DOCSLIB.ORG

Allele Frequency of SLC22A1 Met420del Metformin Main Transporter Encoding Gene Among Javanese-Indonesian Population

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Allele Frequency of SLC22A1 Met420del Metformin Main Transporter Encoding Gene Among Javanese-Indonesian Population Open Access Maced J Med Sci electronic publication ahead of print, published on February 14, 2019 as https://doi.org/10.3889/oamjms.2019.087 ID Design Press, Skopje, Republic of Macedonia Open Access Macedonian Journal of Medical Sciences. https://doi.org/10.3889/oamjms.2019.087 eISSN: 1857-9655 Basic Science Allele Frequency of SLC22A1 Met420del Metformin Main Transporter Encoding Gene among Javanese-Indonesian Population Vitarani DA Ningrum1*, Rochmy Istikharah2, Rheza Firmansyah3 1Laboratory of Pharmaceutical Research, Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia; 2Laboratory of Biochemistry, Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia; 3Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia Abstract Citation: Ningrum VDA, Istikharah R, Firmansyah R. BACKGROUND: Genetic variation in the genes that encode metformin transporters has been proven to cause Allele Frequency of SLC22A1 Met420del Metformin Main pharmacokinetic variability and various glycemic response to metformin. Organic Cation Transporter (OCT) 1 Transporter Encoding Gene Among Javanese-Indonesian Population. Open Access Maced J Med Sci. protein encoded by the SLC22A1 gene is primarily responsible for the process of metformin influx to the https://doi.org/10.3889/oamjms.2019.087 hepatocytes as the target of antihyperglycemic action as well as metformin elimination through the renal. This Keywords: SLC22A1; Met420del; Metformin; Javanese- study aimed to determine the allele frequency distribution of the SLC22A1 Met420del gene in OCT1 among the Indonesian population; Yogyakarta Province Javanese population, the largest ethnic group in Indonesia with T2DM. *Correspondence: Dr Vitarani DA Ningrum. Laboratory of Pharmaceutical Research, Department of Pharmacy, METHODS: The research involved 100 adult patients from 9 healthcare facilities in Yogyakarta Province. The Universitas Islam Indonesia, Yogyakarta, Indonesia. E- mail: [email protected] PCR-RFLP method was employed as a genotype analysis to detect polymorphism using 5'- Received: 10-Nov-2018; Revised: 31-Jan-2019; AGGTTCACGGACTCTGTGCT-3' forward primer and 5'-AAGCTGGAGTGTGCGATCT-3' reverse primer. Accepted: 05-Feb-2019; Online first: 14-Feb-2019 Copyright: © 2019 Vitarani DA Ningrum, Rochmy RESULTS: No AA variant (wild type) type was found in the SLC22A1 Met420del gene, and only 4% of the Istikharah, Rheza Firmansyah. This is an open-access subjects had Aa heterozygote type. The allele frequencies of A and a were 2.0% and 98.0% in all subjects, article distributed under the terms of the Creative respectively. Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0) CONCLUSION: The allele frequencies in the Javanese-Indonesian population were almost the same as those in Funding: This research was partially supported by the Directorate of Research and Community Service of the studies involving Japanese, Chinese-Han, and Asian-American populations. This study recommends further Universitas Islam Indonesia through Hibah Penelitian research on the correlation between the influence of methionine deletion at codon 420 on the variability of Unggulan research grant pharmacokinetic profiles and the glycemic response to metformin as well as the incidence of gastrointestinal Competing Interests: The authors have declared that no intolerance due to metformin administration. competing interests exist Introduction healthcare facilities. The ability of metformin to reduce HbA1c levels in the range of 1.0-2.0% and the low hypoglycemic effects are among its advantages over The prevalence of diabetes mellitus in other oral antidiabetic drugs. However, the glycemic Indonesia continues to increase, reaching 2.1% response to metformin use is varied as 35 to 40% of compared to the last 6 years [1]. Meanwhile, the patients have yet to reach the target of fasting blood International Diabetic Federation estimates that DM glucose levels [4]. Variability in patients’ response to prevalence in Indonesia will reach 14.1 million in 2035 antidiabetic drugs can result from genome variations [2]. Therefore, good management of glycemic control that lead to variations in disposition and response to is required to prevent