DOCSLIB.ORG

The Substrate of UDP-Glucuronosyltransferases 2B7, 2B17 and The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Substrate of UDP-Glucuronosyltransferases 2B7, 2B17 and The Pharmacological Reports 70 (2018) 972–980 Contents lists available at ScienceDirect Pharmacological Reports ELSEVIER journal homepage: www.elsevier.com/locate/pharep Original article Drug-drug interaction potential of antitumor acridine agent C-1748: Check for updates The substrate of UDP-glucuronosyltransferases 2B7, 2B17 and the inhibitor of 1A9 and 2B7 Anna Mróz, Izabela Ryska, Hanna Sominko, Anna Bejrowska, Zofia Mazerska* Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdansk University of Technology, Gdansk, Poland A R T I C L E I N F O A B S T R A C T 0 Article history: Background: The compound 9-(2 -hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), the promis- Received 7 August 2017 ing antitumor agent developed in our laboratory was determined to undergo phase I metabolic pathways. Received in revised form 14 March 2018 The present studies aimed to know its biotransformation with phase II enzymes – UDP- Accepted 21 March 2018 glucuronosyltransferases (UGTs) and its potential to be engaged in drug-drug interactions arising from Available online 22 March 2018 the modulation of UGT activity. Methods: UGT-mediated transformations with rat liver (RLM), human liver (HLM), and human intestine Keywords: (HIM) microsomes and with 10 recombinant human isoenzymes were investigated. Studies on the ability Antitumor agent C-1748 of C-1748 to inhibit UGT were performed with HLM, HT29 colorectal cancer cell homogenate and the Drug-drug interactions selected recombinant UGT isoenzymes. The reactions were monitored using HPLC-UV/Vis method and II phase metabolism Glucuronidation the C-1748 metabolite structure was determined with ESI-TOF-MS/MS analysis. β Enzyme inhibition Results: Pseudo-molecular ion (m/z 474.1554) and the experiment with -glucuronidase indicated that UGT O-glucuronide of C-1748 was formed in the presence of microsomal fractions. This reaction was selectively catalyzed by UGT2B7 and 2B17. High inhibitory effect of C-1748 was shown towards isoenzyme UGT1A9 (IC50 = 39.7 mM) and significant but low inhibitory potential was expressed in HT29 cell homogenate (IC50 = 84.5 mM). The mixed-type inhibition mechanism (Ki = 17.0 mM; Ki’ = 81.0 mM), induced by C-1748 was observed for recombinant UGT1A9 glucuronidation, whereas HT29 cell homogenate resulted in noncompetitive inhibition (Ki = 94.6 mM). Conclusions: The observed UGT-mediated metabolism of C-1748 and its ability to inhibit UGT activity should be considered as the potency for drug resistance and drug-drug interactions in the prospective multidrug therapy. © 2018 The Authors. Published by Elsevier B.V. on behalf of Institute of Pharmacology, Polish Academy of Sciences. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ 4.0/). Introduction supplements can influence the drug metabolism by the inhibition of enzymes activity. UGT inhibition is regarded as one of the most UDP-glucuronosyltransferases (UGTs) catalyze the glucuroni- important factor for clinical drug-drug and herb-drug interactions dation reaction of many endogenous and exogenous compounds (DDIs, HDI) [4]. Common modulation effect on UGT activity is due leading to the metabolites more polar than aglycones, which can be to the fact that glucuronidation accounts for approximately 35% of readily excreted outside the body [1]. To date, at least 22 human phase II drug metabolism reactions [1]. UGT isoenzymes have been identified, which were classified into It was shown that UGT-based DDIs were engaged in antidia- four gene families, UGT1, UGT2, UGT3 and UGT8 [2]. The individual betic rapaglinide metabolism impairment during hypolipidemic UGT isoenzymes exhibit distinct, but overlapping, patterns of the gemfibrozil coadministration [5]. The nonsteroidal anti-inflam- substrates and inhibitor selectivities [3]. matory drug niflumic acid, being the substrate for UGT1A1 and to For a drug that undergoes UGT-mediated