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SYNTHESIS AND CHARACTERIZATION OF RESVERATROL AND ITS CONJUGATED METABOLITES AND CONTRIBUTION OF METABOLISM TO ITS DECREASED BIOVAILABILITY
Okpor, Otito Iwuchukwu
Okpor, Otito Iwuchukwu
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Thesis/Dissertation
Date
2011
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Pharmaceutical Sciences
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http://dx.doi.org/10.34944/dspace/2028
Abstract
The purported chemopreventive and chemotherapeutic properties of the dietary phytochemical resveratrol continue to undergo active investigations. Systemic pharmacokinetics of this compound revealed that it was rapidly and extensively metabolized into its sulfate and glucuronide conjugates. This extensive metabolism leads to high plasma levels of resveratrol sulfates and glucuronides and very low levels of the parent compound (low bioavailability). These observations raised many questions, some of which this body of work examined and has helped to explain. Chapter 1 presents a detailed introduction to resveratrol and its role in colorectal cancer chemoprevention. It also lays the foundation for the hypotheses generated and the studies presented in succeeding chapters. In chapter 2, we explored the possibility that resveratrol metabolites possess intrinsic activity and thus contribute to the observed effects of the parent. The mono-sulfated and glucuronidated conjugates of trans-resveratrol were synthesized and tested for antiproliferative activity in a panel of mammalian cell lines. Their activity was then compared with the parent compound. Resveratrol was shown to be antiproliferative in all cell lines studied while no discernible antiproliferative activity was observed for the metabolites. Chapter 3 details the results of the glucuronidation kinetics of cis and trans-resveratrol isomers across a wide concentration range chosen to mimic blood levels following high dose consumption. Human tissue microsomes and recombinant supersomes over-expressing the enzymes (UGTs) of interest were used for these studies. Our results show the presence of atypical kinetics for the formation of resveratrol glucuronides across most of the protein sources used. Prior to this study, the full glucuronidation kinetics of total resveratrol had not been conducted. In chapter 4, we examined the association between genetic polymorphisms in the major enzymes (UGT1A1 and UGT1A6) and rates of glucuronidation of trans and cis-resveratrol. We set out to correlate functional genetic variations in these UGTs with their catalytic rates and a positive association was made for cis-resveratrol and UGT1A6 where the UGT1A6 variants mediated higher glucuronidation rates compared to the reference genotype. Chapter 5 explored the inherent ability of resveratrol to induce its own glucuronidation upon chronic dosing. Enzyme induction has been proposed as a mechanism that may contribute to the low bioavailability of resveratrol. Since dietary polyphenols like resveratrol are not consumed in isolation, we also studied the effects of combining resveratrol with two dietary polyphenols (curcumin and chrysin) on two chemoprevention endpoints - i) antiproliferation and ii) UGT enzyme induction. Our results indicate that resveratrol is capable of inducing UGT1A1 expression and activity in a non-concentration dependent manner and this induction as well as its antiproliferative effects are enhanced by both curcumin and chrysin. In summary, en route to probing the activity of resveratrol metabolites, we optimized two synthetic routes and generated measurable quantities of these compounds for future use. While the in vitro kinetics of resveratrol did not allow for any in vivo predictions, we were able to show alterations in resveratrol metabolism with respect to genotypic differences and enzyme induction that may contribute to the observed low bioavailability profile.
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