Ellagic Acid: A Potent Anticarcinogen
Cancer is a leading cause of death in the United States, second only to heart disease. One-third of the 556,500 cancer deaths expected to occur in 2003 will be related to lifestyle factors, such as nutrition, obesity, and physical activity.[1] Epidemiologic data from humans and experimental data from animal model studies indicate that a strong relationship between diet and cancer incidence exists. Today's consumers are more aware of that link than ever and are seeking to minimize risk and treat disease states through diet.
Many of the health benefits associated with the consumption of plant-based foods are attributed to the presence of phytochemicals. Phytochemicals are biologically active components that impart health benefits beyond basic nutrition when consumed in typical or optimal servings. To date, literally hundreds of phytochemicals have been identified and are being evaluated as potential anticarcinogens. Ellagic acid is one such compound. It has been under investigation for the last three decades and is only beginning to receive the well-deserved attention of the scientific community. In their book, Complementary and Alternative Cancer Methods Handbook, as well as on their website (www.cancer.org), the American Cancer Society acknowledges that ellagic acid induces apoptosis in cancerous cells. They also note that ellagic acid "prevents the binding of carcinogens to DNA, and strengthens connective tissue, which may keep cancer cells from spreading".
Sources and Structure
Ellagic acid has been shown to be an effective antimutagen, anticarcinogen, and, in some cases, cancer inhibitor. Ellagic acid is the dilactone of hexahydroxydiphenic acid, derived from the hydrolysis of ellagatannins. It is plentiful in the food supply regularly consumed by humans. It is present in plants, fruits, and nuts in its free form, as a series of ellagitannins, or as a glucoside. The highest content of ellagic acid has been identified in raspberries, strawberries, cranberries, blackberries and nuts[2] (Table 1). Daily consumption of as little as 150g of red raspberries, or about 1 cup, has been shown to slow the growth of abnormal colon cells in humans and prevent human papilloma virus (HPV)-infected cells from developing.
Ellagic acid is an extremely stable polyphenol (Figure 1). Its polycyclic aromatic structure allows for charge-transfer complexes. Rossi et al.[3] used x-ray diffraction techniques to study the crystal and molecular structure of ellagic acid dehydrate. Ellagic acid is a complex planar compound that forms a strong hydrogen-bonding network with surrounding water molecules. The crystalline molecules stack in planes, such that the center of one of the six-member rings in one molecule lies above and below an atom in other molecules. The four hydroxyl and two lactone functional groups act as hydrogen bond acceptors and donors, enabling ellagic acid to participate in a number of reactions.
Mechanisms of Anticarginogen Action
The antitumour activity of ellagic acid has proven an effective inhibitor of chemically induced cancer in the pulmonary and hepatic systems, as well as in the epidermis of mice.[[2,4-5] Several mechanisms by which phytochemicals, such as ellagic acid, can alter carcinogenesis have been identified. Potential mechanisms include the inhibition of Phase I enzymes; modification of carcinogen detoxification through Phase II pathways; antioxidation activities, including scavenging DNA reactive agents; suppressing abnormal proliferation of early preneoplastic lesions; and inhibiting certain properties of the cancer cell.[6]
Ellagic acid decreases the rate of carcinogen metabolism by Phase I enzymes by directly inhibiting the catalytic activity and frequency of gene expression.[4] The inhibitory effect of ellagic acid on the arylamine N-acetyltransferase (NAT) activity exemplifies this action. Arylamines are extremely potent carcinogens, inducing tumours in humans. Cystolic arylamine NAT catalyzes the acetylation of arylamine, thereby activating the procarcinogen. Growth studies of H. pylori demonstrated inhibition by ellagic acid in a dose-dependant relationship.[7] Ellagic acid appears to act as a noncompetitive inhibitor, as evidenced by decreases in kinetic constants of cytosol and intact bacteria examinations.
NAD(P)H:quinone reductase (QR) is a phase II detoxification enzyme. It functions to prevent the formation of superoxide radicals and detoxify a variety of foreign compounds. Barch and Rundhaugen[8] found that ellagic acid induced QR expression through activation of the antioxidant responsive element of the QR gene. Dietary ellagic acid significantly increased pulmonary and hepatic QR activity by 9- and 2-fold, respectively. An 8-fold increase in hepatic QR mRNA was associated with an increase in hepatic QR activity. In this way, ellagic acid effectively increases detoxification of carcinogens and reduces mutagenesis and tumourigenesis. Further studies of the structure-function relationship indicate an interaction between the lactones of ellagic acid and antioxidant responsive elements of the 5´ regulatory region induces NAD(P):
QR activation.[[9]
The inhibitory effect of ellagic acid on aflatoxin-induced mutagenicity is most likely related to its antioxidant property. Aflatoxin B1 (AFB1) is a potent carcinogen and fungal metabolite produced by Aspergillus parasiticus and A. flavus. Cytochrome P450 metabolizes AFB1 to it 2,3-epoxide, which readily forms adducts with DNA. Ellagic acid inhibits the activation of AFB1, thereby reducing its mutagenicity.[10] Loarca-Pina et al.[11] observed similar antimutagenic effects of ellagic acid against AFB1 using a Salmonella microsuspension assay. The results of this study indicated that in addition to antioxidant effect of ellagic acid, two additional mechanisms may also come into play. Ellagic acid may act directly to form an extracellular complex with AFB1, and/or interact with DNA to reduce the number of binding sites available for the activation of AFB[1].
Perchellet, et al.[5] demonstrated the inhibitory effects of ellagic acid on biochemical markers of skin tumour promotion. Epidermal tumourigenesis progresses in 3 defined stages; initiation, propagation and promotion. Tumour initiation results in alterations in programme of grown and differentiation, as well as resistance to cytotoxic agents. Stage 2 propagation is marked by accelerated 12-O-tetradecanoyl-phorbol-13-acetate(TPA)-induced ornithine decarboxylase activity, increased hydrogen peroxide production and altered DNA synthesis. Topically applied ellagic acid significantly inhibited carcinogenesis, as determined by reduced activity of Stage 2 biochemical markers. Although the mechanism of inhibition is unclear, it was concluded that ellagic acid inhibits the biochemistry and biology of tumour promotion beyond its antioxidant effects.
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