as well as reduce morbidity and antidiabetic drugs including metformin [5]. mortality due to diabetes mellitus [3]. Our previous study found a variety in the From 2013 to 2017, metformin remained in minimum as well as maximum metformin steady-state the list of Indonesia’s National Formulary as one of concentrations, reaching > 100-fold and 15-fold the oral antidiabetic drugs available up to primary respectively, in 82 T2DM patients who received _______________________________________________________________________________________________________________________________ Open Access Maced J Med Sci. 1 Clinical Science _______________________________________________________________________________________________________________________________ metformin at the similar dosage (1000 mg/day) [6]. As consent was obtained from each patient who was a drug with renal excretion as the primary route of willing to be involved in the study. The research has elimination, metformin has > 0.6 rGC (genetic obtained ethical clearance from the Ethics component), indicating that variations in steady-state Commission of the Faculty of Medicine of Gadjah concentration can result from the involvement of Mada University. genetic factors during the renal clearance of metformin [7]. Genotype Analysis of SLC22A1 Met420del As a hydrophilic base existing at physiological in OCT1 pH as a cationic species (> 99.9%), the effectiveness of metformin pharmacokinetics depends on the Genotyping at SLC22A1 Met420del was function of the transporters involved [8]. One of the carried out using PCR followed by Restriction major transporters known to play an important role in Fragment Length Polymorphism (RFLP). The PCR metformin pharmacokinetics to date is Organic Cation primer design used the forward primer 5'- Transporter 1 (OCT1), a protein mainly expressed in AGGTTCACGGACTCTGTGCT-3' and the reverse liver sinusoidal cells, renal basolateral membrane [9], primer 5'-AAGCTGGAGTGTGCGATCT-3'. The PCR and apical membrane of tubule cells [10], which conditions for amplification consisted of initial transports metformin to hepatocytes as the target of denaturation at 93°C for 3 minutes followed by 35 its antihyperglycemic action as well as plays a part in denaturation cycles at 93°C for 45 seconds, annealing the elimination and reabsorption in the renal tubules. at 58°C for 35 seconds, and extension at 72°C for 35 Variations in SLC22A1 gene have led to changes in seconds as well as a final extension at 72°C for 5 the function of OCT1 protein, which results in varied minutes. The amplification products (600bp) were plasma concentrations of metformin and decreased then analysed in 1% agarose gel for 30 minutes at amount of metformin in the receptors, making the 100 Volt followed by restriction digestion using BspHI, therapeutic response to metformin decline. Such incubated for ± 12 hours at 37°C. BspHI enzyme cut genetic variations can take the form of methionine T-CATGA sequence at the 197th base of DNA deletion at codon 420 located in the ninth template. AA genotype was recognised and digested transmembrane domain of SLC22A1, which is the by the enzyme. PCR products with the T-CATTT highest functional variant in the gene. Several studies sequence would not be recognised by the BspHI have found that SLC22A1 gene variants cause enzyme, leaving the product undigested. The resulted variability in both steady-state concentrations of products were then analysed in 1% agarose gel and metformin and glycemic response [11], [12], [13], [14]. quantified using floor safe. Digestion of amplification Also, recent research showed that genetic variations products resulted in 600 bp fragments for AA (wild in the gene are related to the level of gastrointestinal type) genotype as well as 403 bp and 197 bp intolerance due to the use of metformin [15], [16]. fragments for aa (mutant) genotype, and 600 bp, 403 bp, and 197 bp for heterozygotes (Aa). This research is a part of pharmacogenetic studies of metformin use among the Indonesian The results were presented in percentage population suffering from T2DM. Analysis of genetic using the Hardy-Weinberg principle. Referring to the variants in the target gene that encodes metformin previous research, the A allele (wild type) showed a transporters is important to provide information on the GAT base deletion on DNA target sequences, and an profile of genetic variation in Indonesian population allele (mutant) indicated GAT base insertion