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Enzymatic Regulation of Vitamin E Status: Identification and Characterization of the Novel Tocopherol-Omega-Hydroxylase Pathway of Vitamin E Catabolism

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Enzymatic Regulation of Vitamin E Status: Identification and Characterization of the Novel Tocopherol-Omega-Hydroxylase Pathway of Vitamin E Catabolism ENZYMATIC REGULATION OF VITAMIN E STATUS: IDENTIFICATION AND CHARACTERIZATION OF THE NOVEL TOCOPHEROL-OMEGA-HYDROXYLASE PATHWAY OF VITAMIN E CATABOLISM A Dissertation Presented to the Faculty of the Graduate School of Cornell University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Timothy Joseph Sontag January 2005 © 2005 Timothy Joseph Sontag ENZYMATIC REGULATION OF VITAMIN E STATUS: IDENTIFICATION AND CHARACTERIZATION OF THE NOVEL TOCOPHEROL-OMEGA-HYDROXYLASE PATHWAY OF VITAMIN E CATABOLISM Timothy Joseph Sontag, Ph.D. Cornell University 2005 Tocopherols and tocotrienols all possess to varying levels the vitamin E activity of α-tocopherol, the most bioactive form of the vitamin in vivo. α- Tocopherol is the most abundant vitamer in vivo, potentially explaining its higher bioactivity. This is despite higher dietary levels of other vitamers. The preferential retention of α-tocopherol appears to be at the level of elimination. Urinary metabolites of tocopherols, with the phytyl tail truncated to a three-carbon carboxylated moiety, were reported previously. The goal of this work was to elucidate the pathway(s) by which these metabolites are formed. Incubations of tocopherols in hepatocyte culture produced all expected intermediates in the predicted pathway of catabolism of vitamin E. This pathway involves ω-hydroxylation of a terminal methyl group of the phytyl tail, followed by step-wise removal of two or three carbon units by a β-oxidation mechanism. Analysis of microsomal enzyme activity led to the elucidation of CYP4F2 as the major P450 involved in the initial ω-hydroxylation reaction. Substrate-specificity of this enzyme was high, with activity toward γ- tocopherol being 10-fold greater than toward α-tocopherol. Sesamin, known to raise plasma γ-tocopherol to levels near those of α-tocopherol in vivo, was a potent inhibitor of this enzyme. Together, these data supported the hypothesis that the ω- oxidation pathway is an important regulator of vitamin E status. Kinetic analyses revealed key features of the tocopherol molecule which govern the affinity and activity of the enzyme toward its substrates. These studies also revealed an allosteric nature of CYP4F2. The finding that α-tocopherol is a positive effector of γ-tocopherol metabolism may explain why supplementation with α- tocopherol decreases plasma concentrations of non-α-tocopherols. Tocotrienols differed from tocopherols in their effects on lateral and rotational mobility of the microsomal membrane components, and inhibited the activity of membrane-bound P450 enzymes, possibly through inhibition of interaction of components of the cytochrome P450 multi-enzyme complex. These effects may play a role in the cytotoxic nature of the tocotrienols and highlight the importance of the tocopherol-ω-oxidation pathway in minimizing their concentration in biomembranes. BIOGRAPHICAL SKETCH Timothy J. Sontag was born in Englewood, New Jersey, and at the age of ten made the decision to accept Jesus Christ as being the Son of God and his Lord. Everything else in his life was affected by that decision. It gave him someone to look to for direction throughout his youth. As he got older, it made him want to use the blessings God had given him for whatever purposes God had for him. From the time he was young Tim loved science and learning how things worked. In 1993, he entered the Massachusetts Institute of Technology where he was a Course 7 (Biology) major. After finishing his Bachelor’s degree in 1997, Tim stayed on as an undergraduate for one extra year to learn a new language, studying Spanish at the Universidad de Granada in Spain. During this year, he became interested in a more applied approach to biological science and entered the graduate program in Nutritional Sciences at Cornell University the following year. After a month-long rotation in the laboratory of Robert Parker, Tim felt that this was the right place to carry out his doctoral research studying lipid metabolism. Obtaining his Ph.D. in 2004, Tim is moving on to a post-doctoral position at the University of Chicago to continue learning about lipids. After that, where the next step will lead, only God knows. iii To God, who brought me this far and who is always there to guide my way and light my path. Psalm 119:105; Matthew 28:18-20 To Mom, Jess, Hanna, and Stine, for your love, hope and faith. 