Influence of the metabolic profile on the in vivo antioxidant activity of quercetin under a low dosage oral regimen in rats.

BACKGROUND AND
PURPOSE: Flavonoids are known to possess a broad set of pharmacological effects, some of which have been attributed to their antioxidant properties and, more recently, to cell signalling modulation. Nevertheless, flavonoids are extensively metabolized and their metabolites are the potential bioactive forms in vivo. Therefore, a first and crucial step to understand the mechanisms underlying potential health benefits of flavonoids is knowledge of their metabolites and their biological activities. EXPERIMENTAL APPROACH: To approximate a human dietary pattern of intake of flavonoids, regular rat chow was supplemented with 0.02% quercetin and fed to Sprague-Dawley rats over 3 weeks. Plasma samples were analysed by HPLC and electrospray tandem mass spectrometry, and plasma antioxidant capacity was measured by the 2,2'-azino-bis(3-ethylbenzothiazoline sulphonate) assay. KEY
RESULTS: Major metabolites were 3'-methylquercetin (isorhamnetin) glucuronide sulphate conjugates, the most plausible conjugation positions being at the 3-, 5- and 7-hydroxyl positions. Isorhamnetin conjugates are methylated at the 3'-OH position, which decreases the high antioxidant activity of quercetin and its metabolites and their contribution to plasma antioxidant potential. CONCLUSIONS AND IMPLICATIONS: This metabolic pattern differs from that observed after a single high-dose administration, where the major metabolites were quercetin conjugates at 5- and 7-hydroxyl positions and a significantly increased plasma antioxidant activity was observed. These data show altogether that the different metabolic patterns obtained under a prolonged low-dosage regimen or after a single high dose, crucially affected the antioxidant potential of plasma in treated animals. Our data also allow for the establishment of structure-antioxidant activity relationships for quercetin metabolites.