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THE EFFECT of OXIDATION PHENOTYPE Department St. Mary's London, W2 on the DISPOSITION of CERTAIN ENDOGENOUS STEROIDS HIKMAT HAMD

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THE EFFECT of OXIDATION PHENOTYPE Department St. Mary's London, W2 on the DISPOSITION of CERTAIN ENDOGENOUS STEROIDS HIKMAT HAMD THE EFFECT OF OXIDATION PHENOTYPE ON THE DISPOSITION OF CERTAIN ENDOGENOUS STEROIDS HIKMAT HAMDI NADIR A Thesis Submitted For The Degree Of DOCTOR OF PHILOSOPHY In The UNIVERSITY OF LONDON Department of Pharmacology, St. Mary's Hospital Medical School, London, W2 IPG. March 1985 To My Wife and In Memory ot My Father » -3 ABSTRACT 1. This thesis addresses the question as to whether or not the allelomorphic gene which governs the oxidative metabolism of a number of drugs including debrisoquine, influences the oxidative metabolism of certain steroids in both man and rat. ft 2. Human subjects, both male and female, of known oxidation phenotype were investigated for urinary excretion of seven individual 17- oxosteroids and three progesterone metabolites by gas-liquid chromatography. Persons of the recessive poor metaboliser phenotype excreted only half the pregnanetriolone of extensive metabolisers. 3. Urinary oestrogen excretion did not differ between phenotypes, including for E^, E^, Eg and their 2- and 16-oxygenatea metabolites. 4. Serum cholesterol concentration in extensive and poor metaboliser volunteers did not differ. In patients with excessively high or low serum cholesterol concentrations, there was no association with oxidation phenotype. 5. It was concluded that, in man, no simple determinant of endogenous I steroid disposition had been found that could be used as a non- invasive phenotyping test. 6. Similar investigations were also carried out in rats of known oxidation phenotype. No differences between female DA (phenotypically poor metaboliser) and Lewis (phenotypically extensive metaboliser) rats were found for urinary 17-oxosteroid and progesterone metabolite excretion. » * -4 7. DA rats given [i^C]-oestrone (20 mg i.p.) recovered four-fold more 14 C in the first day urine than Lewis rats. However, Lewis rats excreted 50% more water, Na+ and K+ in the first day than DA rats. l Whether or not this finding has a metabolic origin is not known. Biliary cannulated Lewis rats excreted 2-3-fold more 2-hydroxy- oestrone than DA rats in the 0-1 h bile after a dose of 16 pg 14 [ C]-oestrone. 8. Additionally, serum cholesterol of DA rats was 50% greater than Lewis rats and a number of other extensive metabolising rat strains. Neither K nor V for cholesterol 7ci-hydroxyl ase showed an m max interphenotype difference in rats. However, 3-methylcholanthrene treatment increased the K and V approximately twice as much in m max J DA than Lewis rats. 9. It is concluded that no non-invasive phenotyping test was uncovered during the course of this work. However, a number of clues emerged which may lead to such a test in the future. * » CONTENTS Abstract List of Tables i List of Figures Acknowledgements CHAPTER ONE INTRODUCTION 1. Introduction 1.1 Drug absorption 1.2 Drug distribution 1.3 Drug excretion 1.4 Drug metabolism 1.4.1 Involvement of different forms of cytochrome P-450 1.4.2 Steroid metabolism 1.5 Pharmacogenetics 1.6 Regulation of drug oxidation by the debrisoquine hydroxylation locus I 1.7 Animal model for drug oxidation 1.8 Aims of the present study ... CHAPTER TWO EFFECT OF POLYMORPHIC OXIDATION ON URINARY STEROID PROFILES IN MAN AND RAT ... 2.1 Introduction ... f -6- Contents, continued Page 2.1.1 Urinary 17-oxosteroids 42 2.1.1.1 Androsterone 45 2.1.1.2 Aetiocholanolone 45 2.1.1.3 Dehydroepiandrosterone 46 2.1.1.4 The 11-oxo- and 118-hydroxy- 17-oxosteroids 46 2.1.2 Urinary progesterone metabolites 47 2.1.3 The involvement of cytochrome P-450 in steroid hydroxylations 49 2.1.4 The genetic abnormalities of steroid hydroxylation 54 2.1.5 Aims of the investigation 55 4 2.2 Materials and Methods 58 2.2.1 Materials 58 2.2.2 Animals 59 2.2.3 Human subjects 59 2.2.4 Methods 60 2.2.4.1 Determination of oxidation phenotype ... 60 t 2.2.4.2 Determination of individual 17-oxosteroids, pregnanediol, pregnanetriol and pregnanetriolone in urine 62 2.2.4.3 The colorimetric quantitative determination of creatinine in urine 70 2.2.4.4 Determination of total urinary 17-oxosteroids 71 ¥ Contents, continued Page 2.3 Results 74 2.3.1 Population study 74 2.3.2 Steroid profiles in man 74 2.3.2.1 The effect of sex 74 2.3.2.2 The effect of phenotype 87 2.3.3 Steroid profiles in rats 87 2.3.4 Total 17-oxosteroids in a panel of subjects arid two different phenotyped strains of rats 88 2.3.5 Analysis of the 5$/5a and DEA/A + Ae ratios 88 2.3.6 Comparison of urinary 17-oxosteroid concentration determined by colorimetry and by summation of individual 17-oxosteroids determined by gas chromatography 94 2.4 Discussion 98 CHAPTER THREE EFFECT OF POLYMORPHIC OXIDATION ON URINARY OESTROGEN EXCRETION IN MAN AND RAT 103 3.1 Introduction 104 3.2 Materials and Methods 113 3.2.1 Materials 113 3.2.2 Animals 113 3.2.3 Human subjects 114 3.2.4 Dosing of animals and collection of excreta 114 -8- Contents, continued Page 3.2.5 Preparation of faeces for g.c. analysis 114 14 3.2.6 Preparation of faeces for C analysis 114 » 3.2.7 Counting of [14C]-oestrone 116 3.2.8 Analytical procedures 116 3.2.8.1 Determination of oestrogens and metabolites in urine employing gas-liquid chromatography ... 