Dietary flavonoid/polyphenolic reactive metabolites and their biological properties.
Published: 2004
Language: eng
Description: Flavonoids and other polyphenolics form a major part of the dietary antioxidant capacity of most plant-derived foods and beverages including fruits, vegetables, tea and wine. Besides antioxidant properties, these dietary components have also been identified as having a number of other pharmacological activities including antimutagenic and antiproliferative actions. While their antioxidant activity has been widely researched, their prooxidant activity has not been as well studied. The central hypothesis of this thesis is that some dietary antioxidants also behave as cytotoxic prooxidants which generate ROS. This property, as well as that of causing mitochondrial dysfunction, are identified as novel means by which these compounds may induce cell death. This thesis will provide evidence which, for the first time, indicates that dietary antioxidant flavonoids and other polyphenolics do show prooxidant activity in the absence of transition metals. This was shown using both a cell-free in vitro peroxidase model as well as a cellular model, utilizing isolated rat hepatocytes. The prooxidant activity of these dietary compounds seemed to correlate in part with their redox potential. Upon oxidation by peroxidase/H2O2, high redox potential phenol ring containing flavonoids, simple phenolic acids and more complex polyphenolics, were metabolized to prooxidant phenoxyl radicals which, in some cases were sufficiently reactive to cooxidize GSH to a thiyl radical, accompanied by extensive oxygen uptake and ROS formation. In contrast, low redox potential catechol and gallic acid-containing dietary compounds depleted GSH by forming GSH conjugates. Cytotoxicity catalyzed by these compounds correlated with their lipophilicity, planarity, redox potential and ability to collapse the mitochondria) membrane potential. In addition, this cytotoxicity was significantly increased in UDP-glucuronyltransferase-inhibited cells compared to control cells, suggesting a role for glucuronidation in detoxifying these dietary compounds. Liver toxicity was also associated with these dietary components  in vivo as administration of these compounds to CD-1 mice significantly increased plasma alanine aminotransferase levels. The flavonoids/polyphenolics which were best at causing cell death in non-tumor cells were also best at inhibiting tumor cell proliferation. A novel anticancer mechanism for these dietary compounds is proposed which involves their prooxidant activity and mitochondria) toxicity.
Notes: Adviser:  Peter J. O'Brien.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2359.