Health Effects Support Document for Perfluorooctane Sulfonate (PFOS)

Total Page:16

File Type:pdf, Size:1020Kb

Health Effects Support Document for Perfluorooctane Sulfonate (PFOS) United States Office of Water EPA 822-R-16-002 Environmental Protection Mail Code 4304T May 2016 Agency Health Effects Support Document for Perfluorooctane Sulfonate (PFOS) Perfluorooctane sulfonate (PFOS) –May 2016 i Health Effects Support Document for Perfluorooctane Sulfonate (PFOS) U.S. Environmental Protection Agency Office of Water (4304T) Health and Ecological Criteria Division Washington, DC 20460 http://www.epa.gov/dwstandardsregulations/drinking-water-contaminant-human-health-effects- information. EPA Document Number: 822-R-16-002 May 2016 Perfluorooctane sulfonate (PFOS) –May 2016 ii BACKGROUND The Safe Drinking Water Act (SDWA), as amended in 1996, requires the Administrator of the U.S. Environmental Protection Agency (EPA) to establish a list of unregulated microbiological and chemical contaminants known or anticipated to occur in public water systems and that might require control in the future through national primary drinking water regulations. The SDWA also requires the Agency to make regulatory determinations on at least five contaminants on the Contaminant Candidate List (CCL) every 5 years. For each contaminant on the CCL, before EPA makes a regulatory determination, the Agency needs to obtain sufficient data to conduct analyses on the extent to which the contaminant occurs and the risk it poses to populations via drinking water. Ultimately, this information will assist the Agency in determining the most appropriate course of action in relation to the contaminant (e.g., developing a regulation to control it in drinking water, developing guidance, or deciding not to regulate it). The PFOS health assessment was initiated by the Office of Water, Office of Science and Technology in 2009. The draft Health Effects Support Document for Perfluorooctane Sulfonate Acid (PFOS) was completed in 2013 and released for public comment in February 2014. An external peer-review panel meeting was held on August 21 and 22, 2014. The final document reflects input from the panel as well as public comments received on the draft document. Both the peer-reviewed draft and this document include only the sections of a health effects support document (HESD) that cover the toxicokinetics and health effects of PFOS. If a decision is made to regulate the contaminant, this document will be expanded. One of the challenges inherent in conducting this assessment was the wealth of experimental data published before and during its development. This section provides a synopsis of the approach used in identifying and selecting the publications reflected in the final assessment. Data were identified through the following: Monthly/bimonthly literature searches conducted by EPA library staff (2009–2015) and New Jersey Department of Environmental Protection library staff (2012–2015). • Papers identified by EPA internal and external peer reviewers. • Papers identified through public comments on the draft assessments. • Papers submitted to EPA by the public. In mid-2013, the EPA library searches were expanded to cover other members of the perfluorocarboxylic acids (C-4 to C-12) and sulfonate families (C-4, C-6, C-8). Appendix A describes the literature search strategy used by the libraries. Through the literature search, documents were identified for retrieval, review, and inclusion in the HESD using the following criteria: • The study examines a toxicity endpoint or population not examined by studies already included in the draft document. • Aspects of the study design such as the size of the population exposed or quantification approach make it superior to key studies already included in the draft document. • The data contribute substantially to the weight of evidence for any of the toxicity