biotransformation, a lesser extent for several other UGTs is capable of inhibiting both simultaneous administration of medications and dietary UGT1A9 and UGT2B7 [6]. Miners et al. demonstrated that niflumic acid inhibited propofol and acetaminophen glucuronidation by HLM and recombinant isoenzymes [7]. Antitumor kinase inhib- itors such as sorafenib, erlotinib and gefitinib were shown to * Corresponding author. fi E-mail address: zofi[email protected] (Z. Mazerska). inhibit UGT1A1 [8]. As a result the signi cant increase in the https://doi.org/10.1016/j.pharep.2018.03.007 1734-1140/© 2018 The Authors. Published by Elsevier B.V. on behalf of Institute of Pharmacology, Polish Academy of Sciences. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). A. Mróz et al. / Pharmacological Reports 70 (2018) 972–980 973 exposure to irinotecan and its active metabolite SN-38 was Cell culture and homogenate preparation observed [9]. Sorafenib exhibited also strong inhibition towards microsomal UGT1A9 [10]. Human colorectal adenocarcinoma cell line HT29 was obtained Recently, many reports related to UGT-based HDIs have been from D. Banerjee from Department of Medicine and Pharmacology, published. For example licorice flavonoid licochalcone A exhibited Cancer Institute of New Jersey, USA. The cells were maintained as a broad spectrum of inhibition against most of the human UGTs described previously [14]. Confluent cells were trypsinized with [11 ], whereas lactone compounds from Andrographis paniculata Trypsin-EDTA solution (Sigma-Aldrich, St. Louis, MO, USA) and specifically inhibited UGT2B7 isoenzyme [12]. Specific stereo- centrifuged (1000 rpm, 5 min, 4 C). The pellet was washed two selective inhibitory effect on most UGT isoenzymes was demon- times with phosphate-buffered saline (pH 7.4). The cell suspension strated for triterpenoid saponins found in ginseng [13]. was subjected to homogenization for 5 min in glass tissue grinder. 0 The studied here compound 9-(2 -hydroxyethylamino)-4- Total cell homogenate protein concentration (28 mg/ml) was methyl-1-nitroacridine, C-1748 is one of the most promising determined using the Bradford assay (Bio-Rad, USA). antitumor agents developed in our laboratory. It exhibited strong cytotoxic activity towards colon cancer cell lines [14] as well as Reactions with microsomal and recombinant UGTs high antitumor activity against prostate carcinoma xenografts in nude mice [15]. Animal toxicity studies revealed C-1748 to have Screening for glucuronidation activity towards C-1748 was very low systemic toxicity, which allowed its selection for conducted with RLM, HLM, HIM and 10 recombinant human UGT preclinical studies [16,17]. We showed earlier that C-1748 isoenzymes. The proteins at a final concentration of 1 mg/ml were underwent phase I metabolism with human liver microsomes, incubated with 0.1 mM C-1748 (20 mM stock solution in DMSO human recombinant cytochrome P450 reductase (CPR) and in diluted with water) in a buffer containing 50 mM Tris-HCl (pH 7.5), HepG2 cell line with the crucial role of hypoxic conditions. 8 mM MgCl2 and 25 mg/ml alamethicin. After preincubation for Metabolites identified as 1-aminoacridine derivatives and this one 5 min at 37 C, UDPGA in water (final concentration of 5 mM) was with an additional 6-membered ring were found. The key role of added to initiate the reaction. The metabolism process was CPR, not cytochrome P450 3A4, in the activation mechanism of maintained at 37 C for incubation times: 0/10/30/60/90/120/180/ C-1748, was demonstrated recently. However, the overexpression 240 min and 0/30/60/120/240 min in the case of microsomal of both CPR and P450 3A4 changed the proapoptotic activity and fractions and recombinant UGT isoenzymes, respectively. For sensitized pancreatic cancer cells AsPC-1 to this drug [18,19]. kinetic analyses of C-1748 glucuronidation in HLM and HIM the Our current research is focused on phase II metabolism of substrate concentrations were: 0.01/0.025/0.05/0.1/0.25 mM. C-1748 UGT, as well as to investigate the effect of this compound on