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  • ASPECTS OF PERIPHERAL THYROID HORMONE METABOLISM

  • ASPECTS OF PERIPHERAL THYROID HORMONE METABOLISM

    Aspecten van het perifere schildklierhormoon metabolisme

    PROEFSCHRIFT

    TER VERKRIJGI:\G VAN DE GRAAD VAN

    DOCTOR I:\ DE GENEESKUNDE

    AAN DE ERASMUS UNIVERSITEIT ROTTERDAM

    OP GEZAG VAN DE RECTOR MAGNIFICUS

    PROF. DR. M.W. VAN HOF

    EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN.

    DE OPEN BARE VERDEDIGI:\G ZAL PLAATSVI:\DEN OP

    WOENSDAG 22 FEBRUARI 1984

    TE 15.45 UUR

    DOOR

    MARTEN HENK OTTEN geboren te 's-Gravenhage

    1984

    grafische verzorging:

    5IOJ3GDAVIDS ALBLASSERDAM

  • PROMOTOR

    PROMOTIECOMMISSIE

    : PROF. DR. G. HE\"NEMA!\TN

    : PROF. DR. J.C. BIRKENHAGER

    PROF. DR. W.C. HOLSMANN

    PROF. DR. H.J. VAN DER MOLEN

    The studies reported in this thesis were carried out under the direction of Dr. T.J. Visser in the laboratory of the Thyroid Hormone Research Unit (head Prof. Dr. G. Hennemann) at the Department of Internal Medicine Ill and Clinical Endocrinology (head Prof. Dr. J.C. Birkenhiiger), Medical Faculty, Erasmus University, Rotterdam, The Netherlands.

    The investigations were supported by grant 13-34-110 from the Devision for Health Research TNO and a contribution from Organon International BV. The support from Glaxo BV for the publication of the manuscript is gratefully acknowledged.

    Author's present address: Devision of Gastroenterology University Hospital St. Radboud Geert Grooteplein 8 zuid P.O.Box 9101 6500 HB Nijmegen

  • Aan Mieke, Annette en Christine

    Aan mijn ouders

  • CONTENTS

    LIST OF ABBREVIATIONS

    PREFACE

    SECTION I

    CHAPTER I.

    CHAPTER 2.

    CHAPTER 3.

    CHAPTER 4.

    CHAPTER 5.

    REFERENCES

    ASPECTS OF PERIPHERAL THYROID HORMONE METABOLISM

    MECHANISMS OF PERIPHERAL THYROID HORMONE METABOLISM

    A. Deiodination: a Tissue-Specific Pathway B. Conjugation of Iodothyronines

    I. Glucuronidation 2. Sulfation

    C. Oxidative Deamination D. Ether Link Cleavage

    FACILITATED DEIODINATION AFTER SULFATION OF IODOTHYRONINES: The Concerted Action of Two Metabolic Pathways

    SULFATION OR GLUCURONIDATION OF T3: The Significance of Dual Metabolism

    THE INTERACTION OF DIFFERENT TISSUES IN THYROID HORMONE METABOLISM: The Proposal of a Hypothetical Model

    A. Metabolism of 3,3'-T2 B. Metabolism of Reverse T3 C. Metabolism of T3 D. Metabolism of Thyroxine E. Concluding Remarks

    FUTURE ASPECTS

    9

    ll

    15

    17

    19 23 25 27 29 31

    33

    39

    47

    49 51 53 55 56

    59

    61

  • SECTION II APPENDIX PAPERS

    PAPER 1.

    PAPER 2.

    PAPER 3.

    PAPER 4.

    PAPER 5.

    PAPER 6.

    PAPER 7.

    SUMMARY

    The Role of Dietary Fat in Peripheral Thyroid Hormone Metabolism. M.H. Otten, G. Hennemann, R. Docter, T.J. Visser. Metabolism 1980; 29: 930.

    Iodothyronine Metabolism in Isolated Rat Hepatocytes: initial results. M.H. Otten, H. Bernard, J. Blom, R. Docter, G. Hennemann, T.J. Visser.

    Sulfation Preceding Deiodination of Iodothyronines in Rat Hepatocytes. M.H. Otten, J.A. Mol, T.J. Visser. Science 1983; 221:81.

    Metabolism of 3,3'-Diiodothyronine in Rat Hepatocytes: interaction of sulfation with deiodination. M.H. Otten, G. Hennemann, R. Docter, T.J. Visser. Endocrinology, accepted for publication.

    Rapid Deiodination of Triiodothyronine Sulfate by Rat Liver Microsomal Fraction. T.J. Visser, J.A. Mol, M.H. Otten. Endocrinology 1983; 112: 1547.

    3,3',5-Triiodothyronine Metabolism in Rat Hepatocytes: the significance of sulfation for metabolic clearance and deiodination. M.H. Otten, G. Hennemann, R. Docter. T.J. Visser. Submitted for publication.

    Iodothyronine Sulfatase Activity of Two Anaerobic Bacterial Strains from Rat Intestinal Microflora. M.H. Otten, W.W. de Herder, M.P. Hazenberg, M. van de Boom, G. Hennemann. FEMS Microbiology Letters 1983; 18: 75.

