DOCSLIB.ORG

Identification of Novel Inhibitors of the Steroid Sulfate Carrier 'Sodium

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of Novel Inhibitors of the Steroid Sulfate Carrier 'Sodium Molecular and Cellular Endocrinology 428 (2016) 133e141 Contents lists available at ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Identification of novel inhibitors of the steroid sulfate carrier ‘sodium- dependent organic anion transporter’ SOAT (SLC10A6)by pharmacophore modelling* Gary Grosser a, Karl-Heinz Baringhaus b, Barbara Doring€ a, Werner Kramer b, * Ernst Petzinger a, Joachim Geyer a, a Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, 35392 Giessen, Germany b Sanofi-Aventis Deutschland GmbH, R&D, LGCR, Structure, Design and Informatics, Building G 878, 65926 Frankfurt am Main, Germany article info abstract Article history: The sodium-dependent organic anion transporter SOAT specifically transports sulfated steroid hormones Received 27 November 2015 and is supposed to play a role in testicular steroid regulation and male fertility. The present study aimed Received in revised form to identify novel specific SOAT inhibitors for further in vitro and in vivo studies on SOAT function. More 25 February 2016 than 100 compounds of different molecular structures were screened for inhibition of the SOAT- Accepted 21 March 2016 mediated transport of dehydroepiandrosterone sulfate in stably transfected SOAT-HEK293 cells. Available online 23 March 2016 Twenty-five of these with IC50 values covering four orders of magnitude were selected as training set for 3D pharmacophore modelling. The SOAT pharmacophore features were calculated by CATALYST and Keywords: consist of three hydrophobic sites and two hydrogen bond acceptors. By substrate database screening, SOAT m DHEAS transport compound T 0511-1698 was predicted as a novel SOAT inhibitor with an IC50 of 15 M. This value was ASBT confirmed by cell-based transport assays. Therefore, the developed SOAT pharmacophore model Pharmacophore model demonstrated its suitability in predicting novel SOAT inhibitors. Inhibitor © 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC- SLC10 ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction (Mueller et al., 2015). However, sulfo-conjugated steroid hormones can actively be imported into specific target cells via uptake carriers Sulfated steroid hormones, such as dehydroepiandrosterone and, after hydrolysis by the steroid sulfatase (StS) (so-called sulfa- sulfate (DHEAS) or estrone-3-sulfate, are usually considered to be tase pathway), contribute to the overall steroid regulation (Reed biologically inactive metabolites as they cannot activate classical et al., 2005; Pasqualini and Chetrite, 2012; Labrie, 2015). In 2004 steroid receptors (Strott, 2002). They are present in the blood cir- we identified a novel uptake carrier, named sodium-dependent culation at quite high concentrations, but generally exhibit low organic anion transporter SOAT, which specifically transports membrane permeation due to their physicochemical properties sulfated steroid hormones, such as DHEAS, estrone-3-sulfate, b- estradiol-3-sulfate, pregnenolone sulfate, and androstenediol-3- sulfate in a sodium-dependent manner (Geyer et al., 2004). In rat Abbreviations: ASBT, apical sodium-dependent bile acid transporter; BSP, bro- and mouse, Soat showed a broader tissue expression, including mosulfophthalein; DHEAS, dehydroepiandrosterone sulfate; FRT, Flp recombinase skin, testis and lung (Geyer et al., 2004; Grosser et al., 2013), while target site; HEK293, Human Embryonic Kidney 293 cells; IC50, inhibitory concen- þ in humans SOAT is predominantly expressed in the testis with tration 50; NTCP, Na /taurocholate co-transporting polypeptide; PBS, phosphate- buffered saline; QSAR, quantitative structure-activity