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AN ABSTRACT OF THE DISSERTATION OF Meltem Yilmazer for the degree of Doctor of Philosophy in Toxicology presented on January 5, 2001. Title: Xanthohumol, A Flavonoid From Hops(Humulus lupulus): In Vitro and In Vivo Metabolism, Antioxidant Properties of Metabolites, and Risk Assessment In Humans. Abstract approved: Redacted for Privacy Donald R. Buhler Reported here is an investigation to determine thein vitroandin vivometabolism of xanthohumol (XN). XN is the major prenylated flavonoid of the female inflorescences (cones) of the hop plant(Humulus lupulus).It is also a constituent of beer, the major dietary source of prenylated flavonoids. Recent studies have suggested that XN may have potential cancer chemopreventive activity but little is known about its metabolism. We investigated the in vitro metabolism of XN by rat and human liver microsomes, and cDNA-expressed cytochrome P450s, and the in vivo metabolism of XN by rats. The metabolites and conjugates were identified by using high-pressure liquid chromatography, liquid chromatography-mass spectrometry, and nuclear magnetic resonance. The antioxidant properties of two metabolites and two glucuronides were examined. The possible risk of XN consumption from beer or dietary supplements is discussed. The involvement of metabolites of XN in cancer chemoprevention remains to be established. ©Copynght by Meltem Yilmazer January 5, 2001 All Rights Reserved XANTHOHUMOL, A FLAVONOID FROM HOPS (Humulus lupulus): IN VITRO AND IN VIVO METABOLISM, ANTIOXIDANT PROPERTIES OF METABOLITES, AND RISK ASSESSMENT IN HUMANS by Meltem Yilmazer A DISSERTATION submitted to Oregon State University In partial fulfillment of the requirements for the degree of Doctor of Philosophy Presented January 5, 2001 Commencement June 2001 Doctor of Philosophy dissertation of Meltem Yilmazer presented on January 5, 2001 APPROVED: Redacted for Privacy Major Professor, representing Toxicology Redacted for Privacy of Department of EnvironThental and Molecular Toxicology Redacted for Privacy Dean I understand that my dissertation will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my dissertation to any reader upon request. Redacted for Privacy Meltem Yilmazer, Author ACKNOWLEDGEMENTS I am sincerely grateful for the support and advice receivedfrom colleagues at Oregon State University. Particular thanks go to Dr.Donald R. Buhler who allowed me to flourish in his lab and provided me ideas and mentorship.I also thank Drs. David E. Williams, Jeff J. Jenkins, Catherine M. Neumann, andJohn M. Christensen, who graciously offered their knowledge, support and time in serving as members of my graduate committee. Ithank Jan F. Stevens and Chnstobol L. Miranda for many hours of input on my research. I thank Max L. Deinzerfor use of the mass spectrometry facilities and his help. I thank MarilynHenderson, my officemate, friend, for her professional expertise, research assistance andadvice beyond the call of duty. I thank Monika Ivancic, Brian Arbogast, and DonGriffin for assistance with mass spectrometry and nuclear magnetic resonance.I thank Roseanne Lorenzana for her help to learn risk assessment at the U.S.EPA.I thank Rosita J. Rodriguez for her help in my in vivo studies and toxicokineticstudies. I thank Margaret M. Pratt, Bonnie J. Bailey, Su-Jun Lee, Robert A.Grove, and Jun- Lan Wang-Buhler for their help and support in persuing my research. I thank the Turkish Council of Higher Education, Oregon State UniversityFoundation, the Hop Research Council, and the National Institute of EnvironmentalHealth Sciences for financial support. Most importantly, I thank my parents,family, and friends for their patience and support. In particular I want to thank Mehmet M. Musa for his encouragement and patience in helping me successfullycomplete this great Oregon State adventure. CONTRIBUTION of AUTHORS Dr. Donald R. Buhler was instrumental in the preparation of all manuscripts (Chapters 2, 3, 4, 5, 6, and 7) and was responsible for their submission. Dr. Buhier provided advice and expertise in experimental design of the studies in this thesis. Dr. Jan Stevens and Dr. M.L. Deinzer trained me in the analysis of LCIMS and helped in the analysis of NMR (Chapter 2, 3, and 5). Dr. Cristobal L Miranda instructed me in the antioxidation experiments of xanthohumol metabolites (Chapter 6). Dr. Bonnie J. Bailey helped me in the risk evaluation of xanthohumol exposure in Chapter 7. TABLE of CONTENTS CHAPTER 1INTRODUCTION..................................................................................................1 Biological Effects of Flavonoids and Xanthohumol.....................5 Bioavailability of Flavonoids..............................................11 Metabolism of Flavonoids..................................................13 CHAPTER 2IN VITRO BIOTRANSFORMATION OF XANTHOHUMOL, (A FLAVONOID FROM HOPS,HUMULUS LUPULUS),BY RAT LIVER MICROSOMES...................................................................................................15 Abstract.............................................................................................16 Introduction.......................................................................................17 Materials And Methods.....................................................................18 Results...............................................................................................23 Discussion.........................................................................................38 Acknowledgements...........................................................................42 References.........................................................................................43 CHAPTER 3IN VITRO GLUCURONIDATION OF XANTHOHUMOL, (A FLAVONOID FROM HOPS, HUMULUS LUPULUS), BY RAT AND HUMAN LIVER MICROSOMES .....................................................................45 Abstract.............................................................................................46 Introduction.......................................................................................46 Materials And Methods.....................................................................48 Results and Discussion.....................................................................51 Acknowledgements...........................................................................60 References.........................................................................................61 TABLE of CONTENTS, CONTINUED Page CHAPTER 4 METABOLISM OF XANTHOHUMOL, APRENYLATED FLAVONOID IN HOPS AND BEER, BYCDNA-EXPRESSED HUMAN CYTOCHROME P450S AND HUMAN LIVERMICROSOMES ................. 63 Abstract .............................................................................................64 Introduction .......................................................................................64 Experimental Procedures ..................................................................66 Results And Discussion ....................................................................67 Acknowledgements .....................................................................78 References .........................................................................................78 CHAPTER 5IN VIVO BIOTRANSFORMATION OFXANTHOHUMOL, A CHALCONE FLAVONOID FROM HOPS, INRATS ................................... 80 Abstract .............................................................................................81 Introduction .......................................................................................82 MaterialAnd Methods ......................................................................83 Results ...............................................................................................86 Discussion .........................................................................................96 Acknowledgements ...........................................................................99 References .........................................................................................99 CHAPTER 6 ANTIOXIDANT PROPERTYOF XANTHOHUMOL METABOLITES AND GLUCURONIDES, AGAINSTRADICAL OXIDATION INDUCED HYDROCHLORINE ............. 102 BY 2,2'-AZOBIS-(2-AMIDINOPROPANE) Abstract ...........................................................................................103 Introduction .....................................................................................104 Materials And Methods ....................................................................105 Results and Discussion ..............................................................108 Acknowledgements .........................................................................112 References .......................................................................................113 TABLE of CONTENTS, CONTINUED Page CHAPTER 7APPROACH TO RISK ASSESMENT EVALUATION OF HUMAN HEALTH RISKS OF FLAVONOIDS AND XANTHOHUMOL FROM FOOD ..................................................................................................................116 Abstract ........................................................................................... 117 Introduction ..................................................................................... 117 Risk Assessment Approach ................................................... 118 Toxicity Assessment of Flavonoids and Xanthohumol ................ 119 Exposure Assessment

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