in DNA which can then be further researched on the sequences [13]. implications for the use of metformin as a first-line antidiabetic drug for T2DM and its safety for the allele gastrointestinal tract. Therefore, this study aims to determine the allele frequency distribution of SLC22A1 Met420del gene encoding OCT1 among the a allele Javanese population, the largest ethnic group in Indonesia with T2DM. Results Methods A total of 100 Javanese-Indonesian patients with T2DM were involved for the genotype analysis of Recruitment of Subjects the SLC22A1 Met420del gene in OCT1. T2DM patients were recruited from 9 existing Characteristics of the research subjects are described healthcare facilities in Yogyakarta Special Province in Table 1. categorised as Javanese based on their three The patients involved in
Load more

Recommended publications
  • Table S1 the Four Gene Sets Derived from Gene Expression Profiles of Escs and Differentiated Cells
    Table S1 The four gene sets derived from gene expression profiles of ESCs and differentiated cells Uniform High Uniform Low ES Up ES Down EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol 269261 Rpl12 11354 Abpa 68239 Krt42 15132 Hbb-bh1 67891 Rpl4 11537 Cfd 26380 Esrrb 15126 Hba-x 55949 Eef1b2 11698 Ambn 73703 Dppa2 15111 Hand2 18148 Npm1 11730 Ang3 67374 Jam2 65255 Asb4 67427 Rps20 11731 Ang2 22702 Zfp42 17292 Mesp1 15481 Hspa8 11807 Apoa2 58865 Tdh 19737 Rgs5 100041686 LOC100041686 11814 Apoc3 26388 Ifi202b 225518 Prdm6 11983 Atpif1 11945 Atp4b 11614 Nr0b1 20378 Frzb 19241 Tmsb4x 12007 Azgp1 76815 Calcoco2 12767 Cxcr4 20116 Rps8 12044 Bcl2a1a 219132 D14Ertd668e 103889 Hoxb2 20103 Rps5 12047 Bcl2a1d 381411 Gm1967 17701 Msx1 14694 Gnb2l1 12049 Bcl2l10 20899 Stra8 23796 Aplnr 19941 Rpl26 12096 Bglap1 78625 1700061G19Rik 12627 Cfc1 12070 Ngfrap1 12097 Bglap2 21816 Tgm1 12622 Cer1 19989 Rpl7 12267 C3ar1 67405 Nts 21385 Tbx2 19896 Rpl10a 12279 C9 435337 EG435337 56720 Tdo2 20044 Rps14 12391 Cav3 545913 Zscan4d 16869 Lhx1 19175 Psmb6 12409 Cbr2 244448 Triml1 22253 Unc5c 22627 Ywhae 12477 Ctla4 69134 2200001I15Rik 14174 Fgf3 19951 Rpl32 12523 Cd84 66065 Hsd17b14 16542 Kdr 66152 1110020P15Rik 12524 Cd86 81879 Tcfcp2l1 15122 Hba-a1 66489 Rpl35 12640 Cga 17907 Mylpf 15414 Hoxb6 15519 Hsp90aa1 12642 Ch25h 26424 Nr5a2 210530 Leprel1 66483 Rpl36al 12655 Chi3l3 83560 Tex14 12338 Capn6 27370 Rps26 12796 Camp 17450 Morc1 20671 Sox17 66576 Uqcrh 12869 Cox8b 79455 Pdcl2 20613 Snai1 22154 Tubb5 12959 Cryba4 231821 Centa1 17897
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Interplay Between Metformin and Serotonin Transport in the Gastrointestinal Tract: a Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin
    INTERPLAY BETWEEN METFORMIN AND SEROTONIN TRANSPORT IN THE GASTROINTESTINAL TRACT: A NOVEL MECHANISM FOR THE INTESTINAL ABSORPTION AND ADVERSE EFFECTS OF METFORMIN Tianxiang Han A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy. Chapel Hill 2013 Approved By: Dhiren R. Thakker, Ph.D. Michael Jay, Ph.D. Kim L. R. Brouwer, Pharm.D., Ph.D. Joseph W. Polli, Ph.D. Xiao Xiao, Ph.D. © 2013 Tianxiang Han ALL RIGHTS RESERVED ii ABSTRACT TIANXIANG HAN: Interplay between Metformin and Serotonin Transport in the Gastrointestinal Tract: A Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin (Under the direction of Dhiren R. Thakker, Ph.D.) Metformin is a widely prescribed drug for Type II diabetes mellitus. Previous studies have shown that this highly hydrophilic and charged compound traverses predominantly paracellularly across the Caco-2 cell monolayer, a well-established model for human intestinal epithelium. However, oral bioavailability of metformin is significantly higher than that of the paracellular probe, mannitol (~60% vs ~16%). Based on these observations, the Thakker laboratory proposed a “sponge” hypothesis (Proctor et al., 2008) which states that the functional synergy between apical (AP) transporters and paracellular transport enhances the intestinal absorption of metformin. This dissertation work aims to identify AP uptake transporters of metformin, determine their polarized localization, and elucidate their roles in the intestinal absorption and adverse effects of metformin. Chemical inhibition and transporter-knockdown studies revealed that four transporters, namely, organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT), serotonin reuptake transporter (SERT) and choline high-affinity transporter (CHT) contribute to AP uptake of metformin in Caco-2 cells.