relationship; SLC10, lower expression in the placenta and breast tissue (Geyer et al., solute carrier family 10; SOAT, sodium-dependent organic anion transporter; TC, 2007). In the testis, SOAT/Soat was localised to spermatocytes and taurocholic acid; TLCS, taurolithocholic acid 3-sulfate. round spermatids and, therefore, this carrier is supposed to play a * This manuscript is dedicated to Prof. Dr. Ernst Petzinger who suddenly died role in testicular steroid regulation and male fertility (Fietz et al., fi during nalizing of this manuscript, in remembrance of his person and his aca- 2013; Grosser et al., 2013). More recently, SOAT expression was demic achievements. * Corresponding author. Justus Liebig University of Giessen, Institute of Phar- also demonstrated in breast cancer tissue (unpublished data). Here, macology and Toxicology, Biomedical Research Center Seltersberg (BFS), Schu- SOAT may contribute to the hormone-dependent proliferation due bertstr. 81, 35392 Giessen, Germany. to the import of estrone-3-sulfate and even DHEAS, making SOAT a E-mail address: [email protected] (J. Geyer). http://dx.doi.org/10.1016/j.mce.2016.03.028 0303-7207/© 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). 134 G. Grosser et al. / Molecular and Cellular Endocrinology 428 (2016) 133e141 potential drug target for anti-proliferative therapy. number NM_000452. SOAT (gene symbol SLC10A6) phylogenetically belongs to the solute carrier family SLC10, which overall consists of seven mem- bers (SLC10A1eSLC10A7). The founding members of this carrier þ 2.3. Inhibition studies in SOAT-HEK293 and ASBT-HEK293 cells family, the hepatic Na /taurocholate co-transporting polypeptide NTCP (SLC10A1) and the intestinal apical sodium-dependent bile For inhibition studies, 24-well plates were coated with poly-D- acid transporter ASBT (SLC10A2) are important factors for the lysine for better attachment of the cells. Cells (1.25 Â 105 per well) maintenance of the enterohepatic circulation of bile acids between were plated and grown in standard medium for 72 h. SOAT and the liver and the gut (Geyer et al., 2006; Doring€ et al., 2012). ASBT expression was induced by pre-incubation with tetracycline Furthermore, ASBT is of particular interest in several pharmaco- (1 mg/ml). SOAT and ASBT non-expressing control cells were logical aspects. Regarding molecular drug design, ASBT-mediated not pre-treated with tetracycline. Before starting the transport uptake from the gut is used to improve the oral bioavailability of experiments, cells were washed three times with phosphate- drugs by coupling them with bile acids (Kramer et al., 1994; Kramer, buffered saline (PBS; 137 mM NaCl, 2.7 mM KCl, 1.5 mM KH PO , 2011). Furthermore, ASBT is a drug target for cholesterol-lowering 2 4 7.3 mM Na HPO , pH 7.4, 37 C) and equilibrated with transport therapy, because inhibition of bile acid reuptake in the gut stimu- 2 4 buffer (142.9 mM NaCl, 4.7 mM KCl,1.2 mM MgSO , 1.2 mM KH PO , lates de novo bile acid synthesis from cholesterol in the liver 4 2 4 1.8 mM CaCl , 10 mM glucose and 20 mM HEPES, adjusted to pH (Kramer and Glombik, 2006). 2 7.4). Then, cells were pre-incubated with transport buffer con- In the present study, we searched for novel SOAT inhibitors for taining increasing concentrations of the tested compound for further in vitro and in vivo studies in order to clarify the role of SOAT 5 min. For control, transport buffer without the test compound was in testicular steroid regulation and for proliferation of hormone- used. Transport measurements were started by adding 200 nM dependent breast cancer cells. Therefore, we analysed the SOAT [3H]DHEAS or 200 nM [3H]TC, while keeping the concentrations of inhibitory pattern in detail with a set of more than 100 different the test compounds constant. All uptake experiments