endpoints covered by the draft document. • Elements of the study design merit its inclusion in the draft document based on its contribution to the mode of action or the quantification approach. Perfluorooctane sulfonate (PFOS) –May 2016 iii • The study elucidates the mode of action for any toxicity endpoint or toxicokinetic property associated with PFOS exposure. • The effects observed differ from those in other studies with comparable protocols. In addition to each publication being evaluated against the criteria above, the relevance of the study to drinking water exposures and to the U.S. population also were considered. The studies included in the final draft were determined to provide the most current and comprehensive description of the toxicological properties of PFOS and the risk it poses to humans exposed to it in their drinking water. Appendix B summarizes the studies evaluated for inclusion in the HESD following the August 2014 peer review and identifies those selected for inclusion in the final assessment. Appendix B includes epidemiology data that provide a high- level summary of the outcomes across the studies evaluated. Development of the hazard identification and dose-response assessment for PFOS has followed the general guidelines for risk assessment forth by the National Research Council (1983) and EPA’s Framework for Human Health Risk Assessment to Inform Decision Making (USEPA 2014a). Other EPA guidelines used in the development of this assessment include the following: • Guidelines for the Health Risk Assessment of Chemical Mixtures (USEPA 1986a) • Guidelines for Mutagenicity Risk Assessment (USEPA 1986b) • Recommendations for and Documentation of Biological Values for Use in Risk Assessment (USEPA 1988) • Guidelines for Developmental Toxicity Risk Assessment (USEPA 1991) • Interim Policy for Particle Size and Limit Concentration Issues in Inhalation Toxicity Studies (USEPA 1994a) • Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (USEPA 1994b) • Use of the Benchmark Dose Approach in Health Risk Assessment (USEPA 1995) • Guidelines for Reproductive Toxicity Risk Assessment (USEPA 1996) • Guidelines for Neurotoxicity Risk Assessment (USEPA 1998) • Science Policy Council Handbook: Peer Review (2nd edition) (USEPA 2000a) • Supplemental Guidance for Conducting Health Risk Assessment of Chemical Mixtures (USEPA 2000b) • A Review of the Reference Dose and Reference Concentration Processes (USEPA 2002) • Guidelines for Carcinogen Risk Assessment (USEPA 2005a) • Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (USEPA 2005b) • Science Policy Council Handbook: Peer Review (USEPA 2006a) • A Framework for Assessing Health Risks of Environmental Exposures to Children (USEPA 2006b) • Highlights of the Exposure Factors Handbook (USEPA 2011) • Benchmark Dose Technical Guidance Document (USEPA 2012) • Child-Specific Exposure Scenarios Examples (USEPA 2014b) Perfluorooctane sulfonate (PFOS) –May 2016 iv AUTHORS, CONTRIBUTORS, AND REVIEWERS Joyce Morrissey Donohue, Ph.D. (Chemical Manager) Office of Water U.S. Environmental Protection Agency, Washington, D.C. Amal Mahfouz, Ph.D. (Chemical Manager, pre-retirement). Office of Water U.S. Environmental Protection Agency, Washington, D.C. Tina Moore Duke, M.S. (previously with Office of Water, U.S. Environmental Protection Agency) John Wambaugh, Ph.D. Office of Research and Development U.S. Environmental Protection Agency, Research Triangle Park, NC The following contractor authors supported the development of this document: Dana F. Glass-Mattie, D.V.M. Environmental Sciences Division Oak Ridge National Laboratory, Oak Ridge, TN Carol S. Wood, Ph.D., D.A.B.T. Environmental Sciences Division Oak Ridge National Laboratory, Oak Ridge, TN This document was prepared under the U.S. EPA Contract No. DW-8992342701, Work Assignment No. 2011-001 with Oak Ridge National Laboratory. The Lead U.S. EPA Scientist is