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ABSTRACT M. Sc. Siang Yong Tan Experimental Medicine

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ABSTRACT M. Sc. Siang Yong Tan Experimental Medicine ABSTRACT M. Sc. Siang Yong Tan Experimental Medicine "SULFATES AND SULFOGLUCOSIDURONATES OF CERTAIN ESTROGENS IN HUMAN PREGNANCY URINE" Glucosiduronates and non-glucosiduronates of various estrogens were measured in 6 different human late pregnancy urine samples. The difference between the amount of free steroid :r'pleased by solvolysis aione and by the sequentiai use of B-glucu­ ronidase and solvolysis was taken to represent the sulfoglucosidu- ronate. Estrioi was shown to be present predominantly (93%) as the glucosiduronate, compared with 72% for the ring D a ketols. In the case of 16-keto-17B-estradiol, 15% was present as the sulfoglucosiduronate, and 19% as sulfate; in marked contrast, 20% of total 16a -hydroxyestrone Was the sulfoglucosiduronate with only 3% as the sulfate. U rinary conjugates were also anaIyzed following the administration of 3H-Iabelled 17B-estradiol to 2 pregnant diabetic women, an~ evidence was furnished for the presence of the sulfo­ glucosiduronate of estriol, 16a-hydroxyestrone and 16-keto-17B- estradiol as radioactive metabolites. The quantitative importance of urinary estrone sulfate was aiso demonstrated in one of these subjects. ESTROGEN CONJUGATES IN HUMAN PREGNANCY URINE , SULFATES AND SULFOGLUCOSIDURONATES OF CERTAIN ESTROGENS IN HUMAN PREGNANCY URINE A Thesis by Siang Yang Tan, B.Sc. Submitted ta the Faculty of Graduate Studies and Research in Partial Fulfilment of the Requirements for the Degree of Master of Science. Department of Experimental Medicine Mc Gill University Montreal, Canada November 1969 cv Siang Yang Tan 1970 i e. TABLE OF CONTENTS PAGE ACKNOWLEDGEMENTS ........•..... vii STEROID NOMENCLATURE......... ix CHAPTER 1. REVIEW 0 P THE il TERATURE •.... 1 A. General historical perspective .•.... 1 B. E strogen glucosiduronates • . • • • . 3 C. E strogen sulfates 9 D. E strogen double conjugates . 14 E. Metabolism and interconversion 17 of various estrogen conjugates •.•... THE AIM OF THE INVESTIGATION 25 CHAPTER II. EXPERIMEN'I'AL - MATERIALS AND METHODS ........................... 26 MATE RIAIS ......................... 26 A. Radioactive steroids ............... 26 B. Non-radioactive steroids ..........• 27 C. Reagents... • . 28 METHODS ........................... 32 A. Procedure with subjeds and 32 patients .•...............•......... B. Methods of separation and analysis . 34 ii PAGE C. Methods involving radioactivity ....... 39 D. Recovery experiments .............. 40 CHAPTER III. RESULTS ............................ 42 CHAPTER IV. DISCUSSION ..•..•.................. 96 S UMMARY .................•.....•.... 107 BI BLIOGRAPHY ...................... 109 .. iii LIST OF TABLES TABLE NO. TITLE PAGE l Conjugates of estriol (E 3) in 6 different urine samples from 4 subjects •••••••.•.••.• 44 II Conjugates of the ring D a ketols in 6 different urine samples from 5 subjects ...... 45 III Conjugates of 16a-hydroxyestrone (l6a-OHE 1) in 6 different urine samples from 5 subjects 47 IV Conjugates of 16-keto-17~-estradiol (16-KE 2) in 6 different urine samples from 5 subjects 48 V Conjugates of estriol, 16a-hydroxyestrone (16a-OHE1) and 16-keto-17~-estradiol (16- KE 2) in 2 subjects, corrected for methodo- 10 gical losses ............................. 50 VI Percentages as non-glucosiduronates, sulfates and sulfoglucosiduronates of 16u-OHE l' 16-KE 2 and E 3 in the urine samples studied 51 VII Conjugates of estrone (E 1) in 6 different urine samples from 4 subjects ........•..••.•.••.. 52 VIII Material released following various enzymatic hydrolyses of pools A, B, and C (subject M) 56 IX Relative amounts of estriol ring D a ketols and estrone in pools Band Cafter DEAE- Sephadex chromatography (subject M) ...... 59 X Relative percentages of 16a-hydroxyestrone and 16-keto-17~-estradiol in the BI and BI l fractions of pool B (subject M) ...........•.•........ 60 XI Recovery of radioactivity following injection of 24. 1 x 106 d. p. m. of 3H-Iabelled 17~-estradiol into subject C .•..........•................ 62 XII Relative amounts of radioactivity in peaks land II following DEAE- Sephadex chromatography (subject c) .............................. 64 iv TABlE NO. TITLE PAGE XIII Crystallization data on estrone released by Mylase-P incubation of peak II from the DEAE-Sephadex column (subject C) 000000 70 XIV Crystallization data on estrone released by ~-glucuronidase incubation of peak l from the DEAE-Sephadex column (subject C) 71 XV Recovery of radioactivity following injection of 24.4 x 106 d.pom. of 3H-Iabelled 17~- estradiol into subject CV 73 XVI Relative amounts of radioactivity in peaks I-IV following DEAE-Sephadex chromato­ graphy (subject CV) (starting material = 1,314,700 do p 0 m.) .. 