were per- compounds and established a 3D pharmacophore model for the formed over 5 min at 37 C. Although SOAT uptake of DHEAS was identification of further inhibitors of SOAT. Because of the very high only linear over 1 min (Geyer et al., 2007), this longer uptake phase amino acid sequence identity of SOAT and ASBT, we also compared was required to ensure adequate uptake ratios for subsequent IC the SOAT pharmacophore model with the already established 50 determinations. However, comparative uptake experiments with pharmacophore model of rabbit Asbt (Baringhaus et al., 1999)in 1 min or 5 min uptake phase revealed identical IC values for order to determine the potential cross-inhibition between both 50 selected compounds (data not shown). The transport phase was carriers. Such a cross-inhibition after oral application of an SOAT terminated by removing the transport buffer and washing the cells inhibitor would be of pharmacological relevance as ASBT inhibition five times with ice-cold PBS. Cell-associated radioactivity and would hamper the enterohepatic circulation of bile acids. protein contents were determined as described previously (Geyer et al., 2007). For calculation of the IC values, the negative con- 2. Material and methods 50 trol (uptake in not carrier expressing HEK293 cells) was set to 0% and the respective positive control (uptake in carrier expressing 2.1. Chemicals and radiochemicals HEK293 cells without inhibitor) was set to 100%. All chemicals, unless otherwise stated, were from Sigma- eAldrich. Zeocin and hygromycin were purchased from Invitrogen. Materials used for cultivation of HEK293 cells were purchased from 2.4. Generation of the 3D QSAR model Gibco and SigmaeAldrich. [3H]Dehydroepiandrosterone sulfate ([3H]DHEAS, 94.5 Ci/mmol) and [3H]taurocholic acid ([3H]TC, 10 Ci/ The 3D quantitative structure-activity
Load more

Recommended publications
  • Bile Acid Recognition by NAPE-PLD
    Articles pubs.acs.org/acschemicalbiology Bile Acid Recognition by NAPE-PLD † ‡ ‡ # † ‡ Eleonora Margheritis, Beatrice Castellani, Paola Magotti, , Sara Peruzzi, Elisa Romeo, § ∥ ∥ ‡ ⊥ † ‡ Francesca Natali, Serena Mostarda, Antimo Gioiello, Daniele Piomelli, , and Gianpiero Garau*, , † Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro 12, 56127 Pisa, Italy ‡ Department of Drug Discovery-Validation, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy § Institute Laue-Langevin (ILL) and CNR-IOM, 71 avenue des Martyrs, 38042 Grenoble, France ∥ Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06125 Perugia, Italy ⊥ Department of Anatomy & Neurobiology, University of California - Irvine, Gillespie NRF 3101, Irvine, California 92697, United States ABSTRACT: The membrane-associated enzyme NAPE-PLD (N- acyl phosphatidylethanolamine specific-phospholipase D) gener- ates the endogenous cannabinoid arachidonylethanolamide and other lipid signaling amides, including oleoylethanolamide and palmitoylethanolamide. These bioactive molecules play important roles in several physiological pathways including stress and pain response, appetite, and lifespan. Recently, we reported the crystal structure of human NAPE-PLD and discovered specific binding sites for the bile acid deoxycholic acid. In this study, we demonstrate that in the presence of this secondary bile acid, the stiffness of the protein measured by elastic neutron scattering increases, and NAPE-PLD is ∼7 times faster to catalyze the hydrolysis of the more unsaturated substrate N-arachidonyl-phosphatidylethanolamine, compared with N-palmitoyl- phosphatidylethanolamine. Chenodeoxycholic acid and glyco- or tauro-dihydroxy conjugates can also bind to NAPE-PLD and drive its activation. The only natural monohydroxy bile acid, lithocholic acid, shows an affinity of ∼20 μM and acts instead as a ≈ μ fi reversible inhibitor (IC50 68 M).