Joyce Morrissey Donohue, Ph.D., Health and Ecological Criteria Division, Office of Science and Technology, Office of Water. The Oak Ridge National Laboratory is managed and operated by UT-Battelle, LLC., for the U.S. Department of Energy under Contract No. DE-AC05-00OR22725. CONTRIBUTORS AND REVIEWERS Internal Contributors and Reviewers Office of Water, U.S. Environmental Protection Agency Elizabeth Doyle, Ph.D. (retired) Edward Hackett Office of Research and Development, U.S. Environmental Protection Agency Glinda Cooper, Ph.D. Barbara Glenn, Ph.D. Erin Hines, Ph.D. Christopher Lau, Ph.D. Matthew Lorber, Ph.D. Jaqueline Moya Linda Phillips, Ph.D. Perfluorooctane sulfonate (PFOS) –May 2016 v Paul White, Ph.D. Michael Wright, Sc.D. Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency E. Laurence Libelo Andrea Pfehales-Hutchens, Ph.D. Tracy Williamson David Lai, Ph.D. (retired) Jennifer Seed, Ph.D. (retired) Office of Children’s Health Protection, U.S. Environmental Protection Agency Gregory Miller Office of Land and Emergency Management, U.S. Environmental Protection Agency External Reviewers James Bruckner, Ph.D. Department of Pharmacology and Toxicology University of Georgia, Athens, GA Deborah Cory-Slechta, Ph.D. Department of Environmental Medicine University of Rochester Medical Center, Rochester, NY Jamie DeWitt, Ph.D. Pharmacology and Toxicology East Carolina University, Greenville, NC Jeffrey Fisher, Ph.D. Biochemical Toxicology, National Center for Toxicological Research U.S. Food and Drug Administration, Jefferson, AK William Hayton, Ph.D. College of Pharmacy (Emeritus) The Ohio State University, Columbus, OH Matthew Longnecker, M.D., Sc.D. Biomarker-based Epidemiology Group National Institute of Environmental Health Sciences, Research Triangle Park, NC Angela Slitt, Ph.D.
Recommended publications
  • 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]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
    [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]
  • Linkage Disequilibrium of UGT1A1*6 and UGT1A1*28 in Relation to UGT1A6 and UGT1A7 Polymorphisms
    801-806 11/9/06 12:25 Page 801 ONCOLOGY REPORTS 16: 801-806, 2006 801 Linkage disequilibrium of UGT1A1*6 and UGT1A1*28 in relation to UGT1A6 and UGT1A7 polymorphisms NAOHITO URAWA, YOSHINAO KOBAYASHI, JUN ARAKI, RYOSUKE SUGIMOTO, MOTOH IWASA, MASAHIKO KAITO and YUKIHKO ADACHI Division of Clinical Medicine and Biomedical Sciences, Department of Gastroenterology and Hepatology, Institute of Medical Science, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Received April 17, 2006; Accepted May 17, 2006 Abstract. UDP-glucuronosyltransferase (UGT) enzymes are first time that the LD of UGT1A1*6 in relation to UGT1A6 responsible for the glucuronidation and detoxification of many and 1A7 polymorphisms is far stronger than UGT1A1*28. endogenous or exogenous xenobiotics. Gilbert's syndrome The UGT1A1*6 allele appears to be independent of the (GS) and Crigler Najjar syndrome type 2 (CNS-II) are UGT1A1*28 allele. Although patients with GS and CNS-II characterized by unconjugated hyperbilirubinemia due to are believed to have good prognosis, a subgroup of GS or reduced enzymatic activity of UGT1A1. Recent studies have CNS-II patients with the UGT1A1*6 polymorphism might be demonstrated the frequent co-existence of UGT1A1*28 (-53 at risk of abnormal drug metabolism and of developing [TA]6>7) with other polymorphisms of UGT1A6 and malignant disease. UGT1A7. This finding suggests the occurrence of linkage disequilibrium (LD) among UGT1A1, UGT1A6 and UGT1A7 Introduction polymorphisms. UGT1A1*6 (211G>A, G71R) and UGT1A1*28 are common in Asian populations. In the present study, we UDP-glucuronosyltransferase (UGT) enzymes are responsible investigated the LD of UGT1A1*6 and UGT1A1*28 in for the glucuronidation and detoxification of many xenobiotics relation to UGT1A6 and UGT1A7 polymorphisms.
