Intestinal epithelial cell accumulation of the cancer preventive polyphenol ellagic acid - Extensive binding to protein and DNA
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). "
ABSTRACT: Cellular polarity concerns the spatial asymmetric organization of cellular components and structures. Such organization is important not only for biological behavior at the individual cell level, but also for the 3D organization of tissues and organs in living organisms. Processes like cell migration and motility, asymmetric inheritance, and spatial organization of daughter cells in tissues are all dependent of cell polarity. Many of these processes are compromised during aging and cellular senescence. For example, permeability epithelium barriers are leakier during aging; elderly people have impaired vascular function and increased frequency of cancer, and asymmetrical inheritance is compromised in senescent cells, including stem cells. Here, we review the cellular regulation of polarity, as well as the signaling mechanisms and respective redox regulation of the pathways involved in defining cellular polarity. Emphasis will be put on the role of cytoskeleton and the AMP-activated protein kinase pathway. We also discuss how nutrients can affect polarity-dependent processes, both by direct exposure of the gastrointestinal epithelium to nutrients and by indirect effects elicited by the metabolism of nutrients, such as activation of antioxidant response and phase-II detoxification enzymes through the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In summary, cellular polarity emerges as a key process whose redox deregulation is hypothesized to have a central role in aging and cellular senescence.Genes & Nutrition 01/2014; 9(1):371. DOI:10.1007/s12263-013-0371-5 · 3.42 Impact Factor
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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). "
ABSTRACT: Abstract In recent years, the therapeutic use of non-drug substances such as herbal and medicinal foods is increasing progressively. Of these substances, Punica granatum L., which is an ancient and highly distinctive fruit, has been proposed for treatment of several different illnesses. Ellagic acid (EA) is one of those biological molecules found in pomegranate and may have therapeutic potential in many diseases. EA has been detected not only in pomegranate but also in a wide variety of fruits and nuts such as raspberries, strawberries, walnuts, grapes and black currants, and is becoming an increasingly popular dietary supplement over recent years. Similar to other ellagitannins (ETs), EA is quite stable under physiological conditions in the stomach. EA and ETs as active agents induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-inflammatory and anti-carcinogenic activities in various animal preparations call an attention to the need for designing adequate tests in humans to assess these potentially useful properties in diseased states.International Journal of Food Sciences and Nutrition 05/2013; DOI:10.3109/09637486.2013.798268 · 1.20 Impact Factor
Inflammatory Bowel Disease - Advances in Pathogenesis and Management, 01/2012; , ISBN: 978-953-307-891-5
- "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. "