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Recent Breakthroughs In Antioxidant Research



SMART: Recently you attended a meeting of the Oxygen Society in Charleston, South Carolina, and I know you brought back with you a lot of new information regarding free radicals and antioxidants. What can you tell us?

DURK: The information on free radicals in biology and in medicine has grown incredibly. In 1968 when Dr. William Pryor wrote an article on free radicals in biology and medicine for Chemical Engineering News he said he found about 12 scientists in the entire world that were interested in that field and doing something in it. Well, there where about 450 such scientists in Charleston, and much to my delight many of them were from pharmaceutical manufacturing firms and research companies.

SANDY: And among the attendees there was definitely some concern that the value of these antioxidant nutrients were not being fully utilized simply because the FDA does not permit health claims for them. The awareness of what the FDA is doing has become more widespread.

DURK: In fact, someone asked a scientist who worked at a pharmaceutical firm and presented a paper at the conference, why the pharmaceutical firms weren't doing anything with natural antioxidants such as vitamin E, beta carotene, vitamin C and so forth. Why, instead, are they making analogs of these compounds? He said, "Well, I hope I don't get fired for this, but it costs about a quarter of a billion dollars to get a new drug approved and if you can't patent it, you're crazy to do it, and it's just that simple."

SANDY: It's been shown that the use of an antioxidant can sometimes improve the efficacy of an approved drug. For example, adriamycin, which is a chemotherapeutic drug, causes a lot of damage to tissues which can be partially prevented by using vitamin E along with the adriamycin. The studies indicate that the vitamin E doesn't reduce the effectiveness of the adriamycin against the cancer but does provide some protection to the normal tissues. It's so obvious, why isn't there a version of the adriamycin in which vitamin E is included?

DURK: Well, in fact, it would be classified as an unapproved new drug, and we'd have to start over from scratch and spend a quarter billion dollars on it. But since this is something that's been reported in the literature you wouldn't even be able to get a patent on it. Moreover, you can't even recommend in the labeling or package insert on the product or even in seminars concerning the product that it be used in conjunction with vitamin E because that would be recommending an unapproved new drug.

SANDY: So in the meantime people may suffer from cardiac toxicity with adriamycin who other wise might not have.

DURK: One of the most interesting things is that the proper use of antioxidants along with chemotherapeutic agents may allow much higher doses which have a greater chance of killing the cancer without killing the patient. However, there's something that's more interesting than better ways of killing cancer cells coming out of this free radical meeting, and that is some of the mechanisms by which a cell is transformed into a cancerous cell. For a long time it's been known that free radicals are a major cause of cancer.

SANDY: But there really hasn't been a lot of knowledge about how this works.

DURK: Several years ago Dr. Denham Harmam, who created the free radical theory of aging, said that the real action is in the mitochondria, those little free radical factories. Those are the power plants that do oxidative metabolism on your food and make the universal energy molecule ATP, and they do it by single electron transfer reactions.

SANDY: Just because you have antioxidant protection in the blood stream doesn't necessarily mean that you have it in the mitochondria. The mitochondria are surrounded by their own special membranes within the cell. They have their own particular antioxidant protecting substances. They have a different superoxide dismutase (SOD) than the superoxide dismutase that protects the DNA that's in the nucleus.

DURK: The SOD in the mitochondria is based on manganese rather than copper and zinc, which is what you have in the cytoplasmic SOD. Now what would be the ideal cure for cancer? It wouldn't be poisoning the cancer cells without poisoning the rest of the body. It wouldn't even be getting your immune system to attack the cancer cells and destroy them. The ideal cure for cancer is simply to turn the cancer cells back into normal cells and everybody livers happily forever after.

Well, that sort of thing has been a dream that very few people even dare think about, but at this conference this dream was being made a reality for the nastiest cancer around, malignant melanoma. If you have malignant melanoma and it becomes more than about 2 millimeters thick, your chances of living 5 years are almost zilch.