    [Show full text]
  • PHASE II DRUG METABOLIZING ENZYMES Petra Jancovaa*, Pavel Anzenbacherb,Eva Anzenbacherova
    Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Jun; 154(2):103–116. 103 © P. Jancova, P. Anzenbacher, E. Anzenbacherova PHASE II DRUG METABOLIZING ENZYMES Petra Jancovaa*, Pavel Anzenbacherb, Eva Anzenbacherovaa a Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic b Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc E-mail: [email protected] Received: March 29, 2010; Accepted: April 20, 2010 Key words: Phase II biotransformation/UDP-glucuronosyltransferases/Sulfotransferases, N-acetyltransferases/Glutathione S-transferases/Thiopurine S-methyl transferase/Catechol O-methyl transferase Background. Phase II biotransformation reactions (also ‘conjugation reactions’) generally serve as a detoxifying step in drug metabolism. Phase II drug metabolising enzymes are mainly transferases. This review covers the major phase II enzymes: UDP-glucuronosyltransferases, sulfotransferases, N-acetyltransferases, glutathione S-transferases and methyltransferases (mainly thiopurine S-methyl transferase and catechol O-methyl transferase). The focus is on the presence of various forms, on tissue and cellular distribution, on the respective substrates, on genetic polymorphism and finally on the interspecies differences in these enzymes. Methods and Results. A literature search using the following databases PubMed, Science Direct and EBSCO for the years, 1969–2010. Conclusions. Phase II drug metabolizing enzymes play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologi- cally active compounds. Reduced metabolising capacity of Phase II enzymes can lead to toxic effects of clinically used drugs. Gene polymorphism/ lack of these enzymes may often play a role in several forms of cancer.
    [Show full text]
  • Endogenous Protein Interactome of Human
    Human UGT1A interaction network 1 Endogenous protein interactome of human UDP- 2 glucuronosyltransferases exposed by untargeted proteomics 3 4 5 Michèle Rouleau, Yannick Audet-Delage, Sylvie Desjardins, Mélanie Rouleau, Camille Girard- 6 Bock and Chantal Guillemette* 7 8 Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre 9 Hospitalier Universitaire (CHU) de Québec Research Center and Faculty of Pharmacy, Laval 10 University, G1V 4G2, Québec, Canada 11 12 13 14 15 *Corresponding author: 16 Chantal Guillemette, Ph.D. 17 Canada Research Chair in Pharmacogenomics 18 Pharmacogenomics Laboratory, CHU de Québec Research Center, R4720 19 2705 Boul. Laurier, Québec, Canada, G1V 4G2 20 Tel. (418) 654-2296 Fax. (418) 654-2298 21 E-mail: [email protected] 22 23 24 25 26 27 28 29 30 31 32 Running title: Human UGT1A interaction network 33 1 Human UGT1A interaction network 1 Number of: Pages: 26 2 Tables: 2 3 Figures: 5 4 References: 62 5 Supplemental Tables: 7 6 Supplemental Figures: 5 7 8 Number of words: Total: 7882 9 Abstract: 229 10 Introduction: 549 11 Results: 1309 12 Discussion: 1403 13 Body Text: 3261 14 15 16 17 18 Abbreviations: AP: affinity purification; UGT, UDP-glucuronosyltransferases; IP, immuno- 19 precipitation; PPIs, protein-protein interactions; UDP-GlcA, Uridine diphospho-glucuronic acid; 20 ER, endoplasmic reticulum; MS, mass spectrometry. 21 22 Keywords: UGT; Proteomics; Protein-protein interaction; Affinity purification; Mass 23 spectrometry; Metabolism; Human tissues; 24 2 Human UGT1A interaction network 1 ABSTRACT 2 3 The conjugative metabolism mediated by UDP-glucuronosyltransferase enzymes (UGTs) 4 significantly influences the bioavailability and biological responses of endogenous molecule 5 substrates and xenobiotics including drugs.