    [Show full text]
  • Erythromycin Versus Tetracycline for Treatment of Mediterranean Spotted Fever
    Arch Dis Child: first published as 10.1136/adc.61.10.1027 on 1 October 1986. Downloaded from Archives of Disease in Childhood, 1986, 61, 1027-1029 Erythromycin versus tetracycline for treatment of Mediterranean spotted fever T MUNOZ-ESPIN, P LOPEZ-PARtS, E ESPEJO-ARENAS, B FONT-CREUS, I MARTINEZ- VILA, J TRAVERIA-CASANOVA, F SEGURA-PORTA, AND F BELLA-CUETO Hospital de Sant Llatzer, Terrassa, Clinica Infantil del Nen Jesus, Sabadell, and Hospital Mare de Deu de la Salut, Sabadell, Barcelona, Spain SUMMARY Eighty one children aged between 1 and 13 years participated in a randomised comparative trial of tetracycline hydrochloride and erythromycin stearate for treatment of Mediterranean spotted fever. Both therapeutic regimens proved effective, but in patients treated with tetracycline both clinical symptoms and fever disappeared significantly more quickly. Likewise, when those patients who began treatment within the first 72 hours of illness are considered the febrile period had a significantly shorter duration in the group treated with tetracycline. One patient was switched to tetracycline because there was no improvement of clinical manifestations, with persistence of fever, myalgias, and prostration, after receiving eight days of treatment with erythromycin. These results suggest that tetracyclines are superior to erythromycin in the treatment of Mediterranean spotted fever. copyright. Mediterranean spotted fever is an acute infectious were not included in the trial; neither were those disease caused by Rickettsia conorii. During the
    [Show full text]
  • Use of Antibiotics to Prevent Calf Diarrhea and Septiceinia
    PEER REVIEWED Use of Antibiotics to Prevent Calf Diarrhea and Septiceinia Peter D. Constable, BVSc, PhD, DACVIM Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802 Abstract l'oxytetracycline (0.15 to 6.0 mg/lb [0.32 to 13.2 mg/kg] au 24 h, per os) sont efficaces dans le traitement de la This article reviews studies related to the use of diarrhee chez les veaux et permettent un accroissement antimicrobial agents to prevent calf diarrhea and septi­ du taux de croissance des veaux nourris au lait. De cemia, and discusses whether prophylactic administra­ plus, la chlortetracycline permet la diminution du taux tion of antibiotics in neonatal calves is effective and de mortalite lorsque administree chez les veaux indicated. Orally administered chlortetracycline, oxytet­ nouveau-nes pour prevenir la diarrhee. 11 n'y a pas racycline, tetracycline and neomycin have label claims d'antibiotiques qui promettent de prevenir la in the US for the "control" or "aid in the control" of calf septicemie chez les veaux. Paree qu'il ne semble pas diarrhea caused by bacteria susceptible to the antibi­ exister d'etudes sur l'efficacite de la tetracycline et de otic. Chlortetracycline and oxytetracycline (0.15 to 6.0 la neomycine et parce que !'utilisation hors homologa­ mg/lb [0.32 to 13.2 mg/kg], q 24 h, PO) are efficacious tion des medicaments. n'est pas permise pour la for preventing calf diarrhea and increasing growth rate prevention routiniere des maladies ou !'augmentation in milk-fed calves, and chlortetracycline (3 mg/lb [7 mg/ du taux de croissance et du taux de conversion kg], q 12 h, PO) is efficacious for decreasing mortality alimentaire, selon le code de l'AMDUCA de 1994, seule when administered to prevent diarrhea in neonatal !'administration orale de chlortetracycline et calves.