116 3.2.8.2 Determination of biliary, faecal and urinary metabolites of labelled oestrone in rats by HPLC 120 3.2.8.3 Collection of bile from rats.. 128 3.2.8.4 Determination of sodium and potassium excretion in rat urine 128 3.3 Results ... ... ... 131 3.3.1 Human urinary oestrogen profiles - effect of phenotype ... 131 3.3.2 Faecal and urinary oestrogen metabolite profiles after administration of labelled oestrone to DA and Lewis rats 134 3.3.3 Oestrogen profiles in bile of DA and Lewis rats after an intramesenteric venous dose of labelled oestrone 139 3.3.4 Sodium and potassium excretion and urine volume in Lewis and DA rats after oestrone administration 142 - 9 - Contents, continued Page 3.3.5 Administration of 2-hydroxyoestrone and 16oi-hydroxyoestrone to Lewis and DA rats 146 3.4 Discussion ... 147 ► CHAPTER FOUR EFFECT OF POLYMORPHIC OXIDATION ON SERUM CHOLESTEROL IN MAN AND RAT AND CHOLESTEROL 7a-HYDROXYLATION IN THE RAT ... 156 4.1 Introduction 157 4.1.1 Cholesterol biosynthesis 157 4.1.2 Metabolism of cholesterol in vivo 159 4.1.3 Metabolism of cholesterol in vitro 161 4.1.4 The involvement of cytochrome P-450 in cholesterol 7a-hydroxylation 164 4.1.5 Deficiency of the LDL receptor leads to hypercholesterolaemia and premature atherosclerosis 165 4.1.6 Aims of the study 167 4.2 Materials and Methods 168 4.2.1 Materials 168 4.2.2 Animals ... 168 4.2.3 Human subjects 169 4.2.3.1 Healthy subjects 169 4.2.3.2 Volunteers with "high" or "low" serum cholesterol 169 - 10- Contents, continued Page 4.2.4 Methods ... ... ... 170 4.2.4.1 Determination of human/rat cholesterol by colorimetry ... 170 4.2.4.2 Determination of the activity of cholesterol 7a-hydroxylase in the liver t of DA and Lewis rats ... 171 4.2.4.2.1 Preparation of liver cell fractions and incubations ... 171 4.2.4.2.2 Determination of protein ... 172 4.2.4.2.3 Isolation of radioactive products by thin layer chromatography ... 172 4.2.4.2.4 Radiochromatogram scanning ... 173 4.2.4.2.5 Quantitation of radioactive peaks 173 4.3 Results ... ... ... 176 4.3.1 Serum cholesterol levels of different strains of rats ... ... 176 4.3.2 Effect of 3-methylcholanthrene induction on the serum cholesterol in the rat ... 180 4.3.3 Relationship between oxidation phenotype and serum cholesterol in human ... 180 4.3.4 Determination of cholesterol 7a-hydroxylase I activity in rat liver fraction ... 183 4.3.5 Derivation of Km and Vmax of the cholesterol 7a-hydroxylase system ... ... 187 4.3.6 The effect of 3-methylcholanthrene induction on the activity of cholesterol 7ot-hydroxylase 189 4.4 Discussion ... ... ... 196 Contents, continued Page CHAPTER FIVE GENERAL DISCUSSION AND CONCLUDING REMARKS ... 200 5.1 General Discussion ... ... 201 BIBLIOGRAPHY 208 APPENDIX 252 % - 12- LIST OF TABLES Table Page 1.1 Polymorphic drug oxidation ... ... 34 1.2 Regulation/inf1uence of the debrisoquine i hydroxylation locus on various metabolic pathways ... ... ... 36 2.1 Urinary excretion (ranges, pg/24h) of individual 17-oxosteroids in male and female children and adults ... ... ... 44 2.2 Spectral dissociation constants (Ks) for compounds interacting with human foetal adrenal microsomes ... ... ... 53 2.3 Classification of the adrenal hyperplasias ... 56 2.4 Different methods used for determination of steroids ... ... ... 63 2.5 Gas chromatographic characteristics of derivatized 17-oxosteroids, pregnanediol, pregnanetriol and prenanetriolone on 3% OV-17 ... ... 66 2.6 Mean (+ S.D.) of 17-oxosteroids, pregnanediol, pregnanetriol and pregnanetriolone/creatinine i ratios (pM/mM) in human urine. The effect of sex ... ... ... 85 2.7 Mean (+S.D.) of 17-oxosteroids, pregnanediol, pregnanetriol and pregnanetriolone/creatinine ratios (pM/mM) in human urine. The effect of phenotype ... ... ... 86 Table Page 2.8 Mean (+S.D.) values of individual 17-oxosteroids/ creatinine in rats 89 2.9 Urinary excretion of total 17-oxosteroids (mg/24h) in human 90 2.10 Urinary excretion of total 17-oxosteroids (mg/48h) in rats 91 2.11 Mean (+ S.D.) of Ae/A and DEA/A + Ae ratios in human. The effect of sex 92 2.12 Mean (+ S.D.) of Ae/A and DEA/Ae + A ratios in human.
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