    SAMENVATTING

    NAWOORD

    CURRICULUM VITAE

    75

    77

    83

    93

    97

    117

    121

    139

    143

    145

    149

    151

  • cAMP 0 !/II OCNP diac OTT FCS GSH IRO 1/ II Km NBCS ORO I/11 PCP PTU R(n)

    RIA rT3 3'-T1 3,3'-T, 3,3'-T2S

    TJ T3G T3S T, T4G TBG TBPA tetrac triac TSH TU Vmax

    LIST OF ABBREVIATIONS

    cyclic adenosine 3', 5' -monophosphate deiodinase type I I II 2,6-dichloro-4-nitrophenol 3,3'-diiodothyroacetic acid dithiotreitol fetal calf serum glutathione (reduced) inner ring deiodinase I/ II (catalysing 3- or 5-deiodination) Michaelis constant new-born calf serum outer ring deiodinase I/ II (catalysing 3'- or 5'-deiodination) pentachlorophenol 6-propy 1-2-thiouracil reaction number corresponding with Table I and fold-out in back of the manuscript radioimmunoassay 3,3',5'-triiodothyronine (reverse T3) 3 '-iodothyronine 3,3 '-diiodothyronine 3,3'-T2 sulfate 3,3 ',5-triiod a thyronine T 3 glucuronide T3 sulfate 3,3 ',5,5'-tetraiodothyronine (thyroxine) T 4 glucuronide thyroxine-binding globulin thyroxine-binding prealbumin 3,3 ',5,5 '-tetraiodothyroacetic acid 3,3',5-triiodothyroacetic acid thyroid-stimulating hormone (thyrotropin) 2-thiouracil maximal velocity

    9

  • PREFACE

    The research into thyroid function has a long history. The recognition of

    goiter as pathology of the thyroid gland dates back to the ancient world of Rome

    and Greece and possibly even to the early history of chinese medicine. In an

    excellent review of the historical aspects of the discovery of thyroid hormones

    and their biological action (1) Pitt-Rivers describes the growing awareness of

    the significance of iodine for thyroid function early in the 19th century.

    The actual presence of organic iodine in the thyroid gland was demonstrated

    for the first time in 1896 1:y Ba1.llTBnn who called his concentrate of a thyroid

    extract "Iodothyrin". In 1914 Kendall isolated a crystalline material from thy-

    roid hydrolysates and named it "Thyroxin" after thyroxindole, since he believed

    this sUbstance to be an indole derivative. The compound proved to have biologi-

    cal activity in hypothyroid man and aninals. The actual structure fonnula of

    the thyroxine rrolecule was disclosed by Harington in 1926. Only in 1952 the ex-

    istence of 3,3' ,5-triiodothyronine was simultaneously demonstrated in beef thy-

    roid and human serum by Gross and Pitt-Rivers and in rat thyroid by RoChe et al.

    At the same time it appeared that this triiodothyronine was about three times as

    potent as thyroxine in the goiter prevention assay in rats. The original postu-

    late by Gross and Pitt-Rivers (1953) that triiodothyronine originates by degra-

    dation of thyroxine in peripheral tissues and constitutes the principal active

    thyroid hormone was established by Sterling and Braverman in as late as 1970.

    Since this time thyroid research has explosively expanded in many fields,

    such as thyroidal synthesis and secretion of iodothyronines, feedback regula-

    tions of the hypothalamic-pituitary-thyroid axis, goiter etiology and autoimmune

    rrechanisrns with associated hyper- and hyp::>thyroidism, thyroid cancer, vascular

    transport proteins, nuclear thyroid hormone receptors with post-receptor biolog-

    ical effects and the br03.d field of peripheral thyroid honnone rnetal.:::olism. This

    last sUbject in its turn can be subdivided into smaller areas, suCh as kinetic

    studies with isotope labeled thyroid hormones ,the processes involved in mem-

    brane transport, as well as the subcellular distribution of either locally pro-

    11

  • duced or plasma-bome iodothyronines. But also, and this represents an impor-

    tant section in this tllesis, the intracellular metabolism of the m.lltiple thy-

    roxine-derived metaJ:.:olites. It is obvious that the above list is far from com-

    plete, but it gives an irrpression of the wide scope of current thyroid research.

    This thesis is a compilation of various investigations in the field of peri-

    pheral thyroid horrrone metabolism. The rrain objective of the presented work has

    been to obtain rrore kno.vledge about the physiology of the various metalx>lic

    pathways of iodothyronines. This objective was chosen in the hope to contribute

    to a better understanding of the complex metabolic adaptations in iodothyronine

    :metabolism, known to be induced by several drugs, dietary changes or diseases.

    At first sight the rather diverse subjects of investigation in Section II of

    this thesis bear no apparent relation. Ha.vever, in the next chapters a tenta-

    tive linkage of the various results will be discussed.

    Essentially three different lines of researCh have been followed. The first

    line consists of the investigation of dietary influences on peripheral thyroid

    horrrone rnetab:Jlism. Since the observation of Spaulding et al ( 2) that 800 kCal

    of dietary carbohydrates nullified the changes of hurran serum

    3,3' ,5-triiodothyronine {T3) and 3,3' ,5'-triiodothyronine (reverse T3) norm