    [Show full text]
  • Plasma Membrane Transporters As Biomarkers and Molecular Targets in Cholangiocarcinoma
    cells Review Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma Jose J.G. Marin * , Rocio I.R. Macias , Candela Cives-Losada, Ana Peleteiro-Vigil , Elisa Herraez y and Elisa Lozano y HEVEFARM Group, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health. University of Salamanca, IBSAL, 37007-Salamanca, Spain; [email protected] (R.I.R.M.); [email protected] (C.C.-L.); [email protected] (A.P.-V.); [email protected] (E.H.); [email protected] (E.L.) * Correspondence: [email protected]; Tel.: +34-663182872 These authors contributed equally to the coordination of this review article. y Academic Editors: Pietro Invernizzi and Chiara Raggi Received: 25 January 2020; Accepted: 19 February 2020; Published: 21 February 2020 Abstract: The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively.
    [Show full text]
  • Screening of Genetic Variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 Genes
    Journal of Human Genetics (2011) 56, 666–670 & 2011 The Japan Society of Human Genetics All rights reserved 1434-5161/11 $32.00 www.nature.com/jhg ORIGINAL ARTICLE Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes Hyun Sub Cheong1,4, Hae Deun Kim2,4, Han Sung Na2,JiOnKim1, Lyoung Hyo Kim1, Seung Hee Kim2, Joon Seol Bae3, Myeon Woo Chung2 and Hyoung Doo Shin1,3 A growing list of membrane-spanning proteins involved in the transport of a large variety of drugs has been recognized and characterized to include peptide and organic anion/cation transporters. Given such an important role of transporter genes in drug disposition process, the role of single-nucleotide polymorphisms (SNPs) in such transporters as potential determinants of interindividual variability in drug disposition and pharmacological response has been investigated. To define the distribution of transporter gene SNPs across ethnic groups, we screened 450 DNAs in cohorts of 250 Korean, 50 Han Chinese, 50 Japanese, 50 African-American and 50 European-American ancestries for 64 SNPs in four transporter genes encoding proteins of the solute carrier family (SLC15A2, SLC22A1, SLC22A2 and SLC22A6). Of the 64 SNPs, 19 were core pharmacogenetic variants and 45 were HapMap tagging SNPs. Polymorphisms were genotyped using the golden gate genotyping assay. After genetic variability, haplotype structures and ethnic diversity were analyzed, we observed that the distributions of SNPs in a Korean population were similar to other Asian groups (Chinese and Japanese), and significantly different from African-American and European-American cohorts. Findings from this study would be valuable for further researches, including pharmacogenetic studies for drug responses.
    [Show full text]
  • Clinical Relevance of a Pharmacogenetic Approach Using
    Cancer Therapy: Clinical Clinical Relevance of a Pharmacogenetic Approach Using Multiple Candidate Genes to Predict Response and Resistance to Imatinib Therapy in Chronic Myeloid Leukemia Dong Hwan (Dennis) Kim,1, 5 Lakshmi Sriharsha,1 Wei Xu,2 Suzanne Kamel-Reid,3 Xiangdong Liu,4 Katherine Siminovitch,4 Hans A. Messner,1and Jeffrey H. Lipton1 Abstract Purpose: Imatinib resistance is major cause of imatinib mesylate (IM) treatment failure in chronic myeloid leukemia (CML) patients. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including amplification and overexpression of the BCR/ABL gene, the tyrosine kinase domain point mutations, and MDR1 gene overexpression. Experimental Design: We investigated the impact of 16 single nucleotide polymorphisms (SNP) in five genes potentially associated with pharmacogenetics of IM, namely ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5,cytochrome P450-3A5; SLC22A1, human organic cation transporter 1; and AGP, a1-acid glycoprotein. The DNAs from peripheral blood samples in 229 patients were genotyped. Results: The GG genotype in ABCG2 (rs2231137), AA genotype in CYP3A5 (rs776746), and advanced stage were significantly associated with poor response to IM especially for major or complete cytogenetic response, whereas the GG genotype at SLC22A1 (rs683369) and advanced stage correlated with high rate of loss of response or treatment failure to IM therapy. Conclusions: We showed that the treatment outcomes of imatinib therapy could be predicted using a novel, multiple candidate gene approach based on the pharmacogenetics of IM. Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor, amplification andoverexpression of the BCR/ABL gene, point especially against BCR/ABL fusion tyrosine kinase, that has mutations in the ATP-binding site with kinase reactivation (3), achievedsuccessful treatment outcomes andimprovedthe life or overexpression of the MDR1 gene (4).
