Site-specific accumulation of the cancer preventive dietary polyphenol ellagic acid in epithelial cells of the aerodigestive tract

Abstract

Ellagic acid (EA), a polyphenol present in berries, has been demonstrated to prevent oesophageal and colon cancer in animals. To better understand the site-specificity of these effects, we studied the accumulation and transport of [14C]EA in rat aerodigestive epithelial cells in-vivo and in cultured human cells. When [14C]EA was administered to rats by gavage, a high content of EA was found in the oesophagus and small intestine at 0.5 h after oral administration and in the colon at 12 h, with very low amounts in plasma and peripheral tissues. Studies in human intestinal Caco-2 and human oesophageal HET-1A cells found very limited transcellular transport (Caco-2) of EA but high accumulation (Caco-2 and HET-1A) in the cells. In more detailed studies in the Caco-2 cells, accumulation of EA displayed ATP- and Na+-dependency. Multiple interventions permitted the exclusion of a number of transporters as mediators of this uptake. A dramatically reduced transport of EA at low pH (5.5) compared with high pH (7.4) suggested an important role for the negative charge of EA. This was supported by the organic anion transport inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and bromosulfophthalein. The latter produced as much as 78% inhibition at the 100 microM concentration. Finally, Caco-2 cells were shown to express organic anion transporter 4 (OAT4) mRNA, as was the human large intestine. EA appears to be accumulated along the aerodigestive tract using OAT-like transporters, one of which might be OAT4.

Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts

“…However, although EA solubility greatly increased at pH over 7.5, this did not match in the human study where higher EA absorption at longer post-ingestion times was only observed in a few cases, especially after the intake of PE-1. This supported the idea that EA intestinal absorption was hampered and/or saturated, which was in agreement with preclinical studies where EA showed a limited transcellular transport (Whitley, Sweet, & Walle, 2006). In addition, this saturation phenomenon is also sustained by in vitro studies that have also reported the efficient EA transport by intestinal organic anion transporters (OATs) with a very high affinity for hOAT1 (Whitley, Sweet, & Walle, 2005), which resulted inhibited at EA concentrations (5-25 µM) that can be reached in the human colonic mucosa (Núñez-Sánchez et al, 2014).…”

“…This low solubility is partly due to its high degree of crystallinity, which is directly related to its planar and symmetrical structure and the hydrogen-bonding network formed in the crystal (Li, Harich, Wegiel, Taylor, & Edgara, 2013). Indeed, previous animal studies identified the low solubility of EA in aqueous media as a major drawback in EA absorption (Daniel, Ratnayake, Kinstle, & Stoner, 1991) as well as its ability to bind the intestinal epithelium (Whitley, Sweet, & Walle, 2006). In the present study, we confirmed the very low recovery of free EA under in vitro gastric conditions, i.e.…”

Polyphenols, oral health and disease: A review

“…85 In addiction, several cancer preventive PPs selectively accumulate in the epithelial cells of the upper digestive tract of rats, with an ATP-and Na + -dependent organic anion transport mechanism. 86 Epidemiological study results are consistent with experimental studies. Specifically, a recent South African retrospective study reported that diets poor in fruit and vegetables, with consequent low PP content, are responsible for 7% and 10% of oesophageal cancers among females and males, respectively.…”

Gene expression, cell cycle arrest and MAPK signalling regulation in Caco‐2 cells exposed to ellagic acid and its metabolites, urolithins

“…1) [12 -14]. EA and urolithins can accumulate in the intestine and prostate [15,16]. ETs, EA and urolithin-A exhibit cancer chemopreventive activities in various cell and animal models [16 -19] but the antiproliferative activity of EA metabolites in colon cells has not been studied, and the molecular mechanisms involved have not been thoroughly investigated.…”