Other reaction mixture components concentrations and reaction UGT activity. Metabolism of C-1748 catalyzed by UGT in conditions were as described above with the incubation time set at microsomal fractions and with human recombinant UGT iso- 60 min. The reactions were stopped by adding an equal volume enzymes was investigated and the structure of C-1748 glucuronide (50 ml) of ice-cold methanol, which contained 0.025 mM C-857 as metabolite was identified. The effect of the drug on UGT activity an internal standard in the case of microsomal fractions. In order to was studied with three enzymatic systems: microsomal fraction, remove the proteins, the samples were centrifuged (13,400 rpm, HT29 cell homogenate, and the selected human recombinant UGT 10 min). The supernatant fractions were used for HPLC analysis. isoenzymes. β-glucuronidase assay Materials and methods Hydrolysis with β-glucuronidase (GUS) was used to identify Chemicals and reagents the glucuronide peak. After incubation of 0.1 mM C-1748 with 0.5 mg/ml RLM and 5 mM UDPGA for 30 min, 1000 U of GUS was 0 C-1748 9-(2 -hydroxyethylamino)-4-methyl-1-nitroacridine added, and the sample was incubated for the following 90 min. The 0 and C-857 9-(2 -hydroxyethylamino)-1-nitroacridine were syn- reaction was performed and prepared for HPLC analysis as thesised according to the method described in Ref [20] 7-ethyl-10- described above for microsomal and recombinant UGTs. hydroxycamptothecin (SN-38), 7-hydroxy-4-trifluoromethylcou- marin (HFC), 7-hydroxycoumarin, alamethicin 5 mg/ml in DMSO Investigation of UGT inhibition by C-1748 from Trichoderma viride, ammonium formate, dimethyl sulfoxide (DMSO), epirubicin hydrochloride, formic acid, magnesium HFC, a nonselective substrate for UGT, was used as a probe chloride, trifluoperazine dihydrochloride (TFP), Tris hydrochloride, substrate for HLM, UGT1A9, UGT1A10 and HT29 cells homogenate. 0 uridine 5 -diphosphoglucuronic acid trisodium salt (UDPGA) were For UGT1A1, UGT1A4 and UGT2B7 selective substrates: SN-38, TFP purchased from Sigma-Aldrich (St.
Load more

Recommended publications
  • Screening and Identification of Key Biomarkers in Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Screening and identification of key biomarkers in clear cell renal cell carcinoma based on bioinformatics analysis Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignancy of the urinary system. The pathogenesis and effective diagnosis of ccRCC have become popular topics for research in the previous decade. In the current study, an integrated bioinformatics analysis was performed to identify core genes associated in ccRCC. An expression dataset (GSE105261) was downloaded from the Gene Expression Omnibus database, and included 26 ccRCC and 9 normal kideny samples. Assessment of the microarray dataset led to the recognition of differentially expressed genes (DEGs), which was subsequently used for pathway and gene ontology (GO) enrichment analysis.
    [Show full text]
  • Propranolol-Mediated Attenuation of MMP-9 Excretion in Infants with Hemangiomas
    Supplementary Online Content Thaivalappil S, Bauman N, Saieg A, Movius E, Brown KJ, Preciado D. Propranolol-mediated attenuation of MMP-9 excretion in infants with hemangiomas. JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2013.4773 eTable. List of All of the Proteins Identified by Proteomics This supplementary material has been provided by the authors to give readers additional information about their work. © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable. List of All of the Proteins Identified by Proteomics Protein Name Prop 12 mo/4 Pred 12 mo/4 Δ Prop to Pred mo mo Myeloperoxidase OS=Homo sapiens GN=MPO 26.00 143.00 ‐117.00 Lactotransferrin OS=Homo sapiens GN=LTF 114.00 205.50 ‐91.50 Matrix metalloproteinase‐9 OS=Homo sapiens GN=MMP9 5.00 36.00 ‐31.00 Neutrophil elastase OS=Homo sapiens GN=ELANE 24.00 48.00 ‐24.00 Bleomycin hydrolase OS=Homo sapiens GN=BLMH 3.00 25.00 ‐22.00 CAP7_HUMAN Azurocidin OS=Homo sapiens GN=AZU1 PE=1 SV=3 4.00 26.00 ‐22.00 S10A8_HUMAN Protein S100‐A8 OS=Homo sapiens GN=S100A8 PE=1 14.67 30.50 ‐15.83 SV=1 IL1F9_HUMAN Interleukin‐1 family member 9 OS=Homo sapiens 1.00 15.00 ‐14.00 GN=IL1F9 PE=1 SV=1 MUC5B_HUMAN Mucin‐5B OS=Homo sapiens GN=MUC5B PE=1 SV=3 2.00 14.00 ‐12.00 MUC4_HUMAN Mucin‐4 OS=Homo sapiens GN=MUC4 PE=1 SV=3 1.00 12.00 ‐11.00 HRG_HUMAN Histidine‐rich glycoprotein OS=Homo sapiens GN=HRG 1.00 12.00 ‐11.00 PE=1 SV=1 TKT_HUMAN Transketolase OS=Homo sapiens GN=TKT PE=1 SV=3 17.00 28.00 ‐11.00 CATG_HUMAN Cathepsin G OS=Homo