    [Show full text]
  • Full-Text PDF (Final Published Version)
    Alexander, S. P. H., Cidlowski, J. A., Kelly, E., Marrion, N. V., Peters, J. A., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP Collaborators (2017). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Nuclear hormone receptors. British Journal of Pharmacology, 174, S208-S224. https://doi.org/10.1111/bph.13880 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.13880 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1111/bph.13880 . Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2017/18: Nuclear hormone receptors. British Journal of Pharmacology (2017) 174, S208–S224 THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Nuclear hormone receptors Stephen PH Alexander1, John A Cidlowski2, Eamonn Kelly3, Neil V Marrion3, John A Peters4, Elena Faccenda5, Simon D Harding5,AdamJPawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical
    [Show full text]
  • Long-Term Use of Spironolactone for Acne in Women: a Case Series of 403 Patients
    Long-term use of spironolactone for acne in women: A case series of 403 patients Vaibhav Garg, BS,a JulianaK.Choi,MD,PhD,b William D. James, MD,b and John S. Barbieri, MD, MBAb Philadelphia, Pennsylvania Background: There are limited data regarding the long-term outcomes of spironolactone use for women with acne and its effect on truncal acne. Objective: To comprehensively describe outcomes of patients treated with spironolactone in routine clinical practice, including long-term outcomes. Methods: We performed a retrospective case series of 403 adult women treated for acne with spironolactone at an academic medical center between 2008 and 2019. Rates of objective, as assessed by Comprehensive Acne Severity Scale scores, and subjective acne clearance were evaluated, as well as rates of treatment discontinuation, dosage changes, and drug survival. Logistic regression was used to assess for association between incidence of menstrual adverse effects and combined oral contraceptive use. Results: As evaluated by Comprehensive Acne Severity Scale scores, at the first follow-up, 75.5%, 84.0%, and 80.2% of patients with available data had reduction or complete clearance of acne on the face, chest, and back, respectively. The mean drug survival was 470.7 days. Menstrual adverse effects were less common among those using combined oral contraception (odds ratio, 0.23; 95% confidence interval, 0.11-0.50). Limitations: This study was conducted at a single academic medical center. Conclusions: Spironolactone improves clinical outcomes and is well tolerated for many adult women with acne using it for an extended duration. ( J Am Acad Dermatol 2021;84:1348-55.) Key words: acne; acne vulgaris; birth control pill; combined oral contraceptive; comprehensive acne severity scale; oral antibiotics; outcomes; spironolactone.
    [Show full text]
  • Prednisolone / Neomycin / Tetracycline For- Mulation
    SAFETY DATA SHEET Prednisolone / Neomycin / Tetracycline For- mulation Version Revision Date: SDS Number: Date of last issue: 25.08.2020 3.6 09.04.2021 407521-00015 Date of first issue: 07.01.2016 SECTION 1: Identification of the substance/mixture and of the company/undertaking 1.1 Product identifier Trade name : Prednisolone / Neomycin / Tetracycline Formulation 1.2 Relevant identified uses of the substance or mixture and uses advised against Use of the Sub- : Veterinary product stance/Mixture 1.3 Details of the supplier of the safety data sheet Company : MSD 20 Spartan Road 1619 Spartan, South Africa Telephone : +27119239300 E-mail address of person : [email protected] responsible for the SDS 1.4 Emergency telephone number +1-908-423-6000 SECTION 2: Hazards identification 2.1 Classification of the substance or mixture Classification (REGULATION (EC) No 1272/2008) Skin sensitisation, Category 1 H317: May cause an allergic skin reaction. Reproductive toxicity, Category 1A H360D: May damage the unborn child. Effects on or via lactation H362: May cause harm to breast-fed children. Short-term (acute) aquatic hazard, Cate- H400: Very toxic to aquatic life. gory 1 Long-term (chronic) aquatic hazard, Cat- H410: Very toxic to aquatic life with long lasting egory 1 effects. 2.2 Label elements Labelling (REGULATION (EC) No 1272/2008) Hazard pictograms : Signal word : Danger Hazard statements : H317 May cause an allergic skin reaction. H360D May damage the unborn child. H362 May cause harm to breast-fed children. H410 Very toxic to aquatic life with long lasting effects. 1 / 23 SAFETY DATA SHEET Prednisolone / Neomycin / Tetracycline For- mulation Version Revision Date: SDS Number: Date of last issue: 25.08.2020 3.6 09.04.2021 407521-00015 Date of first issue: 07.01.2016 Precautionary statements : Prevention: P201 Obtain special instructions before use.