    [Show full text]
  • ID AKI Vs Control Fold Change P Value Symbol Entrez Gene Name *In
    ID AKI vs control P value Symbol Entrez Gene Name *In case of multiple probesets per gene, one with the highest fold change was selected. Fold Change 208083_s_at 7.88 0.000932 ITGB6 integrin, beta 6 202376_at 6.12 0.000518 SERPINA3 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 1553575_at 5.62 0.0033 MT-ND6 NADH dehydrogenase, subunit 6 (complex I) 212768_s_at 5.50 0.000896 OLFM4 olfactomedin 4 206157_at 5.26 0.00177 PTX3 pentraxin 3, long 212531_at 4.26 0.00405 LCN2 lipocalin 2 215646_s_at 4.13 0.00408 VCAN versican 202018_s_at 4.12 0.0318 LTF lactotransferrin 203021_at 4.05 0.0129 SLPI secretory leukocyte peptidase inhibitor 222486_s_at 4.03 0.000329 ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 1552439_s_at 3.82 0.000714 MEGF11 multiple EGF-like-domains 11 210602_s_at 3.74 0.000408 CDH6 cadherin 6, type 2, K-cadherin (fetal kidney) 229947_at 3.62 0.00843 PI15 peptidase inhibitor 15 204006_s_at 3.39 0.00241 FCGR3A Fc fragment of IgG, low affinity IIIa, receptor (CD16a) 202238_s_at 3.29 0.00492 NNMT nicotinamide N-methyltransferase 202917_s_at 3.20 0.00369 S100A8 S100 calcium binding protein A8 215223_s_at 3.17 0.000516 SOD2 superoxide dismutase 2, mitochondrial 204627_s_at 3.04 0.00619 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) 223217_s_at 2.99 0.00397 NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 231067_s_at 2.97 0.00681 AKAP12 A kinase (PRKA) anchor protein 12 224917_at 2.94 0.00256 VMP1/ mir-21likely ortholog
    [Show full text]
  • Drug Metabolism Determines Resistance of Colorectal Cancer to Resorcinol-Based HSP90 Inhibitors
    Drug Metabolism Determines Resistance of Colorectal Cancer to Resorcinol-Based HSP90 Inhibitors Dissertation for the award of the degree “Doctor rerum naturalium” (Dr. rer. nat.) in the “Biology of Cells” Program at the Georg August University Göttingen, Faculty of Biology submitted by Hannes Landmann born in Hannover, Germany Göttingen, August 2014 Thesis Committee Prof. Dr. Matthias Dobbelstein Institute for Molecular Oncology, Faculty of Medicine Prof. Dr. Heidi Hahn Tumor Genetics, Department of Human Genetics, Faculty of Medicine Prof. Dr. Dieter Kube Department for Hematology and Oncology, Faculty of Medicine Members of the Examination Board Referee: Prof. Dr. Matthias Dobbelstein, Institute for Molecular Oncology 2nd Referee: Prof. Dr. Heidi Hahn, Tumor Genetics, Department of Human Genetics Further members of the Examination Board Prof. Dr. Dieter Kube Department for Hematology and Oncology, Faculty of Medicine PD Dr. Halyna Shcherbata Research Group Gene Expression and Signaling, Max Planck Institute for Biophysical Chemistry Prof. Dr. Ralph Kehlenbach Department of Molecular Biology, Faculty of Biochemistry PD Dr. Wilfried Kramer Department for Molecular Genetics, Institute for Microbiology and Genetics Date of oral examination: 19th of September 2014 AFFIDAVIT Herewith I declare that I prepared the PhD thesis “Drug Metabolism Determines Resistance of Colorectal Cancer to Resorcinol-Based HSP90 Inhibitors” on my own with no other aids and sources than quoted. _____________________ Hannes Landmann, Göttingen in August 2014 The findings in this work were accepted for publication in the open access journal Cell Death and Disease: Landmann, H., Proia, D.A., He, S., Ogawa, L.S., Kramer, F., Beißbarth, T., Grade, M., Gaedcke, J., Ghadimi, M., Moll, U.
