Flavonoids are a broad class of phenolic phytochemicals that exhibit chemopreventive properties in humans. Extensive evidence suggests that flavonoids display antitumor activities, in terms of protection against DNA damage by neutralization of free radicals and inhibition of tumor development via modulation of hepatic enzymes involved in activation/deactivation of carcinogens. It is generally accepted that flavonoids are hydrolyzed to aglycones upon consumption, then biotransformed to other species. The resulting aglycones and metabolites may be absorbed to different extents and exert different physiological activities, thus making the mapping of pharmacokinetics and bioavailability a complex problem. Moreover, analytical methods to identify flavonoid metabolites have lacked the specificity to detect low levels in plasma, urine, tissues, and cells, as well as suffering from lack of chemical standards necessary to validate methods and allow accurate quantitation. This proposal is aimed directly at addressing these problems via: (i) enzymatic synthesis of flavonoid biotransformation products. We will use commercially available enzymes to produce glucuronides and sulfates from parent flavonoid aglycones. (ii) metal complexation strategies/tandem mass spectrometry: We will develop innovative metal complexation methods, for which we have had outstanding success in recent years, with tandem mass spectrometry for structural characterization of the resulting flavonoid metabolites and for isomer differentiation. The most important outcomes of the proposed work are twofold: 1) the first comprehensive analysis of flavonoid metabolites, and 2) the development of sensitive analytical tools for identification of flavonoid metabolites. This work will provide archival mass spectra of numerous flavonoid metabolites plus validated mass spectrometric methodology, and ultimately afford tremendous inroads for subsequent bioavailability, uptake, distribution, and pharmacokinetic studies of flavonoids.
Flavonoids are a broad class of phenolic phytochemicals found naturally in fruits and vegetables that exhibit chemopreventive anticancer properties in humans, including the inihibition of tumor promotion and protection against DNA damage. This research will identify the specific bioactive metabolites that are responsible for the chemopreventive actions of flavonoids and serve as the foundation for future pharmacokinetic and bioavailability studies.
|Niemeyer, Emily D; Brodbelt, Jennifer S (2013) Regiospecificity of human UDP-glucuronosyltransferase isoforms in chalcone and flavanone glucuronidation determined by metal complexation and tandem mass spectrometry. J Nat Prod 76:1121-32|
|Robotham, Scott A; Brodbelt, Jennifer S (2013) Identification of flavone glucuronide isomers by metal complexation and tandem mass spectrometry: regioselectivity of uridine 5'-diphosphate-glucuronosyltransferase isozymes in the biotransformation of flavones. J Agric Food Chem 61:1457-63|
|Robotham, Scott A; Brodbelt, Jennifer S (2011) Regioselectivity of human UDP-glucuronosyltransferase isozymes in flavonoid biotransformation by metal complexation and tandem mass spectrometry. Biochem Pharmacol 82:1764-70|