Ellagic Acid Miracle Under Our Nose, Part 2

Carcinogens of this kind are called polyaromatic hydrocarbons (PAHs), and they are planar (flat). Ellagic acid is also planar, so it can form a complex with these planar epoxides. In this kind of complex with benzopyrene, two of the OH groups are positioned where they can easily react with the epoxide, rendering it harmless. Studies show that ellagic acid inhibits carcinogenesis induced by benzopyrene in many different tissues (5). Similar studies show that it is equally effective against dimethylbenzanthracene, another PAH found in cigarette smoke (6), and against aflatoxin, a potent carcinogen produced by mold which grows on peanuts (7).

In addition to binding to carcinogens, ellagic acid inhibits the P450s, so that they produce less of the active carcinogen. Carbon tetrachloride is not active until a P450 removes one of the chlorine atoms from it; then it becomes a highly reactive free radical, which can damage many components of cells, including the DNA. Ellagic acid protects against acute toxicity of carbon tetrachloride (8) and inhibits liver fibrosis induced by carbon tetrachloride in small doses over time (9). It also greatly reduces tumors in lung tissue exposed to diethylnitrosamine, a powerful carcinogen also found in cigarette smoke. It is much better than the flavonoid quercetin (10), which demonstrates that it is not simply binding to the activated nitrosamine, as would quercetin, but acting in some other way as well. Nitro compounds can cause similar problems because the P450s turn them into free radicals. Once again, ellagic acid protects against DNA damage induced by 2-nitropropane better than vitamin C, vitamin E, or epigallocatechin gallate (11), a modified flavonoid which has 8 OH groups! Although ellagic acid doesn’t inactivate the free radical as well as epigallo-catechin gallate, it inhibits the P450s better, which is one way it prevents DNA damage better than other antioxidants.

In addition to inhibition of the P450s, ellagic acid also stimulates activity of the “phase II” enzymes, which attach other molecules to the active carcinogens to render them harmless. GST is a very important phase II enzyme, and studies have found that ellagic acid activates the gene for GST in the antioxidant responsive pathway (12).

That ellagic acid can have effects at the level of the DNA is not unexpected. It is not only planar, but also rotationally symmetric, which means that it can intercalate very well into the double helix. The binding is very tight at pH 5.5, and though it is much looser at pH 7, intercalation may still play a role in stopping the binding of PAH epoxides and other active carcinogens to the DNA (13).

Ellagic acid inhibits other enzymes in addition to the P450s. Rapidly dividing cells need one or both of the enzymes DNA gyrase and DNA topoisomerase to “unwind” the DNA so that it can open up to allow the strands to be transcribed or replicated. If these enzymes are not working, the DNA gets “supercoiled” like an overwound spring and can’t open up. Ellagic acid inhibits DNA gyrase (14) and DNA topoisomerases (15) in cancer cells in as little as 0.65 micrograms per milliliter of medium; that’s the equivalent of a 150-pound person taking 42 milligrams of ellagic acid — a very small dose indeed. When the cells can’t make any more DNA, they go into a state called “G1 arrest.” Other studies show that ellagic acid does put cancer cells into G1 arrest, either by keeping the DNA supercoiled or by signaling the anti-cancer “apoptosis” genes, which cause spontaneous death of the cells (16). This is the same mechanism by which b-lapachone, taxol, and other natural products kill cancer cells.

Some researchers have tested compounds similar to ellagic acid, with varied results. Other phenolic acids, such as caffeic and ferulic acids, are not nearly as effective. Studies of ellagic acid show that the lactone groups are needed for binding to DNA and for the stimulation of GST, but not for binding to epoxides or inhibition of the P450s.

On the other hand, both the 3- and the 4- OH groups are needed for binding the epoxides, but only the 4- OH group is needed to inhibit the P450s (17).

Clinical trials of ellagic acid are now underway in Europe and, under Dr. Daniel Nixon, at the Medical University of South Carolina. Results are quite encouraging. But you don’t have to wait for the FDA to approve it; you may be able to get it in formulations, or you can make some raspberry puree. A gram of prevention is worth a pound of cure, so start today!

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