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Phase I and Ii Enzyme Induction and Inhibition by Secoisolariciresinol Diglucoside and Its Aglycone

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Phase I and Ii Enzyme Induction and Inhibition by Secoisolariciresinol Diglucoside and Its Aglycone View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Saskatchewan's Research Archive PHASE I AND II ENZYME INDUCTION AND INHIBITION BY SECOISOLARICIRESINOL DIGLUCOSIDE AND ITS AGLYCONE A Thesis Submitted to the College of Graduate Studies and Research in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Toxicology Graduate Program University of Saskatchewan Saskatoon, Saskatchewan Canada Erin Margaret Rose Boyd ©Copyright Erin Margaret Rose Boyd, April 2007, All rights reserved. PERMISSION TO USE In presenting this thesis in partial fulfillment of the requirements for a Postgraduate degree from the University of Saskatchewan, I agree that the Libraries of this University may make it freely available for inspection. I further agree that permission for copying of this thesis in any manner, in whole or in part, for scholarly purposes may be granted by the professor or professors who supervised my thesis work or, in their absence, by the Head of the Department or the Dean of the College in which my thesis work was done. It is also understood that any copying or publication or use of this thesis or parts thereof for financial gain shall not be allowed without my written permission. It is also understood that due recognition shall be given to me and to the University of Saskatchewan in any scholarly use which may be made of any material in my thesis. Requests for permission to copy or to make other use of material in this thesis in whole or part should be addressed to: Chair of the Toxicology Graduate Program Toxicology Centre University of Saskatchewan 44 Campus Drive Saskatoon, SK, Canada, S7N 5B3 i ABSTRACT The flaxseed lignan, secoisolariciresinol diglucoside (SDG), and its aglycone, secoisolariciresinol (SECO), have demonstrated benefits in the treatment and/or prevention of cancer, diabetes and cardiovascular disease. In order for the lignans to be used therapeutically, the safety of administration alone and in conjunction with other drugs must be determined. The primary cause of drug interactions is induction and inhibition of cytochrome P450 (CYP) and phase II enzymes. A preliminary screen was conducted to assess the potential for SECO and SDG to cause CYP inhibition. A method was established to assess for CYP, glutathione-S-transferase (GST) and uridine diphosphate-glucuronosyltransferase (UGT) induction in rat primary hepatocytes by real-time reverse transcription-polymerase chain reaction (RT-PCR). Preliminary assessments of inhibition measured the metabolism of testosterone to 6β-, 16α- and 2α-hydroxytestosterone, which corresponds to CYP3A, 2B/2C11 and 2C11 enzyme activity in rat hepatic microsomes by a validated high performance liquid chromatography (HPLC) method. Irreversible inhibition studies found that SDG is not an inhibitor of these isoforms up to 1000 μM. Secoisolariciresinol caused reversible inhibition of 6β-hydroxytestosterone at all testosterone concentrations, with an IC50 (inhibitor concentration causing 50% inhibition of enzyme) between 400 and 800 μM. Over the range of SECO concentrations tested, 10 – 1600 μM, 6β-hydroxytestosterone formation was reduced to 95 – 29% of control levels at 50 μM testosterone. Secoisolariciresinol caused a concentration-dependent increase in 16α- hydroxytestosterone formation at 50 μM testosterone. At 10 μM SECO, there was 90% of control activity, but at 1600 μM metabolite formation was 172% of control. The ii formation of 2α-hydroxytestosterone was not affected at any testosterone or inhibitor concentration. Thus, SECO appears to be a CYP3A inhibitor and a CYP2B activator at testosterone KM levels. The mechanism of reversible inhibition could not be determined due to the possibility of non-Michaelis-Menten kinetics observed with CYP3A inhibition and CYP2B activation. The gold standard in vitro model to assess induction is primary hepatocytes. A method was established that allowed for the isolation and culture of these cells. Positive controls caused induction of CYP mRNA levels after 24 hours treatment, demonstrating the ability of enzyme induction in the test system. Primers for real-time RT-PCR were designed that amplified CYP1A1, 1A2, 2B1, 2C11, 2C13, 2D1, 2D2, 3A1 and 3A2, GSTA2, A5 and P1, and UGT1A1, 1A7, 1A8, 2B1 and 2B12 genes. A preliminary assessment of transcriptional upregulation of drug metabolizing enzymes by SECO and SDG can be assessed in isolated and cultured rat primary hepatocytes. iii ACKNOWLEDGEMENTS I would like to acknowledge the support of my supervisors Dr. Jane Alcorn and Dr. Ed Krol. They were committed to my project and my development as a scientist. I would like