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Intestinal epithelial cell accumulation of the cancer preventive polyphenol ellagic acid - Extensive binding to protein and DNA

Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, PO Box 250505, Charleston, SC 29425, USA.
Biochemical Pharmacology (Impact Factor: 4.65). 10/2003; 66(6):907-15. DOI: 10.1016/S0006-2952(03)00413-1
Source: PubMed

ABSTRACT Ellagic acid (EA), a polyphenol present in many berries, has been demonstrated to be preventive of esophageal cancer in animals both at the initiation and promotion stages. To be able to extrapolate these findings to humans we have studied the transcellular absorption and epithelial cell accumulation of [14C]EA in the human intestinal Caco-2 cells. The apical (mucosal) to basolateral (serosal) transcellular transport of 10 microM [14C]EA was minimal with a P(app) of only 0.13 x 10(-6)cm/s, which is less than for the paracellular transport marker mannitol. In spite of observations of basolateral to apical efflux, Caco-2 cell uptake studies showed high accumulation of EA in the cells (1054+/-136 pmol/mg protein), indicating facile absorptive transport across the apical membrane. Surprisingly, as much as 93% of the cellular EA was irreversibly bound to macromolecules (982+/-151 pmol/mg protein). To confirm the irreversible nature of the binding to protein, Caco-2 cells treated with 10 microM [14C]EA were subjected to SDS-PAGE analysis. This resulted in radiolabeled protein bands trapped in the stacking gel, consistent with [14C]EA-crosslinked proteins. Treatment of Caco-2 cells with 10 microM [14C]EA also revealed irreversible binding of EA to cellular DNA as much as five times higher than for protein (5020+/-773 pmol/mg DNA). Whereas the irreversible binding to protein required oxidation of EA by reactive oxygen species, this did not seem to be the case with the DNA binding. The avid irreversible binding to cellular DNA and protein may be the reason for its highly limited transcellular absorption. Thus, EA appears to accumulate selectively in the epithelial cells of the aerodigestive tract, where its cancer preventive actions may be displayed.

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    • "Cancer-preventive activities in the digestive tract have also been identified for the tea flavonoid epicatechin gallate and the non-flavonoid polyphenol ellagic acid. In this regard, it is interesting to note that both compounds have a negligible transcellular absorption in epithelial Caco-2 cells but their cellular uptake is very high (Vaidyanathan and Walle 2003; Whitley et al. 2003). This further reinforces the notion that flavonoids may exert most of their bioactivity in epithelial gastrointestinal cells (Walle 2004). "
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    • "The pharmacokinetic profile of this absorption has poor characteristics, and only a part of this absorption takes place in the stomach (Lei et al., 2003). The metabolism of EA proceeds by conversion of EA to dimethyl-EA-glucuronide, which is the most abundant metabolite detected up to date via a two-step reaction (Whitley et al., 2003). "
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    • "may require its prior oxidation by reactive oxygen species that could be abolished by glutathione (Whitley et al., 2003). In the in vivo study on pigs mentioned above (Espín et al., 2007), ET metabolites were shown to be absorbed in the intestinal tissues. "
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