    [Show full text]
  • Characterization of Centrally Expressed Solute Carriers
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1215 Characterization of Centrally Expressed Solute Carriers Histological and Functional Studies with Transgenic Mice SAHAR ROSHANBIN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-9555-8 UPPSALA urn:nbn:se:uu:diva-282956 2016 Dissertation presented at Uppsala University to be publicly examined in B:21, Husargatan. 75124 Uppsala, Uppsala, Friday, 3 June 2016 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Biträdande professor David Engblom (Institutionen för klinisk och experimentell medicin, Cellbiologi, Linköpings Universitet). Abstract Roshanbin, S. 2016. Characterization of Centrally Expressed Solute Carriers. Histological and Functional Studies with Transgenic Mice. (. His). Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1215. 62 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9555-8. The Solute Carrier (SLC) superfamily is the largest group of membrane-bound transporters, currently with 456 transporters in 52 families. Much remains unknown about the tissue distribution and function of many of these transporters. The aim of this thesis was to characterize select SLCs with emphasis on tissue distribution, cellular localization, and function. In paper I, we studied the leucine transporter B0AT2 (Slc6a15). Localization of B0AT2 and Slc6a15 in mouse brain was determined using in situ hybridization (ISH) and immunohistochemistry (IHC), localizing it to neurons, epithelial cells, and astrocytes. Furthermore, we observed a lower reduction of food intake in Slc6a15 knockout mice (KO) upon intraperitoneal injections with leucine, suggesting B0AT2 is involved in mediating the anorexigenic effects of leucine.
    [Show full text]
  • WO 2016/090486 Al 16 June 2016 (16.06.2016) W P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/090486 Al 16 June 2016 (16.06.2016) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 5/071 (2010.01) CI2N 5/073 (2010.01) kind of national protection available): AE, AG, AL, AM, C12N 11/02 (2006.01) C12Q 1/02 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/CA20 15/05 1297 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 9 December 2015 (09.12.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/089,5 12 9 December 2014 (09. 12.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: NATIONAL RESEARCH COUNCIL OF TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, CANADA [CA/CA]; M-55, 1200 Montreal Road, Ottawa, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Ontario K lA 0R6 (CA).
    [Show full text]
  • Role of SLC22A1 Polymorphic Variants in Drug Disposition, Therapeutic Responses, and Drug–Drug Interactions
    The Pharmacogenomics Journal (2015) 15, 473–487 © 2015 Macmillan Publishers Limited All rights reserved 1470-269X/15 www.nature.com/tpj REVIEW Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions C Arimany-Nardi1, H Koepsell2 and M Pastor-Anglada1 The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration–time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area. The Pharmacogenomics Journal (2015) 15, 473–487; doi:10.1038/tpj.2015.78; published online 3 November 2015 SLC22 GENE FAMILY HOCT1 The SLC22 gene family encodes for more than 30 proteins, some The first organic cation transporter (rOCT) was cloned from rat of them acting as organic cation transporters (OCTs), organic kidney in 1994.4 Some years later the mouse (mOCT1)5 and rabbit cation and zwitterion transporters (OCTNs) and organic anion orthologues (rbOCT1)6 were isolated.