    [Show full text]
  • Elimination Processes of Guest Molecules from the Inclusion Compounds of Deoxycholic Acid῍
    J. Mass Spectrom. Soc. Jpn. Vol. 51, No. 1, 2003 REGULAR PAPER Elimination Processes of Guest Molecules from the Inclusion Compounds of Deoxycholic Acid῍ Takayoshi K>BJG6,῏a) Yuichi K6H6>,a) Tomohide THJ?>BDID,a) Emi K6L6BJG6,a) Tadashi K6B>N6B6,a) and Hatsumi A@>b) (Received November 11, 2002; Accepted December 10, 2002) Thermal behaviors of the inclusion compounds of deoxycholic acid with methanol, ethanol, propane-1-ol, propane-2-ol, and butane-1-ol have been studied by TG-DTA-MS and DSC. Liberation processes of guest molecules from their inclusion compounds of methanol, ethanol were carried out in a single step. Those of propanols and butane-1-ol from the corresponding inclusion compounds proceed in complicated steps. The elimination temperatures, enthalpies and the activation enthalpies of eliminations have been determined by TG, DSC, and MS. 1. Introduction 2. Experimental Bile acids are synthesized from free cholesterol in the Deoxycholic acid (Sigma Chemical Co., Ltd.) was pur- liver and secreted into the small intestine via bile, ified by recrystallization using the purified acetone. All where they aggregate to form micelles in conjunction organic solvents (Kishida Chemical) used as guests with phospholipid or fatty acid. These mixed micelles were fractionally distilled over freshly activated molec- enable the solubilization of lipids and the absorption of ular sieves 4A.6) GLC results of purified solvents fat from the gastrointestinal tract. Also the bile acids showed no trace-impurity peak. Coulometric Karl- form various types of inclusion compounds with many Fischer’s method on a Moisturemeter (Mitsubishi Che- kinds of organic compounds.1) So those inclusion com- mical Ind., CA-02) gave the water content of each pounds might be performed ideal formulation.
    [Show full text]
  • Biliary Bile Acid Composition of the Human Fetus in Early Gestation
    0031-3998/87/2102-0197$02.00/0 PEDIATRIC RESEARCH Vol. 21, No.2, 1987 Copyright© 1987 International Pediatric Research Foundation, Inc. Printed in U.S.A. Biliary Bile Acid Composition of the Human Fetus in Early Gestation C. COLOMBO, G. ZULIANI, M. RONCHI, J. BREIDENSTEIN, AND K. D. R. SETCHELL Department q/Pediatrics and Obstetrics, University q/ Milan, Milan, Italy [C. C., G.Z., M.R.j and Department q/ Pediatric Gastroel1/erology and Nwrition, Children's Hospital Medical Center, Cincinnati, Ohio 45229 [J.B., K.D.R.S.j ABSTRACf. Using analytical techniques, which included the key processes of the enterohepatic circulation of bile acids capillary column gas-liquid chromatography and mass ( 16-19). As a result of physiologic cholestasis, the newborn infant spectrometry, detailed bile acid profiles were obtained for has a tendency to develop a true neonatal cholestasis when 24 fetal bile samples collected after legal abortions were subjected to such stresses as sepsis, hypoxia, and total parenteral performed between the 14th and 20th wk of gestation. nutrition ( 15). Qualitatively, the bile acid profiles of all fetal bile samples Abnormalities in bile acid metabolism have been suggested to were similar. The predominant bile acids identified were be a factor in the development of certain forms of cholestasis in chenodeoxycholic and cholic acid. The presence of small the newborn (20) and in animal models the hepatotoxic nature but variable amounts of deoxycholic acid and traces of of bile acids has been well established (21-24). A greater under­ lithocholic acid suggested placental transfer of these bile standing of the etiology of these conditions requires a better acids from the maternal circulation.
