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: 5.01). 10/2003; 66(6):907-15. DOI: 10.1016/S0006-2952(03)00413-1
Source: PubMed


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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    • "Although remarkable binding of EA to intestinal epithelium has been previously described in rats (Whitley, Stoner, Darby, & Walle, 2003), in a previous clinical trial we did not detect high amounts of EA in the colonic mucosa of colorectal cancer patients who consumed the same pomegranate extracts (Núñez-Sánchez et al., 2014). In the present pharmacokinetic study, the delayed EA absorption did not depend on specific volunteers and was indistinctly observed after the intake of either PE-1 or PE-2, which indicated that other factors could be involved, such as the diet, bowel transit time, interaction with the microbiota, etc. "
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    • "Pomegranate ellagitannin are also being investigated for their potential use as food bio-preservatives and for the formulation of products in the nutraceutical industry [2]. Pomegranate peel attracts attention due to its apparent wound healing properties [4], immune modulatory activity [5], antibacterial activity [6] and antiatherosclerotic and antioxidative capacities [8]. Antioxidative activity has often been associated with a decreased risk of various diseases [12]. "
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    ABSTRACT: Pomegranate (Punicagranatum L. ) fruit is widely being consumed and its fruit’s peel having hydrolysable ellagitannin (ETs: polyphenolic compound) is an underutilized industrial waste from commercial point of view. In this present study an economical and efficient technique has been explored for the production of purified ellagitannin powder from pomegranate peel. Ellagitannin was isolated from fresh and fermented peel, purified with Amberlite XAD- 16 resin packed column and converted into ellagitannin powder by vacuum drying. About 38 gpurified ellagitannin powder was obtained from 1 kg fresh pomegranate peel. Total ellagitannin content(TEC) was 89. 78-91. 78 % as GAE possessing antioxidant activity (AOA) of 91. 16-96. 21 % as DPPH. Cost estimation of purified ellagitannin powder preparation process was Rs. 5510 from 1 kg fresh pomegranate peel. Worth of purified ellagitannin powder (38 g) estimated Rs. 25441 in international market. Studied method can be adopted for commercial production of purified ellagitannin powder.
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    • "EA as a chemopreventive agent inhibits carcinogen bioactivation, carcinogen-to-DNA binding, and cancer cell growth33. For example, the formation of O6-methylguanine (O6-meGua) adducts and their persistence are closely linked to esophageal tumor induction in rats. "
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    ABSTRACT: Cancer is a leading cause of death worldwide. Cancer treatments by chemotherapeutic agents, surgery, and radiation have not been highly effective in reducing the incidence of cancers and increasing the survival rate of cancer patients. In recent years, plant-derived compounds have attracted considerable attention as alternative cancer remedies for enhancing cancer prevention and treatment because of their low toxicities, low costs, and low side effects. Ellagic acid (EA) is a natural phenolic constituent. Recent in vitro and in vivo experiments have revealed that EA elicits anticarcinogenic effects by inhibiting tumor cell proliferation, inducing apoptosis, breaking DNA binding to carcinogens, blocking virus infection, and disturbing inflammation, angiogenesis, and drug-resistance processes required for tumor growth and metastasis. This review enumerates the anticarcinogenic actions and mechanisms of EA. It also discusses future directions on the applications of EA.
    Cancer Biology and Medicine 06/2014; 11(2):92-100. DOI:10.7497/j.issn.2095-3941.2014.02.004
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