    [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]
  • Enzyme DHRS7
    Toward the identification of a function of the “orphan” enzyme DHRS7 Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Selene Araya, aus Lugano, Tessin Basel, 2018 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Alex Odermatt (Fakultätsverantwortlicher) und Prof. Dr. Michael Arand (Korreferent) Basel, den 26.6.2018 ________________________ Dekan Prof. Dr. Martin Spiess I. List of Abbreviations 3α/βAdiol 3α/β-Androstanediol (5α-Androstane-3α/β,17β-diol) 3α/βHSD 3α/β-hydroxysteroid dehydrogenase 17β-HSD 17β-Hydroxysteroid Dehydrogenase 17αOHProg 17α-Hydroxyprogesterone 20α/βOHProg 20α/β-Hydroxyprogesterone 17α,20α/βdiOHProg 20α/βdihydroxyprogesterone ADT Androgen deprivation therapy ANOVA Analysis of variance AR Androgen Receptor AKR Aldo-Keto Reductase ATCC American Type Culture Collection CAM Cell Adhesion Molecule CYP Cytochrome P450 CBR1 Carbonyl reductase 1 CRPC Castration resistant prostate cancer Ct-value Cycle threshold-value DHRS7 (B/C) Dehydrogenase/Reductase Short Chain Dehydrogenase Family Member 7 (B/C) DHEA Dehydroepiandrosterone DHP Dehydroprogesterone DHT 5α-Dihydrotestosterone DMEM Dulbecco's Modified Eagle's Medium DMSO Dimethyl Sulfoxide DTT Dithiothreitol E1 Estrone E2 Estradiol ECM Extracellular Membrane EDTA Ethylenediaminetetraacetic acid EMT Epithelial-mesenchymal transition ER Endoplasmic Reticulum ERα/β Estrogen Receptor α/β FBS Fetal Bovine Serum 3 FDR False discovery rate FGF Fibroblast growth factor HEPES 4-(2-Hydroxyethyl)-1-Piperazineethanesulfonic Acid HMDB Human Metabolome Database HPLC High Performance Liquid Chromatography HSD Hydroxysteroid Dehydrogenase IC50 Half-Maximal Inhibitory Concentration LNCaP Lymph node carcinoma of the prostate mRNA Messenger Ribonucleic Acid n.d.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2003/0082511 A1 Brown Et Al
    US 20030082511A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0082511 A1 Brown et al. (43) Pub. Date: May 1, 2003 (54) IDENTIFICATION OF MODULATORY Publication Classification MOLECULES USING INDUCIBLE PROMOTERS (51) Int. Cl." ............................... C12O 1/00; C12O 1/68 (52) U.S. Cl. ..................................................... 435/4; 435/6 (76) Inventors: Steven J. Brown, San Diego, CA (US); Damien J. Dunnington, San Diego, CA (US); Imran Clark, San Diego, CA (57) ABSTRACT (US) Correspondence Address: Methods for identifying an ion channel modulator, a target David B. Waller & Associates membrane receptor modulator molecule, and other modula 5677 Oberlin Drive tory molecules are disclosed, as well as cells and vectors for Suit 214 use in those methods. A polynucleotide encoding target is San Diego, CA 92121 (US) provided in a cell under control of an inducible promoter, and candidate modulatory molecules are contacted with the (21) Appl. No.: 09/965,201 cell after induction of the promoter to ascertain whether a change in a measurable physiological parameter occurs as a (22) Filed: Sep. 25, 2001 result of the candidate modulatory molecule. Patent Application Publication May 1, 2003 Sheet 1 of 8 US 2003/0082511 A1 KCNC1 cDNA F.G. 1 Patent Application Publication May 1, 2003 Sheet 2 of 8 US 2003/0082511 A1 49 - -9 G C EH H EH N t R M h so as se W M M MP N FIG.2 Patent Application Publication May 1, 2003 Sheet 3 of 8 US 2003/0082511 A1 FG. 3 Patent Application Publication May 1, 2003 Sheet 4 of 8 US 2003/0082511 A1 KCNC1 ITREXCHO KC 150 mM KC 2000000 so 100 mM induced Uninduced Steady state O 100 200 300 400 500 600 700 Time (seconds) FIG.