1 Corinthians 13: 13 iv ACKNOWLEDGEMENTS The author wishes to acknowledge all those who made this dissertation possible. Thanks to Dr. Robert Parker and Dr. Joy Swanson for guiding me throughout my project, providing a great atmosphere for learning, and helping me think about problems in a new way. Thanks to the rest of my committee, Dr. Rui Hai Liu from Food Science, Dr. Wayne Schwark from Pharmacology, and Dr. Patricia Cassano from Nutritional Science. Also, to the other professors for their helpful discussions and advice: Dr Charles McCormick, Dr. Noa Noy, Dr. Danny Manor, Dr. Martha Stipanuk, and Dr. Andre Bensadoun. Thanks to Emeritus Professor Dr. William Arion whose advice went beyond science and into the areas of faith and life. Thanks also to all the lab folk who helped out with stuff, especially Cha-Sook You, who has been around from the start and is one of my favorite people at Cornell. Outside the lab environment, thanks to my family at First Assembly, my brothers and sisters in the Chi Alpha and Worship Team gang, and the Wednesday morning pray-ers. And to Leslie, who spent hours (by phone) with me throughout the writing of this dissertation. From way back to my undergraduate days, a big thank you to my advisor Dr Nelson Kiang for his great advice concerning career paths, and to Drs. Art Agnello and Cathleen Cooper for letting me learn a little something about science and lab life. And there’s no forgetting Dr. Joe (Doc) Peone who loved science enough to be contagious. A lot of the funding for this work was provided by the NIH Training Grant DK07158-25 for which I’m grateful. v To my family, those who have been there from the start: Mom, Jess, Hanna and Stine, and those who have joined in along the way: Peter, Rich, Glen, Mikel, and Natan, love and thanks to you all. Finally, to God in heaven, thank You. vi TABLE OF CONTENTS Page Biographical Sketch.....................................................................................................iii Dedication.....................................................................................................................iv Acknowledgements.......................................................................................................v List of Figures ..............................................................................................................ix List of Tables................................................................................................................xi CHAPTER I. Literature Review.................................................................................1 Vitamin E History.......................................................................................................2 Vitamin E Structure....................................................................................................2 Activity as a Vitamin..................................................................................................4 Vitamin E function .....................................................................................................6 Sources of Vitamin E and average intake...................................................................8 Vitamin E Plasma and Tissue Concentrations..........................................................10 Vitamin E Absorption and Distribution ...................................................................12 Sesame Oil and Vitamin E Plasma and Tissue Concentrations ...............................17 Tocopherol Transfer Protein.....................................................................................19 Vitamin E Catabolism and Excretion.......................................................................22 Metabolism as a Potential Mechanism of Regulation of Vitamin E Status .............24 The Cytochrome P450 Family..................................................................................26 P450 Induction..........................................................................................................29 P450 Inhibition .........................................................................................................29 P450 Polymorphisms................................................................................................30 P450s are Organized in a Membrane-Associated Electron Transfer Complex........30 Cooperativity in P450 Kinetic Activity....................................................................31 Identification of a Potential Tocopherol-ω-hydroxylase P450.................................33 Cytochrome P450 4F2..............................................................................................34 Objectives and Specific Aims ..................................................................................37 References ................................................................................................................39 CHAPTER II. Cytochrome P450 ω-Hydroxylase Pathway of Tocopherol Catabolism: Novel Mechanism of Regulation of Vitamin E Status 51 Abstract.....................................................................................................................52
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