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An Investigation Into the Contribution of Flavin Containing Monooxygenases to the Development and Prevention of Thiourea-Induced Pulmonary Toxicity in the Rat

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An Investigation Into the Contribution of Flavin Containing Monooxygenases to the Development and Prevention of Thiourea-Induced Pulmonary Toxicity in the Rat An investigation into the contribution of flavin containing monooxygenases to the development and prevention of thiourea-induced pulmonary toxicity in the rat Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor of Philosophy By Giovanni Pellegrini November, 2013 DECLARATION This thesis is the result of my own work. The material contained within this thesis has not been presented, nor is currently being presented, either wholly or in part for any degree or other qualification. Giovanni Pellegrini This research was carried out in the Department of Pharmacology and Therapeutics, The University of Liverpool. Abstract NR678, a small thiourea-based rodenticide candidate, is lethal to rats when administered orally at relatively small doses (5 and 10 mg/kg) and causes rapid life-threatening respiratory impairment, characterised by severe hydrothorax and pulmonary oedema. However, rats are protected from a normally lethal dose of NR678, after prior exposure to a low dose (0.5 mg/kg). Similar to other molecules containing the thiourea moiety, NR678 is mainly metabolised by flavin containing monooxygenases (FMOs), a class of enzymes involved in the detoxification, or more rarely, bioactivation of N- or S-containing molecules during phase I metabolism. Rat FMO2, the main FMO expressed in the lungs, like the correspondent human isoform, exhibits a genetic polymorphism which may influence the responses of this organ to NR678 and other drugs metabolised by FMOs. The aims of this thesis were to assess the morphological and functional aspects of NR678-induced acute lung injury (ALI) and to investigate the role of the adaptive pulmonary defence response involved in the prevention of the oxidative injury. In addition, the wild rat, which, in contrast to the laboratory rat, possesses a functional pulmonary FMO2, was explored as a possible animal model to evaluate the metabolic and toxicologic consequences of FMO2 polymorphism in humans. It was shown that pulmonary endothelial cells are the main target of acute NR678 oxidative injury and exhibit ultrastructural alterations, which, coupled with a marked depletion of glutathione (GSH) levels, are likely responsible for the perturbation of pulmonary vascular permeability. The lungs of tolerant animals showed mild and transient changes of the vascular permeability and mildly increased cellularity in the lungs, which was characterised by increased numbers of alveolar macrophages and immature pneumocytes within 24 h after dosing, followed by a rise in the number of mature type II pneumocytes one week later. The microscopic changes resolved by the end of the second week, when rats were found to be again susceptible to a lethal dose of NR678. It was speculated that the adaptive response of the lungs to NR678 could be related to irreversible inhibition of FMOs, rather than increased clearance of the oedema fluid by macrophages and type II pneumocytes, down-regulation of FMOs, evaluated by in situ hybridisation and qPCR, or decreased GSH levels. In addition, it was found that the presence of an active FMO2 isoform enhances pulmonary FMO catalytic activity and leads to increased susceptibility to the toxic effects of NR678. In conclusion, the work presented here contributes evidence that FMO2 polymorphism may be relevant to humans and provides an animal model which can be used to study its implications. NR678 represents an interesting and unique approach to investigate the pathogenesis of ALI and, at the iii same time, understanding the defence mechanisms involved in adaptation may bring new insight into potential therapeutic strategies of lung diseases. iv Acknowledgments Joining a PhD program has been like falling into an enormous debt of gratitude. I have no means to thank here all the friends and colleagues who shared with me their knowledge and gave me support and enthusiasm during these years. I guess the only way to pay them back is to adopt the same attitude in every day of my future professional career. This experience would not have been possible without the guidance and encouragement of my supervisors, Dr. Dominic Williams, Prof. Anja Kipar and Prof. Kevin Park. I would like to thank them for giving me the opportunity to “go back to school” after a few years spent in Toxicologic Pathology and do this work. I also want to acknowledge the continuous support I received from Roger Sharple, Sharon Hughes and all the extremely skilled staff working for BASF Pest Control Solutions-UK, which contributed financially to this project. They were excellent guides as well as good friends, who made me feel at home during the frequent visits to their facility. v Publications Papers Pellegrini G, Starkey Lewis PJ, Palmer L, Hetzel U, Goldring CE, Park BK, Kipar A, Williams DP (2013). Intraperitoneal administration of high doses of polyethylene glycol (PEG) causes hepatic subcapsular necrosis and low-grade peritonitis with a rise in hepatic biomarkers. http://www.ncbi.nlm.nih.gov/pubmed/23831209 doi: 10.1016/j.tox.2013.06.003. [Epub ahead of print] Posters G Pellegrini, D Williams, BK Park and A Kipar. Pulmonary defense mechanisms and their potential role in the prevention of thiourea-induced lung toxicity: histopathological and ultrastructural assessment. European Society of Veterinary Pathology/European Society of Toxicologic Pathology (ESVP/ESTP) meeting, 7- 9/09/2011, Uppsala, Sweden. Best poster award, ToxPath section, French Society of Toxicologic Pathology. G Pellegrini, A Kipar, BK Park and D Williams. An in vivo investigation into thiourea-mediated pulmonary toxicity: a histopathological and ultrastructural assessment. British Society of Toxicology (BTS) autumn meeting, 5-6/09/2011, Nottingham, UK. Commended. G Pellegrini, A Kipar, BK Park and D Williams. From rat poison to personalized drugs: an example of Translational Medicine. Poster day 2012 at the University of Liverpool, 22/03/2012. Best poster award, Health and Life Sciences section. G Pellegrini, PJ Starkey Lewis, L Palmer, U Hetzel, CE Goldring, BK Park, DP Williams and A Kipar. Intraperitoneal administration of high doses of polyethylene glycol (PEG) causes hepatic subcapsular necrosis and low-grade vi peritonitis with a rise in hepatic biomarkers. ESTP meeting, 10-12/09/2013, Ghent, Belgium. Awarded the Charles Capen Trainee award. vii Contents Abstract ................................................................................................................................................ iii Acknowledgments ................................................................................................................................ v Publications .......................................................................................................................................... vi Contents ............................................................................................................................................. viii List of figures ...................................................................................................................................... xii List of tables ....................................................................................................................................... xiv List of abbreviations .......................................................................................................................... xv CHAPTER 1 INTRODUCTION ............................................................................ 1 1.1 Need for novel rodenticides .................................................................................................... 2 1.2 Current use and application of thioureas.............................................................................. 6 1.3 Thiourea-based molecules as rodenticide candidates .......................................................... 7 1.4 Tolerance to thiourea(s) .......................................................................................................... 8 1.5 The role of flavin containing monooxygenases (FMOs) in xenobiotic metabolism ........... 9 1.5.1 History of the FMO enzyme family .................................................................................... 10 1.5.2 Differences from and similarities with cytochrome P450 ................................................... 10 1.5.3 Structure of FMOs .............................................................................................................. 11 1.5.4 FMO catalytic cycle ............................................................................................................ 13 1.5.5 Endogenous and exogenous substrates of FMOs ................................................................ 14 1.5.5.1 Nitrogen-containing drugs as FMO substrates ........................................................... 15 1.5.5.2 Sulphur-containing drugs as FMO substrates ............................................................ 17 1.5.5.3 Endogenous substrates of FMOs ................................................................................ 19 1.5.6 Tissue- and species-specific differences in the expression of FMOs .................................. 19 1.5.6.1 FMO expression in humans ....................................................................................... 21 1.5.6.2 FMO expression in mice ............................................................................................ 22 1.5.6.3 FMO expression in rats .............................................................................................
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