to specifically thank Dr. Alcorn for her guidance academically and otherwise. She was always available to answer questions and required me to examine everything and develop my own scientific skills. I would also like to thank the other members of my committee: Dr. David Janz and Dr. Barry Blakley for their consistent support and my external examiner Dr. Andrew Olkowski. Funding for this research was generously provide by the Natural Sciences and Engineering Research Council of Canada. I would like to thank Dr. Harry Deneer for the use of the SmartCycler, Gloria Woo for her assistance with animal surgery and all the summer students for their assistance. I would also like to thank the members of the Alcorn/Krol lab group: Fawzy Elbarbry, Brian Fahlman, Katie Maloney and BinBing Ling for providing academic and social support throughout the entire project. Thank you for teaching me the scientific skills needed to complete my degree. To Jennifer Billinsky, thanks for all your tireless support and assistance in helping me through my research. Without Dr. Alcorn and Jennifer Billinsky constantly challenging my development, this research would not have been possible. Finally, to Mandy Lee Olsgard, for always listening, always supporting and always being there. I am eternally grateful. iv DEDICATION This thesis is dedicated to all my friends and family. In particular, I would like to dedicate this thesis to my parents, Dorothy Anne Russell Reid Boyd and Kenneth Larry Boyd, whose constant love, support and guidance have been my inspiration. v TABLE OF CONTENTS Page PERMISSION TO USE ................................................................................................. i ABSTRACT................................................................................................................... ii ACKNOWLEDGEMENTS ........................................................................................... iv DEDICATION ............................................................................................................... v TABLE OF CONTENTS............................................................................................... vi LIST OF TABLES ......................................................................................................... xi LIST OF FIGURES ....................................................................................................... xiii LIST OF ABBREVIATIONS........................................................................................ xv CHAPTER 1 .................................................................................................................. 1 1. Literature Review....................................................................................................... 1 1.1 Introduction........................................................................................................... 1 1.2 Natural Health Products ........................................................................................ 2 1.2.1 Natural Health Products – An Introduction ................................................. 2 1.2.2 Natural Health Products and Consumer Use/Attitudes in Canada............... 2 1.3 Flaxseed ............................................................................................................... 3 1.3.1 Components and Growth ............................................................................. 3 1.3.1.1 Flaxseed Industry ............................................................................. 3 1.3.1.2 Flaxseed Components ...................................................................... 3 1.3.2 Health Benefits Related to the Flaxseed Lignans ........................................ 4 1.3.3 Status of Flaxseed as a Natural Health Product ........................................... 5 1.3.4 Plant and Mammalian Lignan Pharmacokinetics......................................... 5 1.3.4.1 Absorption and Intestinal Metabolism in Rats ................................ 7 1.3.4.2 Oxidative and Phase II Metabolism in Rats..................................... 7 1.3.4.3 Distribution in Rats .......................................................................... 8 1.3.4.4 Excretion in Rats.............................................................................. 8 1.3.4.5 Enterohepatic Circulation................................................................. 8 1.3.4.6 Lignan Pharmacokinetics in Humans .............................................. 9 1.3.5 Toxicity ....................................................................................................... 9 1.4 Drug Metabolizing Enzymes ................................................................................ 10 1.4.1 Cytochrome P450 and Phase II Enzymes .................................................... 10 1.4.1.1 Cytochrome
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