    [Show full text]
  • Lipoprotein Lipase: a General Review Moacir Couto De Andrade Júnior1,2*
    Review Article iMedPub Journals Insights in Enzyme Research 2018 www.imedpub.com Vol.2 No.1:3 ISSN 2573-4466 DOI: 10.21767/2573-4466.100013 Lipoprotein Lipase: A General Review Moacir Couto de Andrade Júnior1,2* 1Post-Graduation Department, Nilton Lins University, Manaus, Amazonas, Brazil 2Department of Food Technology, Instituto Nacional de Pesquisas da Amazônia (INPA), Manaus, Amazonas, Brazil *Corresponding author: MC Andrade Jr, Post-Graduation Department, Nilton Lins University, Manaus, Amazonas, Brazil, Tel: +55 (92) 3633-8028; E-mail: [email protected] Rec date: March 07, 2018; Acc date: April 10, 2018; Pub date: April 17, 2018 Copyright: © 2018 Andrade Jr MC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Andrade Jr MC (2018) Lipoprotein Lipase: A General Review. Insights Enzyme Res Vol.2 No.1:3 Abstract Lipoprotein Lipase: Historical Hallmarks, Enzymatic Activity, Characterization, and Carbohydrates (e.g., glucose) and lipids (e.g., free fatty acids or FFAs) are the most important sources of energy Present Relevance in Human for most organisms, including humans. Lipoprotein lipase (LPL) is an extracellular enzyme (EC 3.1.1.34) that is Pathophysiology and Therapeutics essential in lipoprotein metabolism. LPL is a glycoprotein that is synthesized and secreted in several tissues (e.g., Macheboeuf, in 1929, first described chemical procedures adipose tissue, skeletal muscle, cardiac muscle, and for the isolation of a plasma protein fraction that was very rich macrophages). At the luminal surface of the vascular in lipids but readily soluble in water, such as a lipoprotein [1].
    [Show full text]
  • Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics
    ORIGINAL RESEARCH published: 03 February 2017 doi: 10.3389/fphar.2017.00023 Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics Michèle Rouleau, Yannick Audet-Delage, Sylvie Desjardins, Mélanie Rouleau, Camille Girard-Bock and Chantal Guillemette * Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Faculty of Pharmacy, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec, QC, Canada The conjugative metabolism mediated by UDP-glucuronosyltransferase enzymes (UGTs) significantly influences the bioavailability and biological responses of endogenous molecule substrates and xenobiotics including drugs. UGTs participate in the regulation of cellular homeostasis by limiting stress induced by toxic molecules, and by Edited by: controlling hormonal signaling networks. Glucuronidation is highly regulated at genomic, Yuji Ishii, transcriptional, post-transcriptional and post-translational levels. However, the UGT Kyushu University, Japan protein interaction network, which is likely to influence glucuronidation, has received Reviewed by: little attention. We investigated the endogenous protein interactome of human UGT1A Ben Lewis, Flinders University, Australia enzymes in main drug metabolizing non-malignant tissues where UGT expression is Shinichi Ikushiro, most prevalent, using an unbiased proteomics approach. Mass spectrometry analysis Toyama Prefectural University, Japan of affinity-purified UGT1A enzymes and associated protein complexes in liver,
    [Show full text]
  • Ceramide Galactosyltransferase (UGT8) Is a Molecular Marker of Breast Cancer Malignancy and Lung Metastases
    British Journal of Cancer (2010) 103, 524 – 531 & 2010 Cancer Research UK All rights reserved 0007 – 0920/10 www.bjcancer.com Ceramide galactosyltransferase (UGT8) is a molecular marker of breast cancer malignancy and lung metastases 1,6,7 2 3 1 4 1 5 P Dzie¸giel , T Owczarek , E Plaz`uk , A Gomułkiewicz , M Majchrzak , M Podhorska-Około´w , K Driouch , 5 ,2,3 R Lidereau and M Ugorski* 1Department of Histology and Embryology, Medical University, T. Chałubin´skiego 6a, Wrocław 50–368, Poland; 2Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, C. Norwida 31, Wrocław 50–357, Poland; 3 Laboratory of Glycobiology and Cell Interactions, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 4 R. Weigla 12, Wrocław 53–114, Poland; Department of Thoracic Surgery, Medical University, Grabiszyn´ska 105, Wrocław 53–430, Poland; 5 6 ´ Oncogenetics laboratory/INSERM U 735, Saint-Cloud, France; Department of Histology and Embryology, Medical University, Swie¸cickiego 6, 7 Poznan´ 61–781, Poland; Department of Pathology, Lower Silesian Oncology Center, Wrocław 53–413, Pl. Hirszfelda 12, Poland BACKGROUND: It was shown recently on the level of gene expression that UGT8, coding UDP-galactose:ceramide galactosyltransferase, is one of six genes whose elevated expression correlated with a significantly increased the risk of lung metastases in breast cancer patients. In this study primary tumours and their lung metastases as well as breast cancer cell lines were analysed for UGT8 expression at the protein level. METHODS: Expression of UGT8 in breast cancer tissue specimens and breast cancer cell lines was analysed using IHC, real-time PCR and Western blotting.
