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Metabolic and Mechanistic Studies on Hydrazine Hepatotoxicity in The TOXICOLOGY DEPARTMENT THE SCHOOL OF PHARMACY UNIVERSITY OF LONDON W METABOLIC AND MECHANISTIC STUDIES ON HYDRAZINE HEPATOTOXICITY IN THE RAT A Thesis Submitted by Jane Delaney to the University o f London for examination for the degree of Doctor of Philosophy 7996 ProQuest Number: 10104259 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104259 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Hydrazine, a chemical with numerous applications in industry, is carcinogenic and acutely toxic to the central nervous system and liver. Metabolism and mechanisms of toxicity are not yet fully understood. Previous workers have observed increased acute hydrazine hepatotoxicity in cytochrome P4502E 1-induced rats (isoniazid pretreated). In contrast apparent induction of this isoenzyme by pretreatment of rats with hydrazine protected against hydrazine-induced cytotoxicity in isolated hepatocytes but had little effect in vivo. These results may indicate that P4502E1 catalyses a detoxication pathway for hydrazine which plays only a minor role in vivo. Cytochromes P4501A1/2 and P4502B1/2 appear to catalyse detoxication pathways as a reduction in their activities correlates with increased hydrazine toxicity. A further study failed to clarify the induction of P4502E1 by hydrazine as, despite a dose dependent increase in p-nitrophenol hydroxylase activity, there was no apparent increase in enzyme protein, determined by immunohistochemical staining. This could explain the discrepancy between isoniazid and hydrazine pretreatments with regard to acute hydrazine toxicity. There is conflicting data regarding the effect of hydrazine on protein synthesis. Incorporation of ^H-leucine into protein in vitro in isolated ra t hepatocytes was reduced 2 hours after exposure to 0.5mM hydrazine and 1 hour after higher concentrations. In vivo there was some evidence of protein synthesis inhibition 3 hours after 30 and 60mg/Kg hydrazine administration, followed by stimulation 24 hours post dose. The mechanism of action is currently unknown. Fatty liver is the major acute toxic manifestation in liver after exposure to hydrazine and appears to be unrelated to hydrazine metabolism. Microsomal phosphatidate phosphohydrolase activity and triglyceride content (NMR analysis) were raised 24 hours after hydrazine dosing, consistent with increased lipid synthesis. Raised serum triglycerides and control levels of phosphatidylcholine, required for VLDL synthesis, tend to suggest normal triglyceride secretion at this time, however there may have been a transient drop in VLDL production, due to decreased protein synthesis 3 hours post dose, which may have facilitated the accumulation of fat. Phosphatidylinositol was also raised but the reason for this is unknown. 11 ACKNOWLEDGEMENT I would like to express my gratitude to my supervisor, Professor John Timbrell, for his advice and guidance (and not forgetting the occasional piece of Kit-Kat!) over the last 3 years. I would also like to thank everyone that suffered along with me throughout my ordeal, including all my fellow Tox. students, Adrian Rogers for processing many late orders, Dave McCarthy for his help on both light and electron microscopes, and Dr. Cathy Waterfield on whose expertise I constantly relied. Thanks also to Professor Gibbons and Mire Zloh, from the chemistry department, for their assistance in generating and interpretting NMR spectra. Special thanks must go to Alka for her friendship, and to Ian for his patience, and support. PhD life would have been much harder without them. Finally, I would like to thank my parents who have given me the best opportunities in life. Without their continuous support and encouragement I would never have got this far! It is to them that I dedicate this thesis. Ill CONTENTS ABSTRACT................................................................................................................. i ACKNOWLEDGEMENT........................................................................................... iii CONTENTS ............................................................................................................ iv LIST OF FIGURES ...................................................................................................viii LIST OF TABLES .................................................................................................. xi LIST OF PHOTOMICROGRAPHS..................................................................... xii LIST OF ELECTRONMICROGRAPHS ........................................................... xii ABBREVIATIONS..................................................................................................... xiii CHAPTER 1 ............................................................................................................ 1 GENERAL INTRODUCTION ............................................................................ 1 1.1 IN TR O D U C TIO N ............................................................................. 1 1.2 PHYSICAL AND CHEMICAL PROPERTIES .......................... 1 1.3 A PPLIC A TIO N S................................................................................ 2 1.4 METABOLISM OF HYDRAZINE AND ITS DERIVATIVES . 4 1.4.1 Absorbance, Distribution and Urinary Excretion of Hydrazine ............................................................................ 4 1.4.2 Metabolism of the Parent Compound ........................... 5 1.5 INTERACTION OF HYDRAZINE COMPOUNDS WITH METABOLIC SYSTEMS ............................................................. 10 1.5.1 Oxyhaemoglobin ................................................................ 10 1.5.2 Haem-containing Enzymes ............................................ 10 1.5.3 Flavin-containing Enzymes ............................................... 11 1.6 TOXICITY OF HYDRAZINE.......................................................... 11 1.7 BIOCHEMICAL EFFECTS OF HYDRAZINE .......................... 13 1.7.1 CNS Disturbances ............................................................. 13 1.7.2 Carbohydrate Metabolism ................................................. 15 1.7.3 Lipid M etabolism ................................................................ 16 1.7.3.1 Source of precursors for lipid synthesis .... 16 1.7.3.2 Synthesis of Liver L ipids ................................... 17 1.7.3.3 Mechanism for the development of fatty l i v e r............................................................................ 18 1.7.3.4 The Effect of Hydrazine on Liver Lipids .... 20 1.7.4 Protein Metabolism ........................................................... 23 1.7.5 Urea Cycle ............................................................................ 26 1.7.6 Mitochondrial E ffects ......................................................... 28 1.7.7 Depletion of Reduced Glutathione .................................. 30 1.8 MUTAGENICITY AND CARCINOGENICITY OF HYDRAZINE AND ITS DERIVATIVES..................................... 33 IV 1.9 ANTITUMOUR ACTIVITY OF HYDRAZINES ......................... 37 1.10 TERATOGENICITY ........................................................................ 38 1.11 AIM OF STUDY ............................................................................... 39 CHAPTER 2 ............................................................................................................ 40 MATERIALS AND METHODS .......................................................................... 40 2.1 CHEMICALS ..................................................................................... 40 2.2 IN VIVO S T U D IE S ........................................................................... 41 2.2.1 Animal Husbandry ............................................................ 41 2.2.2 Autopsy Procedure ............................................................ 41 2.2.3 Isolation of rat liver microsomes.................................... 42 2.2.4 Total Cytochrome-P450 ..................................................... 42 2.2.5 p-NitrophenoI Hydroxylase .............................................. 43 2.2.6 Ethoxyresorufin o-deethylase (EROD)/ Pentoxyresorufin o-depentylase (PROD) ................................ 44 2.2.7 Determination of Protein ................................................ 45 2.2.8 Adenosine Triphosphate (ATP) ...................................... 45 2.2.9 Total Non-Protein Sulphydryls (TNPSH) .................... 46 2.2.10 Oxidised Glutathione (GSSG) ........................................ 46 2.2.11 Liver Triglyceride Analysis ............................................. 47 2.2.12 Serum Clinical Chemistry ............................................... 47 2.3 IN VITRO ST U D IE S ......................................................................... 48 2.3.1 Animal Husbandry ............................................................ 48 2.3.2 Preparation of Isolated Hepatocytes ............................. 48 2.3.3 Trypan Blue Dye Exclusion
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