    [Show full text]
  • Sunday, April 15, 2018 Monday, April 16, 2018
    Co-Sponsored by: Sunday, April 15, 2018 3:00 pm–5:00 pm Registration Hours 3:00 pm–5:00 pm Exhibit Setup Monday, April 16, 2018 7:00 am–9:00 am Registration Hours 7:00 am–8:00 am Continental Breakfast 7:00 am–9:30 am Exhibit Setup 8:00 am–8:10 am Opening Remarks Steven Louie, Amgen Inc. 8:10 am–9:00 am Keynote Speaker Per Artursson, Ph.D., Uppsala University Session 1: New Transporters, New Transport Mechanisms – Part 1 9:00 am–9:30 am The ABCG5 ABCG8 Sterol Transporter: From Cholesterol Homeostasis to Sitosterolemia Greg Graf, Ph.D., University of Kentucky The session will cover the role of the ABCG5 ABCG8 sterol transporter in neutral sterol absorption and the exclusion of non-cholesterol sterols. Factors that regulate the expression of G5G8 in the liver and intestine, formation of the G5G8 complex, and its trafficking to the cell surface. In addition, the impact of biliary cholesterol and intestinal cholesterol flux on the development of metabolic disease, specifically insulin resistance and hepatic steatosis. Finally, adaptive non-G5G8 pathways for sterol excretion will be explored. 9:30 am–10:00 am Organic Solute Transporter OSTα/β: An Overlooked Transporter in Drug-Bile Acid Interactions Melina Malinen, Ph.D., M.Sc. Pharm., University of North Carolina at Chapel Hill Organic solute transporter OSTα/β is suggested to play a major role in bile acid homeostasis. OSTα- knockout mice and OSTβ-deficient humans exhibit impaired bile acid absorption and synthesis. In addition, OSTα/β is upregulated in the liver of patients with obstructive cholestasis, primary biliary cholangitis, and nonalcoholic steatohepatitis.
    [Show full text]
  • Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
    The Pharmacogenomics Journal (2013) 13, 110–120 & 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13 www.nature.com/tpj ORIGINAL ARTICLE Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3 L Chen1, C Hong2, EC Chen1, Human organic cation transporter 3 (OCT3 and SLC22A3) mediates the 1 1 1 uptake of many important endogenous amines and basic drugs in a variety of SW Yee ,LXu, EU Almof , tissues. OCT3 is identified as one of the important risk loci for prostate cancer, 1 1 3 C Wen , K Fujii , SJ Johns , and is markedly underexpressed in aggressive prostate cancers. The goal D Stryke3, TE Ferrin3, J Simko4, of this study was to identify genetic and epigenetic factors in the promoter X Chen1, JF Costello2 and region that influence the expression level of OCT3. Haplotypes that 1 contained the common variants, g.À81G4delGA (rs60515630) (minor KM Giacomini allele frequency 11.5% in African American) and g.À2G4A (rs555754) 1Department of Bioengineering and Therapeutic (minor allele frequency430% in all ethnic groups) showed significant Sciences, University of California San Francisco, increases in luciferase reporter activities and exhibited stronger transcription San Francisco, CA, USA; 2Department of factor-binding affinity than the haplotypes that contained the major alleles. Neurological Surgery, University of California San Consistent with the reporter assays, OCT3 messenger RNA expression levels Francisco, San Francisco, CA, USA; 3Department of Pharmaceutical Chemistry, University of were significantly higher in Asian (Po0.001) and Caucasian (Po0.05) liver California San Francisco, San Francisco, CA, USA samples from individuals who were homozygous for g.À2A/A in comparison and 4Department of Pathology and Urology, with those homozygous for the g.À2G/G allele.
    [Show full text]
  • RNA Editing of SLC22A3 Drives Early Tumor Invasion and Metastasis In
    RNA editing of SLC22A3 drives early tumor invasion PNAS PLUS and metastasis in familial esophageal cancer Li Fua,b,1,2, Yan-Ru Qinc,1, Xiao-Yan Mingd,1, Xian-Bo Zuoe,f,1, Yu-Wen Diaoa,b,1, Li-Yi Zhangd, Jiaoyu Aic, Bei-Lei Liua,b, Tu-Xiong Huanga,b, Ting-Ting Caoa,b, Bin-Bin Tana,b, Di Xianga,b, Chui-Mian Zenga,b, Jing Gongg,h,i, Qiangfeng Zhangg,h,i, Sui-Sui Dongd, Juan Chend, Haibo Liuj, Jian-Lin Wuk, Robert Z. Qil, Dan Xiem, Li-Dong Wangn, and Xin-Yuan Guand,m,2 aDepartment of Pharmacology, Shenzhen University School of Medicine, Shenzhen, China 518060; bCancer Research Centre, Health Science Center, Shenzhen University, Shenzhen, China 518060; cDepartment of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China 450000; dDepartment of Clinical Oncology, University of Hong Kong, Hong Kong, China; eDepartment of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China 230000; fState Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China 230000; gMOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing 100084, China; hCenter for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China; iCenter for Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China; jKey Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 510150; kState Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China; lDepartment of Biochemistry, Hong Kong University of Sciences and Technology, Hong Kong, China; mState Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China 510275; and nHenan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China 450000 Edited by Dennis A.
    [Show full text]