    [Show full text]
  • (A) Up-Regulated Genes in HCC827-GR-High2 Compared to Parental HCC827
    Table S2. Results of expression profiling analysis (A) Up-regulated genes in HCC827-GR-high2 compared to parental HCC827 Fold Fold Fold Unique ID Symbol Unique ID Symbol Unique ID Symbol change* change* change* ILMN_1709348 ALDH1A1 577.587 ILMN_2310814 MAPT 13.003 ILMN_1741017 PIP4K2B 7.331 ILMN_1651354 SPP1 441.316 ILMN_1748650 MRPL45 12.988 ILMN_3237623 RNY1 7.297 ILMN_1701831 GSTA1 260.591 ILMN_1755897 UGT2B7 12.629 ILMN_1734897 SLC4A4 7.285 ILMN_1658835 CAV2 12.357 ILMN_1746359 RERG 7.280 ILMN_2094875 ABCB1 183.050 ILMN_1678939 VNN2 11.935 ILMN_1671337 SLC2A5 7.257 ILMN_3251540 GSTA2 145.982 ILMN_1729905 GAL3ST1 11.910 ILMN_1691606 LYG2 7.254 ILMN_2062468 IGFBP7 127.721 ILMN_1672536 FBLN1 11.716 ILMN_1785646 PMP22 7.246 ILMN_1795190 CLDN2 111.439 ILMN_1796339 PLEKHA2 11.631 ILMN_1737387 LOC728441 7.207 ILMN_1782937 LOC647169 98.612 ILMN_1676563 HTRA1 11.592 ILMN_1684401 FMO1 7.117 ILMN_1754247 SLC3A1 81.001 ILMN_3263423 LOC100129027 11.346 ILMN_1687035 ADAMTSL4 7.098 ILMN_1662795 CA2 79.581 ILMN_1694898 LOC653857 10.906 ILMN_2153572 MAGEA3 7.086 ILMN_2168747 GSTA2 66.250 ILMN_2404625 LAT 10.560 ILMN_1784283 USH1C 7.079 ILMN_1764228 DAB2 64.709 ILMN_1666546 DUSP14 10.375 ILMN_1731374 CPE 7.046 ILMN_1675797 EPDR1 63.605 ILMN_1764571 ARHGAP23 10.299 ILMN_1765446 EMP3 6.933 ILMN_1708341 PDZK1 59.714 ILMN_3200140 LOC645638 10.284 ILMN_1754002 IL1F8 6.863 ILMN_1713529 SEMA6A 52.575 ILMN_3244343 SNORA21 10.171 ILMN_1878007 FUT9 6.835 ILMN_1708391 NR1H4 43.218 ILMN_1671489 PC 10.075 ILMN_1699208 NAP1L1 6.763 ILMN_2412336 AKR1C2 42.826 ILMN_2404688
    [Show full text]
  • Figure S1. Reverse Transcription‑Quantitative PCR Analysis of ETV5 Mrna Expression Levels in Parental and ETV5 Stable Transfectants
    Figure S1. Reverse transcription‑quantitative PCR analysis of ETV5 mRNA expression levels in parental and ETV5 stable transfectants. (A) Hec1a and Hec1a‑ETV5 EC cell lines; (B) Ishikawa and Ishikawa‑ETV5 EC cell lines. **P<0.005, unpaired Student's t‑test. EC, endometrial cancer; ETV5, ETS variant transcription factor 5. Figure S2. Survival analysis of sample clusters 1‑4. Kaplan Meier graphs for (A) recurrence‑free and (B) overall survival. Survival curves were constructed using the Kaplan‑Meier method, and differences between sample cluster curves were analyzed by log‑rank test. Figure S3. ROC analysis of hub genes. For each gene, ROC curve (left) and mRNA expression levels (right) in control (n=35) and tumor (n=545) samples from The Cancer Genome Atlas Uterine Corpus Endometrioid Cancer cohort are shown. mRNA levels are expressed as Log2(x+1), where ‘x’ is the RSEM normalized expression value. ROC, receiver operating characteristic. Table SI. Clinicopathological characteristics of the GSE17025 dataset. Characteristic n % Atrophic endometrium 12 (postmenopausal) (Control