    [Show full text]
  • Staining and Hypoplasia of Enamel Caused by Tetracycline: Case Report P
    PEDIATRIC DENTISTRY/Copyright © 1987 by The American Academy of Pediatric Dentistry Volume 9 Number 3 Staining and hypoplasia of enamel caused by tetracycline: case report P. Fleming, BDentSc, FDS C.J. Witkop, Jr., DDS, MS W.H. Kuhlmann, DDS, MSD Abstract Case Report Staining of developing teeth due to tetracycline therapy A 23-year-old white male requested restoration of has been publicized widely. However, the ability of tetracy- his stained and hypoplastic anterior teeth (Fig 1). A clines to cause hypoplasia of enamel has not been accepted history revealed that between 2 and 3 years of age he had universally. This is a case report of enamel hypoplasia and received extensive tetracycline therapy for tonsillitis. staining presumably caused byahigh dosage of'tetracy'dines in There was no history of a prolonged fever at the time of childhood. Restoration of the teeth with bonded composite the illness. resins produced an esthetic result. -UK Schwachman and Schuster (1956) were the first to report unsightly staining of teeth due to tetracycline administered during the period of tooth formation in children with cystic fibrosis. This observation was con- y firmed by Zegarelli et al. (1961) who noted staining of the teeth in 38 of 52 cystic fibrosis patients who had been ijgj treated with large doses of antibiotics, frequently tetracy- .^••W^^ clines. With reports by Davies et al. (1962) and articles by Wallman and Hilton (1962) and Witkop and Wolf (1963) this complication of tetracycline therapy became widely recognized. FIG 1. Tetracycline staining and hypoplasia of the permanent Hypoplasia of enamel of the primary dentition asso- anterior teeth.
    [Show full text]
  • Vitamin D Receptor Promotes Healthy Microbial Metabolites
    www.nature.com/scientificreports OPEN Vitamin D receptor promotes healthy microbial metabolites and microbiome Ishita Chatterjee1, Rong Lu1, Yongguo Zhang1, Jilei Zhang1, Yang Dai 2, Yinglin Xia1 ✉ & Jun Sun 1 ✉ Microbiota derived metabolites act as chemical messengers that elicit a profound impact on host physiology. Vitamin D receptor (VDR) is a key genetic factor for shaping the host microbiome. However, it remains unclear how microbial metabolites are altered in the absence of VDR. We investigated metabolites from mice with tissue-specifc deletion of VDR in intestinal epithelial cells or myeloid cells. Conditional VDR deletion severely changed metabolites specifcally produced from carbohydrate, protein, lipid, and bile acid metabolism. Eighty-four out of 765 biochemicals were signifcantly altered due to the Vdr status, and 530 signifcant changes were due to the high-fat diet intervention. The impact of diet was more prominent due to loss of VDR as indicated by the diferences in metabolites generated from energy expenditure, tri-carboxylic acid cycle, tocopherol, polyamine metabolism, and bile acids. The efect of HFD was more pronounced in female mice after VDR deletion. Interestingly, the expression levels of farnesoid X receptor in liver and intestine were signifcantly increased after intestinal epithelial VDR deletion and were further increased by the high-fat diet. Our study highlights the gender diferences, tissue specifcity, and potential gut-liver-microbiome axis mediated by VDR that might trigger downstream metabolic disorders. Metabolites are the language between microbiome and host1. To understand how host factors modulate the microbiome and consequently alter molecular and physiological processes, we need to understand the metabo- lome — the collection of interacting metabolites from the microbiome and host.
