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Junjun Wang, Ting Zhai, Yong Chen
This study was aimed to clarify the effect of honokiol (Hon) on the activity of Cytochrome P450 (CYP450) enzymes, and the level of mRNA expression of liver and kidney transporters in type 2 diabetic rats induced by high-fat diet and strepotozotocin. Rats were randomly divided into normal control (NC) group, diabetic control (DC) group and Hon groups ( n = 6). The activities of hepatic CYP1A2, CYP2E1, CYP2C, CYP2B, CYP3A and CYP4A, and the mRNA expression levels of hepatic and renal transporters, were determined...
March 12, 2018: International Journal of Molecular Sciences
Kang Wang, Lei Hu, Jian-Kang Chen
Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Sébastien Rinaldetti, Markus Pfirrmann, Kirsi Manz, Joelle Guilhot, Christian Dietz, Panayiotidis Panagiotidis, Birgit Spiess, Wolfgang Seifarth, Alice Fabarius, Martin Müller, Maria Pagoni, Maria Dimou, Jolanta Dengler, Cornelius F Waller, Tim H Brümmendorf, Regina Herbst, Andreas Burchert, Carsten Janβen, Maria Elisabeth Goebeler, Philipp J Jost, Stefan Hanzel, Philippe Schafhausen, Gabriele Prange-Krex, Thomas Illmer, Viktor Janzen, Martine Klausmann, Robert Eckert, Gerd Büschel, Alexander Kiani, Wolf-Karsten Hofmann, François-Xavier Mahon, Susanne Saussele
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial...
February 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
Masanori Tachikawa, Yuna Sumiyoshiya, Daisuke Saigusa, Kazunari Sasaki, Michitoshi Watanabe, Yasuo Uchida, Tetsuya Terasaki
The purpose of the present study was to clarify the molecular basis of zonated drug distributions in mouse liver based on the protein expression levels of transporters and metabolizing enzymes in peri-portal vein (PP) and peri-central vein (PC) regions of mouse hepatic lobules. The distributions of sulforhodamine 101 (SR-101), a substrate of organic anion transporting polypeptides (Oatps), and ribavirin, a substrate of equilibrative nucleoside transporter 1 (Ent1), were elucidated in frozen liver sections of mice to which each compound had been intravenously administered...
March 5, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
J Kenneth Baillie, Andrew Bretherick, Christopher S Haley, Sara Clohisey, Alan Gray, Lucile P A Neyton, Jeffrey Barrett, Eli A Stahl, Albert Tenesa, Robin Andersson, J Ben Brown, Geoffrey J Faulkner, Marina Lizio, Ulf Schaefer, Carsten Daub, Masayoshi Itoh, Naoto Kondo, Timo Lassmann, Jun Kawai, Damian Mole, Vladimir B Bajic, Peter Heutink, Michael Rehli, Hideya Kawaji, Albin Sandelin, Harukazu Suzuki, Jack Satsangi, Christine A Wells, Nir Hacohen, Thomas C Freeman, Yoshihide Hayashizaki, Piero Carninci, Alistair R R Forrest, David A Hume
Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA)...
March 1, 2018: PLoS Computational Biology
Ewan R Pearson
In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11...
February 24, 2018: Current Opinion in Genetics & Development
Byoung Hoon You, Young-Won Chin, Hojun Kim, Han Seok Choi, Young Hee Choi
The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT-metformin combination were determined from pharmacokinetic change and glucose-lowering activity using in vitro HEK-293 cells expressing human OCTs or human MATEs and in vivo rats...
February 26, 2018: Phytotherapy Research: PTR
Lisa Chedik, Arnaud Bruyere, Olivier Fardel
1. Organophosphorus pesticides (OPs) are known to interact with human ATP-binding cassette drug efflux pumps. The present study was designed to determine whether they can also target activities of human solute carrier (SLC) drug transporters. 2. The interactions of thirteen OPs with SLC transporters involved in drug disposition, such as organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs), were mainly investigated using transporter-overexpressing cell clones and fluorescent or radiolabeled reference substrates...
February 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Anna Vildhede, Chuong Nguyen, Brian K Erickson, Ryan C Kunz, Richard Jones, Emi Kimoto, Francis Bourbonais, A David Rodrigues, Manthena V Varma
Targeted protein quantification using liquid chromatography-tandem mass spectrometry with stable isotope labelled standards is recognized as the gold standard of practice for protein quantification. Such assays, however, can only cover a limited number of proteins and developing targeted methods for larger numbers of proteins require substantial investment. Alternatively, large-scale global proteomic experiments along with computational methods such as the "total protein approach" (TPA) have the potential to provide extensive protein quantification...