group) Tumor stage I 91 100 Histology Endometrioid adenocarcinoma 79 86.81 Papillary serous 12 13.19 Histological grade Grade 1 30 32.97 Grade 2 36 39.56 Grade 3 25 27.47 Myometrial invasiona Superficial (<50%) 67 74.44 Deep (>50%) 23 25.56 aMyometrial invasion information was available for 90 of 91 tumor samples. Table SII. Clinicopathological characteristics of The Cancer Genome Atlas Uterine Corpus Endometrioid Cancer dataset. Characteristic n % Solid tissue normal 16 Tumor samples Stagea I 226 68.278 II 19 5.740 III 70 21.148 IV 16 4.834 Histology Endometrioid 271 81.381 Mixed 10 3.003 Serous 52 15.616 Histological grade Grade 1 78 23.423 Grade 2 91 27.327 Grade 3 164 49.249 Molecular subtypeb POLE 17 7.328 MSI 65 28.017 CN Low 90 38.793 CN High 60 25.862 CN, copy number; MSI, microsatellite instability; POLE, DNA polymerase ε.
    [Show full text]
  • Resveratrol Inhibits Cell Cycle Progression by Targeting Aurora Kinase a and Polo-Like Kinase 1 in Breast Cancer Cells
    3696 ONCOLOGY REPORTS 35: 3696-3704, 2016 Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells RUBICELI MEDINA-AGUILAR1, LAURENCE A. Marchat2, ELENA ARECHAGA OCAMPO3, Patricio GARIGLIO1, JAIME GARCÍA MENA1, NICOLÁS VILLEGAS SEPÚlveda4, MACARIO MartÍNEZ CASTILLO4 and CÉSAR LÓPEZ-CAMARILLO5 1Department of Genetics and Molecular Biology, CINVESTAV-IPN, Mexico D.F.; 2Molecular Biomedicine Program and Biotechnology Network, National School of Medicine and Homeopathy, National Polytechnic Institute, Mexico D.F.; 3Natural Sciences Department, Metropolitan Autonomous University, Mexico D.F.; 4Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico D.F.; 5Oncogenomics and Cancer Proteomics Laboratory, Universidad Autónoma de la Ciudad de México, Mexico D.F., Mexico Received December 4, 2015; Accepted January 8, 2016 DOI: 10.3892/or.2016.4728 Abstract. The Aurora protein kinase (AURKA) and the MDA-MB-231 and MCF-7 cells. By western blot assays, we Polo-like kinase-1 (PLK1) activate the cell cycle, and they confirmed that resveratrol suppressed AURKA, CCND1 and are considered promising druggable targets in cancer CCNB1 at 24 and 48 h. In summary, we showed for the first time therapy. However, resistance to chemotherapy and to specific that resveratrol regulates cell cycle progression by targeting small-molecule inhibitors is common in cancer patients; thus AURKA and PLK1. Our findings highlight the potential use of alternative therapeutic approaches are needed to overcome resveratrol as an adjuvant therapy for breast cancer. clinical resistance. Here, we showed that the dietary compound resveratrol suppressed the cell cycle by targeting AURKA Introduction and PLK1 kinases. First, we identified genes modulated by resveratrol using a genome-wide analysis of gene expression Cancer development results from the interaction between in MDA-MB-231 breast cancer cells.
    [Show full text]