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Influence of COMT Genotype Polymorphism on Plasma and Urine

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Influence of COMT Genotype Polymorphism on Plasma and Urine View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Minnesota Digital Conservancy Influence of COMT Genotype Polymorphism on Plasma and Urine Green Tea Catechin Levels in Postmenopausal Women A THESIS SUBMITTED TO THE FACULTY OF THE UNIVERSITY OF MINNESOTA BY Alyssa Heather Perry IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE Dr. Mindy Kurzer September 2014 © Alyssa Heather Perry 2014 Abstract Catechins are the major polyphenolic compound in green tea that have been investigated extensively over the past few decades in relation to the treatment of various chronic diseases including diabetes, cardiovascular disease, and cancer. O-methylation is a major Phase II metabolic pathway of green tea catechins (GTCs) via the enzyme catechol-O- methyltransferase (COMT). A single nucleotide polymorphism in the gene coding for COMT leads to individuals with a high-, intermediate-, or low-activity COMT enzyme. An epidemiological case-control study suggests that green tea consumption is associated with reduced risk of breast cancer in women with an intermediate- or low-activity COMT genotype. A cross-sectional analysis discovered that men homozygous for the low- activity COMT genotype showed a reduction in total tea polyphenols in spot urine samples compared to the intermediate- and high-activity genotypes. Several human intervention trials have assessed green tea intake, metabolism, and COMT genotype with conflicting results. The aim of the present study was to determine if the COMT polymorphism would modify the excretion and plasma levels of GTCs in 180 postmenopausal women at high risk for breast cancer consuming a green tea extract supplement containing 1222 mg total catechins daily for 12 months. All participants in the study were a sub-set from the larger parent study “Green Tea and Reduction of Breast Cancer Risk.” Thirty subjects with the high-activity COMT genotype, thirty with intermediate-activity COMT genotype, and thirty with low-activity COMT genotype from each of the placebo and treatment groups were analyzed. No statistically significant differences were found in any urinary or plasma catechin metabolite measurements between the homozygous high-activity and homozygous low-activity COMT genotype in i the treatment group. Additionally, no differences were found when high-, intermediate-, and low-activity COMT genotypes were all compared in the treatment group. This suggests that the COMT genotype does not play a major role in GTC metabolism. Dosing of GTC and timing of biological samples are important factors that may need further research in future trials evaluating the effect of COMT genotype and GTC metabolism. ii Table of Contents List of Tables .......................................................................................................................v List of Figures .................................................................................................................... vi Literature Review.................................................................................................................1 Introduction ..............................................................................................................2 Major Tea Components............................................................................................3 Green Tea Catechins (GTC) ....................................................................................5 Tea & Health Benefits .............................................................................................8 Biotransformation of Catechins .............................................................................16 Methylation of GTC ...............................................................................................18 Catechin Metabolism & COMT Genotype ............................................................22 COMT, Green Tea, & Breast Cancer .....................................................................24 Glucuronidation & Sulfation of GTC ....................................................................25 Microbial Metabolism of GTC ..............................................................................27 Biological Activities of Catechin Metabolites .......................................................28 Pharmacokinetics of GTC ......................................................................................29 Factors Affecting Bioavailability of GTC .............................................................35 Concluding Words: A Need for Research .............................................................39 Manuscript .........................................................................................................................40 Introduction ............................................................................................................41 Materials & Methods .............................................................................................43 Results ....................................................................................................................51 Discussion ..............................................................................................................52 Bibliography ......................................................................................................................72 iii Appendix ............ 84 Telephone Screening Questionnaire ......................................................................85 Telephone Screening Questionnaire Eligibility Information .................................90 Consent Form .........................................................................................................91 Participants Handbook .........................................................................................102 iv List of Tables Literature Review Table 1: Polyphenol Content by Tea Type ..........................................................................6 Manuscript Table 1: Composition of Green Tea Extract Capsules .......................................................59 Table 2: Comparison of Baseline Catechins between Treatment and Placebo Groups .....60 Table 3: Urinary and Plasma Catechins by Treatment Group and Time Point .................61 Table 4: Urinary Catechins in Participants Consuming Green Tea Catechins, by Demographic and Lifestyle Factors ...................................................................................63 Table 5: Plasma Catechins in Participants Consuming Green Tea Catechins, by Demographic and Lifestyle Factors ...................................................................................66 Table 6: Effects of COMT Genotype on Urinary and Plasma Catechins in Participants Consuming Green tea Catechins at month 12 ....................................................................69 Table 7: Spearman Correlation Coefficients Between Urinary and Plasma Catechin Metabolites in Participants who Consumed Green Tea Catechins ....................................71 v List of Figures Literature Review Figure 1: Schematic of the tea extraction processes ............................................................4 Figure 2: Major green tea catechins .....................................................................................7 Figure 3: Major metabolic pathways of green tea catechins ..............................................17 Figure 4: The folate and methionine cycles with COMT enzyme .....................................19 Figure 5: Average EGCG concentration (ng/ml) vs. time after oral administration of EGCG .................................................................................................................................32 Figure 6: Average EGCG concentration (ng/ml) vs. time after oral administration of Polyphenon E .....................................................................................................................32 Figure 7: Suggested outcomes of GTC metabolism in humans .........................................38 Manuscript Figure 1: Study design .......................................................................................................58 vi Literature Review 1 Introduction Tea is one of the most commonly consumed beverages in the world with over two-thirds of the world’s population drinking it. It is enjoyed for its good taste, attractive aroma, and health-promoting effects. Tea is a water infusion made from the dried leaves of Camellia sinensis originating in southern China. The plant is now produced in several countries including China, India, Indonesia, Japan, Taiwan, Sri Lanka, and in countries of central Africa 1. Over 300 different kinds of teas are presently manufactured from the dried plant leaf, but there are only three general categories of tea. They include the unfermented green tea, the partially fermented oolong or pouchong tea, and the fermented black tea 2. Black tea is 78% of the total world tea produced and consumed mostly in the US and Europe. Only 2% of world production consists of oolong tea, while green tea makes up 20% of production and is prevalent in Japan and China 3. Green tea has been studied extensively for its health benefits. Many of the beneficial properties surrounding green tea are associated with a compound called catechins in the tea leaves. Green tea and its catechins have been investigated for its reduction of body weight, protection against diabetes, and prevention
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