    [Show full text]
  • Prednisolone / Neomycin / Tetracycline For- Mulation
    SAFETY DATA SHEET Prednisolone / Neomycin / Tetracycline For- mulation Version Revision Date: SDS Number: Date of last issue: 23.03.2020 5.5 25.08.2020 407516-00013 Date of first issue: 07.01.2016 SECTION 1. PRODUCT AND COMPANY IDENTIFICATION Product name : Prednisolone / Neomycin / Tetracycline Formulation Manufacturer or supplier's details Company name of supplier : MSD Address : 2000 Galloping Hill Road Kenilworth - New Jersey - U.S.A. 07033 Telephone : 908-740-4000 Emergency telephone : 1-908-423-6000 E-mail address : [email protected] Recommended use of the chemical and restrictions on use Recommended use : Veterinary product SECTION 2. HAZARDS IDENTIFICATION GHS Classification Skin sensitization : Category 1 Reproductive toxicity : Category 1A Effects on or via lactation Specific target organ toxicity : Category 2 (Kidney, inner ear) - repeated exposure Specific target organ toxicity : Category 2 (Gastrointestinal tract, Nervous system, Skin, Teeth) - repeated exposure (Oral) GHS label elements Hazard pictograms : Signal Word : Danger Hazard Statements : H317 May cause an allergic skin reaction. H360D May damage the unborn child. H362 May cause harm to breast-fed children. H373 May cause damage to organs (Kidney, inner ear) through prolonged or repeated exposure. H373 May cause damage to organs (Gastrointestinal tract, Nervous system, Skin, Teeth) through prolonged or repeated exposure if swallowed. Precautionary Statements : Prevention: P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. 1 / 24 SAFETY DATA SHEET Prednisolone / Neomycin / Tetracycline For- mulation Version Revision Date: SDS Number: Date of last issue: 23.03.2020 5.5 25.08.2020 407516-00013 Date of first issue: 07.01.2016 P260 Do not breathe dust.
    [Show full text]
  • 2021 Formulary List of Covered Prescription Drugs
    2021 Formulary List of covered prescription drugs This drug list applies to all Individual HMO products and the following Small Group HMO products: Sharp Platinum 90 Performance HMO, Sharp Platinum 90 Performance HMO AI-AN, Sharp Platinum 90 Premier HMO, Sharp Platinum 90 Premier HMO AI-AN, Sharp Gold 80 Performance HMO, Sharp Gold 80 Performance HMO AI-AN, Sharp Gold 80 Premier HMO, Sharp Gold 80 Premier HMO AI-AN, Sharp Silver 70 Performance HMO, Sharp Silver 70 Performance HMO AI-AN, Sharp Silver 70 Premier HMO, Sharp Silver 70 Premier HMO AI-AN, Sharp Silver 73 Performance HMO, Sharp Silver 73 Premier HMO, Sharp Silver 87 Performance HMO, Sharp Silver 87 Premier HMO, Sharp Silver 94 Performance HMO, Sharp Silver 94 Premier HMO, Sharp Bronze 60 Performance HMO, Sharp Bronze 60 Performance HMO AI-AN, Sharp Bronze 60 Premier HDHP HMO, Sharp Bronze 60 Premier HDHP HMO AI-AN, Sharp Minimum Coverage Performance HMO, Sharp $0 Cost Share Performance HMO AI-AN, Sharp $0 Cost Share Premier HMO AI-AN, Sharp Silver 70 Off Exchange Performance HMO, Sharp Silver 70 Off Exchange Premier HMO, Sharp Performance Platinum 90 HMO 0/15 + Child Dental, Sharp Premier Platinum 90 HMO 0/20 + Child Dental, Sharp Performance Gold 80 HMO 350 /25 + Child Dental, Sharp Premier Gold 80 HMO 250/35 + Child Dental, Sharp Performance Silver 70 HMO 2250/50 + Child Dental, Sharp Premier Silver 70 HMO 2250/55 + Child Dental, Sharp Premier Silver 70 HDHP HMO 2500/20% + Child Dental, Sharp Performance Bronze 60 HMO 6300/65 + Child Dental, Sharp Premier Bronze 60 HDHP HMO
    [Show full text]