    [Show full text]
  • Systems Physiology and Nutrition In
    SYSTEMS PHYSIOLOGY AND NUTRITION IN DAIRY CATTLE: APPLICATIONS OF OMICS AND BIOINFORMATICS TO BETTER UNDERSTAND THE HEPATIC METABOLOMICS AND TRANSCRIPTOMICS ADAPTATIONS IN TRANSITION DAIRY COWS BY KHURAM SHAHZAD DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Informatics in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Doctoral Committee: Associate Professor, Juan J. Loor, Chair Professor Gustavo Caetano-Anolles Associate Professor, Juan Steibel, Michigan State University Assistant Professor Phil Cardoso ABSTRACT Application of systems concepts to better understand physiological and metabolic changes in dairy cows during the transition into lactation could enhance our understanding about the role of nutrients in helping to meet the animal’s requirements for optimal production and health. Four different analyses focused on the liver were conducted to analyze metabolic disorder or thermal stress. The first three analyses dealt with supplementation of methionine to prevent clinical ketosis development in high-genetic merit dairy cows. Four groups of cows were formed retrospectively based on clinical health evaluated at 1 week postpartum: cows that remained healthy (OVE), cows that developed ketosis (K), and healthy cows supplemented with one of two commercial methionine products [Smartamine M (SM), and MetaSmart (MS)]. The liver tissue samples (n = 6/group) were harvested at -10 d before calving, and were used for metabolomics (GC-MS, LC-MS; Metabolon Inc.) and transcriptomics (44K-whole-transcriptome microarray; Agilent) analyses. Therefore, the main goals of the analyses were to 1) uncover metabolome and transcriptome patterns in the prepartum liver that were unique to those cows that became ketotic postpartum, and to 2) uncover unique patterns affected by supplemental methionine.
    [Show full text]
  • UGT1A and 2B Isoforms = Key Determinants of Pharmacokinetics, Efficacy and Safety of Many Pediatric Drugs
    Ontogeny and Phase II Metabolism of Drugs Stephan Schmidt, BPharm, PhD, FCP Certara Professor Associate Professor & Associate Director CPSP Department of Pharmaceutics University of Florida Disclaimer I am a consultant to pharmaceutical industry I like applied & interdisciplinary research I am presenting on behalf of an interinstitutional and interdisciplinary research team 2 Thank You To The Research Team Roche Postdoc Fellowship funded project (2017/2019) 3 Knowledge Gaps Phase II metabolism: Conjugation reactions (glucuronidation, methylation, sulphation, acetylation, gluthathione conjugation, glycine conjugation) UGT1A and 2B isoforms = key determinants of pharmacokinetics, efficacy and safety of many pediatric drugs Rapid and continuous differentiation and maturation of metabolic functions Limited knowledge ? Ontogeny pattern of hepatic UGTs using multiple probe substrates ? Differences in maturation of activity between UGT isoforms ? Marked age-related differences in activity across UGT isoforms ? Between-subject variability in UGT activity ? Age-independent factors affecting UGT activity efficiency 4 Goals For This Presentation 1. Outline experimental challenges of automated UGT phenotyping assays 2. Discuss UGT ontogeny patterns of major UGT isoforms 3. Discuss impact of age, sex, and ethnicity on UGT activity 4. Provide a case example for the dynamic interplay between phase I and II metabolism, gene-drug interactions, and drug-drug interactions 5 Goals For This Presentation 1. Outline experimental challenges of automated UGT phenotyping assays 2. Discuss UGT ontogeny patterns of major UGT isoforms 3. Discuss impact of age, sex, and ethnicity on UGT activity 4. Provide a case example for the dynamic interplay between phase I and II metabolism, gene-drug interactions, and drug-drug interactions 6 Challenges of UGT Phenotyping Assays Lack of standardized experimental conditions of UGT assays between laboratories, which hinders the comparison of UGT activity across studies .
    [Show full text]