The oral bioavailability of quercetin in humans is low and highly variable (0-50%) and is rapidly cleared (elimination half-life of 1–2 hours after IV injection). Following dietary ingestion, quercetin undergoes rapid and extensive metabolism that makes the biological effects presumed from in vitro studies unlikely to apply in vivo.
In rats, quercetin did not undergo any significant phase I metabolism. In contrast, quercetin did undergo extensive phase II (conjugation) to produce metabolites that are more polar than the parent substance and hence are more rapidly excreted from the body. The meta-hydroxyl group of catechol is methylated by catechol-O-methyltransferase. Four of the five hydroxyl groups of quercetin are glucuronidated by UDP-glucuronosyltransferase. The exception is the 5-hydroxyl group of the flavonoid ring which generally does not undergo glucuronidation. The major metabolites of orally absorbed quercetin are quercetin-3-glucuronide, 3′-methylquercetin-3-glucuronide, and quercetin-3′-sulfate.
In vitro pharmacology
Quercetin has been reported to inhibit the oxidation of other molecules and hence is classified as an antioxidant. Quercetin contains a polyphenolic chemical substructure that stops oxidation by acting as a scavenger of free radicals that are responsible for oxidative chain reactions.
Quercetin also activates or inhibits the activities of a number of proteins. For example, quercetin is a non-specific protein kinase enzyme inhibitor. Quercetin has also been reported to have estrogenic (female sex hormone like) activities by activating estrogen receptors. Quercetin activates both estrogen receptor alpha (ERα) and beta (ERβ)with binding IC50s of 1015 nM and 113 nM respectively. Hence quercetin is somewhat ERβ selective (9 fold) and is roughly two to three orders of magnitude less potent than the endogenous estrogenic hormone 17β-estradiol. In human breast cancer cell lines, quercetin has also been found to act as an agonist of the G protein-coupled estrogen receptor (GPER).