Dissertation
Pharmacokinetic and pharmacodynamic investigations of selected chiral flavonoids
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2009
DOI:
https://doi.org/10.7273/000005883
Abstract
High-performance liquid chromatographic (HPLC) methods were validated for the determination of homoeriodictyol, isosakuranetin, and taxifolin enantiomers in biological matrices. The quantification and racemization of these flavonoids in lemon, Yerba Santa, grapefruit, tu-fu-ling, tomato, and apple was accomplished. The validated HPLC methods were applied in studying the pharmacokinetics of homoeriodictyol, isosakuranetin, and taxifolin in a rodent animal model. Their stereoisomers were detected in serum and urine of rats primarily as glucuro-conjugates. Different pharmacokinetic parameters were observed for each stereoisomeric form for all three xenobiotics including: half-life, total clearance, volume of distribution, and area under the curve. To assess cytotoxicity, a variety of cancer cell lines were treated with racemic and stereoisomeric homoeriodictyol, isoskuranetin, and taxifolin. (+/- )-Isosakuranetin was most effective in cell growth inhibition of all cell lines studied. To assess amelioration of inflammation in an in vitro colitis model, colon adenocarcinoma cells were treated with the three flavonoids. Inflammation was induced and prostaglandin E2 (PGE2) release was measured. The flavonoids exhibited a concentration-dependent reduction in PGE2 levels. The three flavonoids were also assessed for their antioxidant capacity; and cyclooxygenases and histone deacetylase inhibitory activities. To evaluate experimental reduction of adipogenesis, pre-adipocytes were treated with the flavonoids. Differentiation was induced and triglyceride accumulation was assessed. The flavonoids showed concentration-dependent inhibition of triglyceride accumulation. Using an alternative HPLC method of analysis, separation and quantification of various polyphenols in tomatoes and apples was achieved. Concentrations of polyphenols were measured with higher concentrations found in peel. The pharmacological activity of apple extracts was subsequently examined. Peel extracts demonstrated cell growth inhibition; reduction of inflammatory markers in experimental arthritis and colitis models; anti-oxidant activity; and inhibition of triglyceride accumulation in adipocytes. In conclusion, the developed HPLC methods for the chiral flavonoids were sensitive, and stereospecific. Stereospecific assessment of the quantity of these flavonoids in selected fruit was also achieved. Stereoisomers of homoeriodictyol, isosakuranetin, and taxifolin were functionally distinct; enantio-specific pharmacokinetics and pharmacological activities were observed. Furthermore, analysis of polyphenol content was successfully achieved in tomatoes and apples; and the pharmacological activity of selected apple extracts demonstrated potential phytopreventive health benefits that require further experimental scrutinity.
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Details
- Title
- Pharmacokinetic and pharmacodynamic investigations of selected chiral flavonoids
- Creators
- Karina R. Vega-Villa
- Contributors
- Neal M. Davies (Chair)Preston Keith Andrews (Committee Member) - Washington State University, Department of HorticultureCatherine Ann Elstad (Committee Member) - Washington State University, Honors CollegeArash Hatefi (Committee Member)Steven A Martinez (Committee Member) - Washington State University, Department of Veterinary Clinical Sciences
- Awarding Institution
- Washington State University
- Academic Unit
- College of Pharmacy and Pharmaceutical Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 319
- Identifiers
- 99901055039201842
- Language
- English
- Resource Type
- Dissertation