Scientists at the conference reported that a cell transforms into a melanoma cell when the levels of manganese SOD in the mitochondria drop below around 60% of normal, and then a lot of free radical damage starts occurring the mitochondria and the cell starts dividing uncontrollably and turns into a melanoma. You could just say, "Well, gee, the protective manganese Superoxide Dismutase drops. You've got this sort of non-specific free radical damage inside of the mitochondria and that caused the cell to turn into a melanoma." OK, we know that happens, but what does that say for therapy?

Well, these people decided to do a very, very elegant experiment. What they did was say, "Well, maybe this is the fundamental reason that melanoma happened at all, and that means if we got the levels of the manganese SOD back up, maybe the cell would stop being a melanoma cell." And what they did is gene therapy on melanoma cells. They stuffed them full of genes that would persuade these cells to crank out manganese based mitochondrial SOD. They genetically engineered the melanoma cells. The production of manganese SOD in the mitochondria went up just as you would expect, and lo and behold, they turned back into normal cells. They didn't die or anything like that. They simply untrans-formed and turned back into normal tissue, which when implanted in nude mice no longer caused tumors.

SANDY: The incredible thing was that the depressed level of manganese SOD in the mitochondria is not just something that happens in melanoma cells. There were a few studies on the manganese SOD, and there was agreement that this seems to be something that happens in many different kinds of tumor cells. The ones that have been examined show this reduced level of manganese SOD in the mitochondria.

Another one that was examined by some scientists at this conference was fibrosarcoma which is another difficult to treat type of cancer. They found that by causing manganese SOD to be over-produced by the mitochondria, they suppressed metastasis of transplanted fibrosarcoma tumors. So we're seeing something that is getting down to a very fine level of under-standing, and which even could conceivably be the basis for a treatment and cure of cancer.

DURK: Just think of the ultimate cure for cancer. Someone has a melanoma, you give them a shot of something that cranks up their manganese SOD production, and the tumor turns back into normal tissue!

SANDY: Now, just taking manganese alone is probably not going to be much help because the manganese has to be in the form that can be gotten into the mitochondria and used there. That's something that a number of people are now studying, and it's possible that there may be something that we could just take as a supple-ment that would increase manganese SOD in our mitochondria and thereby provide some protection against cancer.

DURK: The manganese SOD in the mitochondria plays a role in another disease which is really lethal nowadays, and that's AIDS. What's been found recently is that there's a gene in the HIV genome that's called TAT (T-A-T).

SANDY: What was reported at this conference was that HIV TAT protein causes down-regulation of manganese SOD. In other words, it decreases the manganese SOD in the mitochondria, again leading to the increased oxidative stress that can cause the cells to divide, and then you end up with more viruses being replicated when the cells divide.

DURK: Or, even if the cell doesn't divide, just causing a lot of damage. It increases protein synthesis to repair that damage and in the process you replicate the HIV protein.

SANDY: So we're seeing a mechanism that's a common one between HIV infected cells and cancerous cells.

DURK: What we're going to be doing is increasing the amount of manganese in our PERSONAL RADICAL SHIELD. I want to make it clear that just increasing the amount of manganese doesn't mean that you're automatically going to have more manganese SOD in your mitochondria. What it does mean is that you won't have a limitation on the amount of manganese SOD that you can produce, which is set by the amount of manganese you are able to absorb from your diet.

SANDY: Exactly. The amount of manganese is going to be within the safe and accepted range, but it'll be at the top of the range rather than toward the bottom.

DURK: According to the National Research Council the safe and effective range of manganese is about 2 to 5 mg. per day. The average person gets around 2.5 mg. per day in their diet, primarily from things like cereal grain. The problem is that most of the manganese in the diet has a very poor bioavailability. So what we're going to do is supply the manganese as a chelate that will have better bioavailability.

Now, we're changing from the gluconate, which is what we had before, and is a very good chelate and which is available in high purity form. We're gong to change over to an aspartic acid chelate, manganese aspartate. The reason for that is we don't know of the existence of any active uptake system in the gut for gluconate, but there is an active uptake system for aspartate. Moreover, aspartate performs a role in the mitochondria, being part of the citric acid cycle, the Krebs cycle, by which you get most of your oxidative energy. And as a result, there should be a well-established transport systems in the cells and mitochondria for dealing with the aspartate.

