Polyphenols are naturally-occurring phytochemicals, which form an integral part of the human diet. Results from epidemiological studies have associated polyphenol intake with reduced risk of cardiovascular diseases. Previous human intervention studies suggested that dietary polyphenols exert their cardioprotective effects through their antioxidant and anti-inflammatory effects. While most in vitro experiments have not accounted for the bioavailability and metabolism of these polyphenols, our work has provided direct evidence, using quercetin, that metabolic transformation, together with bioavailability, exert profound effects on bioactivity. We examined the effect of quercetin and its major metabolites on the production of pro-inflammatory eicosanoids by human leukocytes. Studies comparing free radical scavenging, antioxidant activity and eicosanoid production demonstrate that there are different structural requirements for antioxidant and anti-inflammatory activity. We also investigated the effect of metabolic transformation on flavonoid bioactivity by comparing the activity of quercetin and its major metabolites to inhibit inflammatory eicosanoid production from human leukocytes. Quercetin was a potent inhibitor of leukotriene B4 formation in leukocytes (IC50 ~ 2μM), and its activity was dependent on specific structural features, particularly the 2,3 double bond of the C ring. Functionalisation of the 3'-OH group with either methyl or sulfate reduced inhibitory activity up to 50% while a glucuronide substituent at the 3-OH effectively removed the leukotriene B4 inhibitory activity. The major quercetin metabolite quercetin-3'-O-sulfate retained considerable lipoxygenase inhibitory activity (IC50 ~ 7 μM) while quercetin-3-O-glucuronide maintained antioxidant activity but had no lipoxygenase inhibitory activity at physiologically relevant concentrations. We conclude that structural modification of quercetin due to metabolic transformation had a profound effect on bioactivity, and that the structural features required for antioxidant activity of 8 quercetin and related flavonoids were unrelated to those required for inhibition of inflammatory eicosanoids.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2008|