrolene and 5-OH dantrolene with solute carrier (SLC) family members occurring in skeletal muscle cells, hepatocytes, and renal proximal tubule cells. SLC22A8 (organic anion transporter 3, OAT3) was very sensitive to both compounds exhibiting IC50 values of 0...
November 3, 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27799064/mipep-recessive-variants-cause-a-syndrome-of-left-ventricular-non-compaction-hypotonia-and-infantile-death
#11
Mohammad K Eldomery, Zeynep C Akdemir, F-Nora Vögtle, Wu-Lin Charng, Patrycja Mulica, Jill A Rosenfeld, Tomasz Gambin, Shen Gu, Lindsay C Burrage, Aisha Al Shamsi, Samantha Penney, Shalini N Jhangiani, Holly H Zimmerman, Donna M Muzny, Xia Wang, Jia Tang, Ravi Medikonda, Prasanna V Ramachandran, Lee-Jun Wong, Eric Boerwinkle, Richard A Gibbs, Christine M Eng, Seema R Lalani, Jozef Hertecant, Richard J Rodenburg, Omar A Abdul-Rahman, Yaping Yang, Fan Xia, Meng C Wang, James R Lupski, Chris Meisinger, V Reid Sutton
BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia...
November 1, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27790710/a-novel-mechanism-of-rs763110-polymorphism-contributing-to-cervical-cancer-risk-by-affecting-the-binding-affinity-of-cebp-%C3%AE-and-oct1-complex-to-chromatin
#12
Shenshen Wu, Shizhi Wang, You Fu, Weiyan Tang, Hua Jin, Qingtao Meng, Chengcheng Zhang, Mengjing Cui, Xiaoli Cao, Xiaobo Li, Zhengdong Zhang, Rui Chen
Recently, several studies have showed that FAS (rs2234767, rs1800682) and FASL (rs763110) functional single nucleotide polymorphisms (SNPs) were associated with the risk of various cancers. However, the association between cervical cancer risk and the three SNPs above remained inconclusive. In this work, we performed a two-stage case-control study on 1155 cervical cancer patients and 1252 matched healthy controls to determine the roles of the mentioned SNPs in cervical cancer susceptibility. We genotyped the FAS rs2234767, rs1800682, and FASL rs763110 polymorphisms by using PCR-TaqMan assays...
October 28, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27787693/intracellular-uptake-of-an-antitumor-active-azole-bridged-dinuclear-platinum-ii-complex-in-cisplatin-resistant-tumor-cells
#13
Shuichi Kishimoto, Megumi Yasuda, Ryosuke Suzuki, Shoji Fukushima
A cationic azolato-bridged dinuclear platinum(II) complex, [{cis-Pt(NH3)2}2(μ-OH)(μ-methyl-pyrazolate)](2+) (4M-PzPt), was developed to overcome resistance to cisplatin (CDDP). This study aimed to assess the cytotoxicity of 4M-PzPt against a CDDP-resistant cell line, H4-II-E/CDDP, and compare the intracellular accumulation of CDDP and 4M-PzPt. H4-II-E and H4-II-E/CDDP displayed similar sensitivity to 4M-PzPt; however, the sensitivity of H4-II-E/CDDP to CDDP was approximately 19-fold lower than that of H4-II-E...
December 2016: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/27782167/renoprotective-effects-of-metformin-are-independent-of-organic-cation-transporters-1-2-and-amp-activated-protein-kinase-in-the-kidney
#14
Michael Christensen, Jonas B Jensen, Steen Jakobsen, Niels Jessen, Jørgen Frøkiær, Bruce E Kemp, Allison L Marciszyn, Hui Li, Núria M Pastor-Soler, Kenneth R Hallows, Rikke Nørregaard
The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs)...
October 26, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27780835/developmental-changes-in-hepatic-oct1-protein-expression-from-neonates-to-children
#15
David Hahn, Chie Emoto, Alexander A Vinks, Tsuyoshi Fukuda
Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinically-important drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Presently, knowledge of OCT1 protein expression in children is very limited, especially among neonates and small infants. Here, we report on the characterization of OCT1 protein expression in neonatal, infant and pediatric liver samples performed by Immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal day 1 - 2...
October 25, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27770655/low-abcb1-and-high-oct1-levels-play-a-favorable-role-in-the-molecular-response-to-imatinib-in-cml-patients-in-the-community-clinical-practice
#16
Flavia da Cunha Vasconcelos, Marcos Antonio Mauricio Scheiner, Arthur Moellman-Coelho, André Luiz Mencalha, Ilana Zalcberg Renault, Vivian Mary Rumjanek, Raquel Ciuvalschi Maia
Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS)...
October 12, 2016: Leukemia Research
https://www.readbyqxmd.com/read/27765726/trospium-chloride-is-absorbed-from-two-intestinal-absorption-windows-with-different-permeability-in-healthy-subjects
#17
Tobias Tadken, Michael Weiss, Christiane Modess, Danilo Wegner, Tarek Roustom, Claudia Neumeister, Ulrich Schwantes, Hans-Ulrich Schulz, Werner Weitschies, Werner Siegmund
Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30mg/250ml=[I]2) for 6h and after swallowing 30mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT)...
October 17, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27720766/metformin-an-anti-diabetic-drug-to-fight-cancer
#18
Marie Daugan, Amélie Dufaÿ Wojcicki, Benoit d'Hayer, Vincent Boudy
Since epidemiologic data have highlighted the positive effects of metformin to reduce cancer incidence and mortality, many in vitro and in vivo studies as well as a large number of clinical trials have been conducted in order to study its potential. The many anticancer actions of metformin lead to a cytostatic effect. Two distinct but not exclusive mechanisms can be implicated in these actions. First, by decreasing insulinemia and glycaemia, metformin can block the PI3K/MAPK signalling pathway implicated in cell growth...
October 5, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27701696/-severe-hypoglycemia-following-tramadol-intake-in-a-79-year-old-non-diabetic-patient
#19
Cornelius Kürten, Mladen Tzvetkov, Volker Ellenrieder, Harald Schwörer
History and clinical findings | We report about a 79 year old non-diabetic patient who was admitted to the emergency room with severe hypoglycemia (blood glucose level: 36 mg / dl and Glasgow Coma Scale Score: 3). After the infusion of G40 % her blood glucose level stabilised. The patient reported to have taken 50 mg of Tramadol during the night to treat her headache. Investigations and diagnosis | No other differential diagnosis for hypoglycemia (i.e. diabetes, insulinoma, severe liver or kidney disease) could be established...
September 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27690235/dnmt3a-is-a-haploinsufficient-tumor-suppressor-in-cd8-peripheral-t-cell-lymphoma
#20
Staci L Haney, G Michael Upchurch, Jana Opavska, David Klinkebiel, Ryan A Hlady, Sohini Roy, Samikshan Dutta, Kaustubh Datta, Rene Opavsky
DNA methyltransferase 3A (DNMT3A) is an enzyme involved in DNA methylation that is frequently mutated in human hematologic malignancies. We have previously shown that inactivation of Dnmt3a in hematopoietic cells results in chronic lymphocytic leukemia in mice. Here we show that 12% of Dnmt3a-deficient mice develop CD8+ mature peripheral T cell lymphomas (PTCL) and 29% of mice are affected by both diseases. 10% of Dnmt3a+/- mice develop lymphomas, suggesting that Dnmt3a is a haploinsufficient tumor suppressor in PTCL...
September 2016: PLoS Genetics
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