hyperoside and spiraeoside

Quercetin is a plant-derived flavonoid and its cytotoxic properties have been widely reported. However, in nature, quercetin predominantly occurs as various glycosides. Thus far the cytotoxic activity of these glycosides has not been investigated to the same extent as quercetin, especially in animal models. In this study, the cytotoxic properties of quercetin (1), hyperoside (quercetin 3-O-galactoside, 2), isoquercitrin (quercetin 3-O-glucoside, 3), quercitrin (quercetin 3-O-rhamnoside, 4), and spiraeoside (quercetin 4'-O-glucoside, 5) were directly compared in vitro using assays of cancer cell viability. To further characterize the influence of glycosylation in vivo, a novel zebrafish-based assay was developed that allows the rapid and experimentally convenient visualization of glycoside cleavage in the digestive tract. This assay was correlated with a novel human tumor xenograft assay in the same animal model. The results showed that 3 is as effective as 1 at inhibiting cancer cell proliferation in vivo. Moreover, it was observed that 3 can be effectively deglycosylated in the digestive tract. Collectively, these results indicate that 3 is a very promising drug candidate for cancer therapy, because glycosylation confers advantageous pharmacological changes compared with the aglycone, 1. Importantly, the development of a novel and convenient fluorescence-based assay for monitoring deglycosylation in living vertebrates provides a valuable platform for determining the metabolic fate of naturally occurring glycosides.

Topics: Animals; Flavonoids; Glucosides; Glycosides; Glycosylation; HCT116 Cells; Humans; Molecular Structure; Quercetin; Structure-Activity Relationship; Vertebrates; Zebrafish

Quercetin is an important dietary flavonoid with putative beneficial effects in the prevention of cancer and CVD. The in vivo bioactivity of quercetin depends on its bioavailability, which varies widely between foods. We used an in situ rat intestinal perfusion model to study whether differential small intestinal hydrolysis of the sugar moiety of five naturally occurring quercetin glycosides determines the small intestinal uptake and subsequent biliary excretion of quercetin. After 30 min perfusion, a decrease of intact quercetin glycoside in perfusate was observed for quercetin-3-O-ss-glucoside (20.9 (sem 1.4) micromol/l) and quercetin-4'-O-ss-glucoside (23.5 (sem 1.6) micromol/l), but not of quercetin-3-O-ss-galactoside, quercetin-3-O-ss-rhamnoside and quercetin-3-O-alpha-arabinopyranoside. Appearance of free quercetin in perfusate and conjugated quercetin metabolites (quercetin, isorhamnetin, and tamarixetin) in portal and peripheral plasma and bile were also significantly greater after treatment with quercetin-3-O-ss-glucoside or quercetin-4'-O-ss-glucoside compared with any of the other glycosides. Thus, the type of sugar moiety is a major determinant of the small intestinal absorption of quercetin glycosides, but the position (3 or 4') of the glucose moiety does not further influence absorption. The poor bioavailability of important dietary quercetin glycosides has implications for their in vivo bioactivities.

Topics: Animals; Bile; Biological Availability; Diet; Glycosides; Intestinal Absorption; Intestine, Small; Male; Perfusion; Portal Vein; Quercetin; Rats; Rats, Wistar

Recent experimental data point to an interaction of dietary flavonol monoglucosides with the intestinal Na-dependent glucose transporter 1 (SGLT1). To investigate this interaction in more detail, we performed experiments with SGLT1-containing brush-border-membrane vesicles (BBMV) from pig jejunum. The flavonol quercetin-3-O-glucoside (Q3G) concentration-dependently inhibited Na-dependent uptake of radioactively labelled d-glucose into BBMV. Uptake of l-leucine was not inhibited by Q3G, indicating a specific interaction of the glucoside with SGLT1. Whereas the maximal transport rate of concentration-dependent initial glucose uptake was not altered in the presence of Q3G, the constant for half-maximal glucose uptake was increased, suggesting a competitive type of inhibition of glucose uptake by Q3G. Trans-stimulation experiments suggested the transport of Q3G via SGLT1. In addition, Q3G decreased the Na-independent diffusive uptake of glucose into BBMV. Other flavonoids were also tested for their inhibitory effect on d-glucose uptake. Among the tested quercetin glycosides, only the 4'-O-glucoside (Q4G) also inhibited Na-dependent glucose uptake into BBMV, whereas the 3-O-galactoside, the 3-O-glucorhamnoside and the aglycone quercetin itself were ineffective. Glucosides of some other flavonoid classes such as naringenin-7-O-glucoside, genistein-7-O-glucoside and cyanidin-3,5-O-diglucoside were ineffective as well. Thus, dietary quercetin monoglucosides, for example, Q3G and Q4G, have an impact on intestinal nutrient transporters such as SGLT1 and related systems.

Topics: Animals; Biological Transport; Diet; Glucose; Glucosides; Intestinal Mucosa; Jejunum; Leucine; Membrane Glycoproteins; Microvilli; Monosaccharide Transport Proteins; Quercetin; Sodium-Glucose Transporter 1; Swine