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

Abstract

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 0 -azino-bis(3-ethylbenzothiazoline sulphonate) assay. Key results: Major metabolites were 3 0 -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 0 -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.

Structure and antioxidant activity of brominated flavonols and flavanones

“…Identification of circulating metabolites has been undertaken for only a few flavonoids and those studies have shown that the circulating form of most flavonoids is as conjugates, mainly as glucuronides. [42] Quercetin is the best characterized, and the major circulating compounds found in rat plasma [29,43] and human plasma [44,45] were identified as quercetin 3-O-glucuronide, 3 -O-methylquercetin 3-glucuronide and quercetin 3 -O-sulfate. The conjugation reactions described above will not have to hinder the bromination of metabolites on the A-ring at C6 and C8 positions.…”

Protective effects of flavonoids and two metabolites against oxidative stress in neuronal PC12 cells

“…In addition, flavonoids undergo transformation in the colon to simple phenolic acids which may also be responsible for the antioxidant activities and neuroprotective effects observed in vivo. Interestingly, the different patterns of metabolites obtained from quercetin after a single high dose administration were shown to significantly increase the antioxidant potential of plasma in treated rats compared with those obtained under a prolonged lowdosage regimen (Santos et al 2008).…”

Antihypertensive properties of flavonoid-rich apple peel extract

“…Flavonoids are commonly found in fruits and their diverse biological functions well reported. Dietary flavonoids are subjected to metabolic conversions when ingested and their bioactivity can be influence by the metabolic conversions (Santos et al, 2008).…”