Metabolism of Antioxidant and Chemopreventive Ellagitannins from Strawberries, Raspberries, Walnuts, and Oak-Aged Wine in Humans:  Identification of Biomarkers and Individual Variability

Abstract

Ellagitannins (ETs) are dietary polyphenols, containing ellagic acid (EA) subunits, with antioxidant and cancer chemopreventive activities that might contribute to health benefits in humans. However, little is known about their metabolic fate. We investigate here the metabolism of different dietary ETs and EA derivatives in humans. Forty healthy volunteers were distributed in four groups. Each group consumed, in a single dose, a different ET-containing foodstuff, i.e., strawberries (250 g), red raspberries (225 g), walnuts (35 g), and oak-aged red wine (300 mL). After the intake, five urine fractions (F) were collected at 8 (F1), 16 (F2), 32 (F3), 40 (F4), and 56 (F5) h. Neither ETs nor EA were detected in urine after LC-MS/MS analysis. However, the microbial metabolite 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one (urolithin B) conjugated with glucuronic acid was detected along the fractions F3-F5 in all of the subjects, independently of the consumed foodstuff. The mean percentage of metabolite excretion ranged from 2.8 (strawberries) to 16.6% (walnuts) regarding the ingested ETs. Considerable interindividual differences were noted, identifying "high and low metabolite excreters" in each group, which supported the involvement of the colonic microflora in ET metabolism. These results indicate that urolithin B (a previously described antiangiogenic and hyaluronidase inhibitor compound) is a biomarker of human exposure to dietary ETs and may be useful in intervention studies with ET-containing products. The antioxidant and anticarcinogenic effects of dietary ETs and EA should be considered in the gastrointestinal tract whereas the study of potential systemic activities should be focused on the bioavailable urolithin B derivatives.

Pomegranate juice supplementation in chronic obstructive pulmonary disease: a 5-week randomized, double-blind, placebo-controlled trial

“…A high individual variability was observed in the metabolism of PJ by COPD patients along the trial (results not shown). This was supported by previous reports regarding the metabolism of ellagitannins by humans (Cerdá et al, 2005) and by the no relationship between metabolism of PJ polyphenols and the diet histories provided by the patients (results not shown). At the end of the 5-week intervention period, a mean concentration of the above metabolites, 2.0171.6 and 2.472.3 mg/ml, respectively, was detected in urine.…”

Quantitative Determination of Ellagic Acid and Gallic Acid in Geum Rivale L. and G. Urbanum L.

“…Our results show that G. rivale and G. urbanum are rich sources of EA, but mostly in the bound form. As hydrolyzable tannins easily undergo hydrolysis in the gastrointestinal tract (Clifford and Scalbert, 2000;Cerdá et al, 2005), its actual bioavailability could be quite substantial. EA is an important natural compound whose potent antioxidant properties may be benefi- (Khanduja et al, 1999;Hwang et al, 2010;Kannan and Quine, 2012).…”

“…EA and GA can exist in plant material in free form but the main sources of these compounds are hydrolyzable tannins (ellagitannins and gallotannins), which upon hydrolysis release a sugar and a respective acid moiety (Haslam, 2007;Serrano et al, 2009). Hydrolytic degradation of hydrolyzable tannins can occur in the gastrointestinal tract after ingestion of the medicine (Clifford and Scalbert, 2000;Cerdá et al, 2005). EA and GA, as the major products of hydrolyzable tannin degradation, might therefore have a significant effect on the activity of herbal remedies containing large amounts of hydrolyzable tannins.…”

Pomegranate Ellagitannin-Derived Metabolites Inhibit Prostate Cancer Growth and Localize to the Mouse Prostate Gland

“…Therefore, UA was studied in detail, since prior studies demonstrated that UA conjugates were the most prevalent metabolites of EA in human subjects and that they persist for up to 56 h after ingestion of ETs (9,10,12).…”

“…In fact, urolithins appear in blood, urine, and feces of human volunteers 12-24 h after consumption of a single dose of several ET-rich foods and persist in vivo for up to 48-56 h after ingestion (9)(10)(11)(12). Despite these advances in understanding ET metabolism in rodents (13,14) and humans (9-12), there have been no studies determining the disposition of ET metabolites to tissues of interest including the prostate.…”