SANDY: We're also going to increase the amount of vitamin B2 in our formulations because there's been increasing evidence and a very good paper presented at this conference that vitamin B2 provides protection against oxidative damage and so as a result it makes sense for us to increase the amount of B2 in our supplements.

DURK: The amount of vitamin B2 that we have in the supplements now was based on the knowledge that we had back when we formulated them. But it turns out that a lot of vitamin B2 in the body exist in the form of dihydrovitamin B2, a quite potent antioxidant. There have been a number of experiments done on systems involving free radical induced inflammation, and this explains something that a nutritionist told me a long, long time ago.

He saw me after I'd visited a friend of mine who owned cats. My eyes were red and itching, the veins were all swelling up. My eyes looked awful and they felt awful, and he said, "You're suffering from a B2 deficiency." And I said, "Well, gee, I'm taking about 15 mg. a day. That's well above the RDA." He said, "No, no. You need a lot more than that." And I said, "Well, why does it work?" and he replied "I don't know why it works. It just works." I tried it, and by God, you know, it took care of the cat allergy problem.

SANDY: The nutritionist was just basing his recommendation on observation. He didn't know anything about mechanisms, but now people do know a lot about the mechanisms that are involved.

DURK: Even though I found out that if I wanted to be around cats I'd better take a lot of extra vitamin B2, I was not willing to suggest that a larger number of people take it in the form of the PERSONAL RADICAL SHIELD because I didn't know what the mechanisms were. And I just don't like doing things without understanding mechanisms.

SMART: Can you tell us something about the toxicity levels of B2?

DURK: If you take hundreds of milligrams a day, it may be a photosensitizer, but we're not talking about putting that much in there. It will still be well below the minimum toxic dose of anything that's been reported in the scientific literature.

SMART: You also have reformulated ROOT FOOD.

DURK: We've put additional vitamin B2 in our ROOT FOOD for a rather different reason, not only the matter of helping to control free radicals, but also because vitamin B2 in sufficient quantities can inhibit the testosterone 5-alpha reductase that converts testosterone into dihydrotestosterone which turns off hair follicles in areas of male pattern baldness.

SANDY: Remember that hair follicles go through cycles. They have resting cycles. They grow a while and then they rest for a while. Well, under a variety of conditions, and aging is one of them, as people get older their hair tends to spend more time in the resting state. If you can find nutrients that will help keep the hairs in the growing stage, you're better off. 5-alpha reductase is an enzyme that converts the testosterone to dihydrotestosterone and that make the hairs stop growing. They go into the resting stage.

DURK: Also the dihydrotestosterone is what causes enlargement of the prostrate, especially in older males. Now we don't want to imply that vitamin B2 has ever been tested as either something to help slow the progress of male pattern baldness, or to help slow the progress of benign prostatic hypertrophy. As far as we know, it hasn't. On the other hand, it seems like a reasonable insurance considering the very small down-side risk for the amounts that we're using.

SMART: The ratio of vitamin C to cysteine in the new formula of ROOT FOOD is about 2:1, and I in your book LIFE EXTENSION A Practical Scientific Approach, you recommend a ratio of 3:1.

DURK: Well, we have learned a few things in the past 10 years. We would rather be really safe than even slightly sorry. The reason that you have to have a bunch of C when you're taking cysteine is because cysteine is very soluble in water. You can dissolve over 600 grams of cysteine into a liter of urine. On the other hand, cystine, the oxidation product where two cysteine molecules are joined together, has a solubility of about 150 mg. per liter under physiological conditions. What that means is that if the cysteine you take in oxidized, you could form cystine stones in your kidneys or bladder, causing a lot of damage. Therefore you've got to keep the cysteine that you take reduced to prevent it from oxidizing into cystine.

Three times the amount of vitamin C is certainly plenty to do that but two times is also plenty. Very few people have trouble with cystine stones even though in a typical diet the ratio of vitamin C to cysteine could be 1:10 rather than 2 or 3 to 1. So when we have a ratio of 2:1 we're a lot farther in the direction of reducing the cysteine than any natural diet ever would be. I would just recommend that anybody who has had cystine stones or has a family history of them check things out with a doctor before they go try it, but for normal people the ratio is a lot better than you get in a regular diet.

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