0 0 ••• 0 • 0 • 0 0 0 • 0 0 0 •• 0 0 0 75 XVII Radioactivity released into ether following various enzyme hydrolyses of pool D. C. (subject CV) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 • 0 0 • 0 0 0 0 0 0 0 87 XVIII Analysis of combined ether-soluble mate rial following sequential enzyme hydrolyses of pool D. Co (subject CV) 0 000 0 0 0 0 0 0 0 0 00000 89 XIX Recovery experiments involving estriol (E 3) 91 XX Recovery experiments involving 16a-hydroxy­ estrone (16a-OHE 1 ) 00000 •• 000000000000000 92 XXI Recovery experiments involving 16-keto-17~­ estradiol (16-KE 2 ) .000000000 •• 00000000000 93 XXII Recovery experiments involving 2-hydroxy- estrone (2-0HE 1 ) 000000 •••• 0.0000000000 •• 95 v LIST OF FIGURES FIGURE NO. TITLE PAGE l Structural formulae of 3 different conjugates of estriol •....••.•••••••.••• xii II DEAE-Sephadex chromatography of urine (subject M) with added radioactive conjugates ...••••........•••••.•••..•• 54 III Celite column (20 cm. x 1 cm.) chroma­ tography of pool C before and a:fter Mylase-P treatment (subject M) in sol­ vent system, 1-butanol:ethyl acetate:O.2% NH4 0H (3:1:4) ......•.••••..•••..... 57 IV DEAE-Sephadex chromatography of urine from subject C injected with 3 H _ labelled 17~-estradiol ....•.•••.•..•.... 63 V Relative amounts of radioactivity and Kober­ positive chromogen released following enzyme hydrolyses of one-haU portion of peak II (subject C) .......... ........ 66 VI Celite column (20 c~. x 1 cm.) chroma­ tography of peak II (DEAE-Sephadex column) in solvent system, 1-butanol: eth)'l a~~tate:0.2% NH4 0H (3: 1:4) ("3ubject C) .••........••..••......... 67 VII Rechromatography of peak II (DEAE­ Sephadex column) in soivent system i iso-octane:tertiary butanoI: 1 :r..[ NH4 0H ( 2: 5: 5) following initial chromatography in soivent system 1-butanoI: ethyl acetate: 0.2% NH4 0H (3: 1:4) (subject C) •..... 69 VIII DEAE-Sephadex chromatography of urine from subject CV injected with 3H-Iabelled 1 7~ -estradiol .•........•.••••....•.... 74 vi FIGURE NO. TITLE PAGE IX Celite column (20 cm. x 1 cm.) chromatography of peak II (DEAE­ Sephadex column) in solvent system, 1-butanoI:ethyI acetate:O.2% NH4 0H ( 3 : 1: 4) (subject CV) ...••...•.•••..... 77 X Celite column (20 cm. x 1 cm.) chroma­ tography of peak III (DEAE-Sephadex column) in solvent system, 1-butanoI: ethyl acetate:0.2% NH 0H (3:1:4) 4 (subject CV) ....••...•.••.••.•••.•••.. 78 XI Celite column (20 cm. x 1 cm.) chroma­ tography of peak IV (DEAE-Sephadex column) in solvent system, 1-butanoI: ethyl acetate:0.2% NH 0H (3:1:4) 4 (subject CV) •..•.••..•...•..•...•••.•• 79 XII Celite column chromatography of peak lIA in solvent system, iso -octane: tertiary 80 butanoI:l M NH4 0H (2:5:5) (subject CV) XIII Rechromatography of peak II lA in solvent system, iso-octane: tertiary butanoI: 1 M NH4 0H (2:5:5) (subject CV) •.•.••..... 81 XIV Celite column (10 cm. x 1 cm.) chroma­ tography of combined methanolic eluates from peak l II and IV columns in solvent system 1-butanoI: ethyl acetate: 0.2% NH4 OH (3: 1: 4) (subject CV) ••....•..................• 83 XV Celite column chromatography of pool D. C. following 13-glucuronidase incubation in solvent system, iso-octane: tertiary butanoI: 1 M NH40H (2:5:5) (subject CV) .•.•• 85 XVI Celite column chromatography of pool D. C. following Mylase-P incubation in solvent system, iso-octane:tertiary butanol: 1 M NH40H (2:5:5) (subject CV) ....•...•. 86 vii ACKNOWLEDGEMENTS l am deeply indebted to P rofessor R. Hobkirk, my research director, for the guidance, encouragement, and inspiration that were accorded me throughout the length of this study. The experimental work done, as recorded in this thesis, was carried out under rather unusual circumstances, during the period when the candidate was a full-time medical student at Mc Gill University. Accordingly, part of the work was performed during the evening hours and over the weekends. N evertheless, there were indeed extremely few occasions when Professor R. Hobkirk was not available for discussion and advice, in spite of such an inconvenient Ume-table impeosed upon him. One direct result of the undertaking of this endeavour is the development of a scientific ;:l,pproach towards investigative problems, a most valuable asset in the unàerstanding of medical and biological phenomena. For this priceless opportunity, and for his encouraging and stimulating supervision, l shall always be grateful. Finally, l am much obliged to Professor R. Hobkirk for his critical review of this thesis. To Miss Mona Nilsen and Mrs. Shona Davidson, both research technicians in our laboratories, much appreciation viii is owed. Throughout, an attempt was always made ta achieve their level of technical expertise, and to emulate their example of dedicated patience in routine and tedious analyses. My appreciation is also due to the Department of Obstetrics and Gynaecology of the Montreal General Hospital, and to the staff of the Endocrine Laboratory for the av ail ab ility of the clînical mate rials used in this study. The External Aid Office in Ottawa, and the Government of the Republic of Singapore, under the Colombo Plan Scholarship, have been most kind in allowing me to under­ take this study. To aIl my friends and colleagues, too numerous to name, for their encouragement and faith, l owe many thanks. Finally, l wish to acknowledge the services of Miss Nicole Larose for the excellent preparation of this manuscript.
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