February 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
I Buß, A Hamacher, N Sarin, M U Kassack, G V Kalayda
Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represent a frequently reported feature of cells with acquired resistance to platinum drugs. Nevertheless, the mechanisms of oxaliplatin uptake and their role in oxaliplatin resistance remain poorly elucidated. The aim of this study was to investigate the relevance of copper transporter 1 (CTR1) and organic cation transporters 1-3 (OCT1-3) for oxaliplatin uptake and resistance to the drug in sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cells...
February 8, 2018: Metallomics: Integrated Biometal Science
Ana Beatriz Santoro, Mariana Rodrigues Botton, Claudio José Struchiner, Guilherme Suarez-Kurtz
AIM: To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. METHODS: The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry...
January 20, 2018: British Journal of Clinical Pharmacology
Karina Vázquez-Arreguín, Jessica Maddox, Jinsuk Kang, Dongju Park, Reuben R Cano, Rachel E Factor, Thomas Ludwig, Dean Tantin
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with pro-glycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells towards a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype...
January 12, 2018: Molecular Cancer Research: MCR
Colby S Shemesh, Rosie Z Yu, Mark S Warren, Michael Liu, Mirza Jahic, Brandon Nichols, Noah Post, Song Lin, Daniel A Norris, Eunju Hurh, Jane Huang, Tanya Watanabe, Scott P Henry, Yanfeng Wang
Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides (2'-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2'-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored...
December 15, 2017: Molecular Therapy. Nucleic Acids
Marleen Julia Meyer, Tina Seitz, Jürgen Brockmöller, Mladen Vassilev Tzvetkov
BACKGROUND: Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity...
2017: PloS One
Michelle Schaefer, Gaku Morinaga, Akiko Matsui, Gerhard Schänzle, Daniel Bischoff, Roderich D Süssmuth
Deficient functional expression of drug transporters incapacitates most hepatic cell lines as a reliable tool for evaluating transporter-mediated drug-drug interactions. Recently, genetically modified cells (referred to as upcyte hepatocytes) have emerged as an expandable, noncancerous source of human hepatic cells. Herein, we quantified mRNA and protein levels of key hepatobiliary transporters and we assessed associated uptake activity in short- and long-term cultures of upcyte human hepatocytes (UHH) in comparison to cryopreserved primary human hepatocytes (cPHH)...
February 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Maciej J Zamek-Gliszczynski, Kathleen M Giacomini, Lei Zhang
Hepatic organic cation transporter 1 (OCT1) can be a determinant of drug clearance and distribution, which can impact drug exposure and response. OCT1 was shown recently to be the rate-determining step in the clearance of several drugs in humans, and thereby a mechanism of pharmacogenetic variability and drug-drug interactions (DDIs). OCT1 mediates metformin distribution to the liver (key biophase). As OCT1 modulation impacts metformin response, but not pharmacokinetics (PK), metformin DDI studies require pharmacodynamic endpoint(s) to inform rational metformin dose adjustment...
November 28, 2017: Clinical Pharmacology and Therapeutics
Markus Keiser, Mahmoud Hasan, Stefan Oswald
Ketamine is a widely used intravenous anesthetic drug that has also a pronounced analgesic effect. Moreover, one of its metabolites was very recently shown to possess antidepressant activity. Consequently, oral administration of ketamine may become of interest in the future. There is evidence from in vitro data, drug-drug interactions, and the physicochemical properties of the drug that ketamine may be a substrate of drug transporters. Thus, it was the aim of this study to investigate the affinity of ketamine to clinically relevant transporter proteins that are expected to affect its intestinal absorption, distribution, and excretion...
January 2, 2018: Molecular Pharmaceutics
Marie Febvre-James, Arnaud Bruyere, Marc Le Vee, Olivier Fardel
The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sarah Billington, Adrian S Ray, Laurent Salphati, Guangqing Xiao, Xiaoyan Chu, W Griffith Humphreys, Mingxiang Liao, Caroline A Lee, Anita A Mathias, Cornelis E C A Hop, Christopher Rowbottom, Raymond Evers, Yurong Lai, Edward J Kelly, Bhagwat Prasad, Jashvant D Unadkat
Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs and P-gp) in cancerous (C, n=8) and adjacent non-cancerous (NC, n=33) liver tissues obtained from chronic hepatitis C patients with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from non-infected non-cirrhotic (control, n=36) and HCV-cirrhotic (n=30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Waleed Elsayed Ahmed Ellawatty, Yusuke Masuo, Ken-Ichi Fujita, Erina Yamazaki, Hiroo Ishida, Hiroshi Arakawa, Noritaka Nakamichi, Ramadan Abdelwahed, Yasutsuna Sasaki, Yukio Kato
Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. In order to characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its intravenous administration...
October 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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