Reversing Arteriosclerosis with Tocotrienols: An interview with Marvin Bierenbaum, M.D. and Tom Watkins, Ph.D.

by

Richard A. Passwater, Ph.D.

A nutritional cure for heart disease? Well, here’s exciting evidence that arteriosclerosis (the thickening, loss of elasticity and calcification of arterial walls; a common form of which is atherosclerosis) can be reversed with a mixture of tocotrienols and tocopherol). Tocotrienols and tocopherols are vitamin E vitamers, that is, they are both sub-families of the vitamin E family. Tocopherols are the more familiar forms of vitamin E, but tocotrienols may have additional functions and health benefits. In a three-year, double-blind clinical study, tocotrienols, which are derived from rice and palm oils, have been shown to regress arteriosclerosis. In the group that received tocotrienols, 92 percent of the patients stabilized or improved, whereas in the control group, 48 percent of the patients deteriorated and none improved.

Before this study showing regression (improvement of artery health and blood flow) of arteriosclerosis in humans, there were hints that antioxidants could have some effect in animals. In 1992, Dr. Anthony Verlangieri of the Atherosclerosis Laboratory at the University of Mississippi discussed his research in reversing atherosclerosis in monkeys with antioxidant nutrients with us. [1,2] Studies with humans showed that antioxidants could slow the progression of arteriosclerosis. In June 1995, the researchers from the Atherosclerosis Research Unit of the University of Southern California reported in the Journal of the American Medical Association that antioxidant vitamins slowed the progression of coronary artery atherosclerosis [3] In January 1997, Drs. Mathias Rath and Aleksandra Niedzwiecki reported in the Journal of Applied Nutrition that a program of dietary supplements slowed the progression of calcium deposits in coronary arteries. [4] Now, a three-year clinical study shows arteriosclerosis has been reversed with a tocotrienol and tocopherol mixture. [5]

Marvin Bierenbaum, M.D. is the Director of the Kenneth L. Jordan Heart Foundation and Research Center in Montclair, N.J. He is a cardiologist and has published over 150 research articles and editorials. Tom Watkins, Ph.D. is a research scientist at the Kenneth L. Jordan Heart Foundation and Research Center. He is the laboratory director and has published over 150 research articles, chapters and books.

 

Passwater: Dr. Bierenbaum, which came first, your practice in cardiology or your research?

Bierenbaum: My trade is in practicing cardiology. I started my practice after having finished my training in cardiovascular disease and internal medicine in 1957. After about six months, I decided that if I didn’t do something a little more stimulating, they would be putting me in one of those special suits that they have for raving lunatics.

 

Passwater: How did you get from deciding you didn’t want to solely be a practicing cardiologist to doing research at the Jordan Heart Foundation?

Bierenbaum: For awhile I did both. I got into research when I talked some of my colleagues into a diet study to look at patients under the age of 50 who had had heart attacks and who were being treated with a 30-percent fat diet which was restricted to 300 milligrams per day in cholesterol. The fat balance required limiting saturated fats to ten percent of total calories and supplementing with polyunsaturated fatty acids to achieve 20 percent. That’s how we got into research, and I liked it so much that I have been out of clinical practice now since 1986 and I have been here ever since. I did both, practice cardiology and conduct clinical research for twenty-nine and a half years. One day I became very dissatisfied with the direction that clinical medicine was heading and decided to stick with research alone.

 

Passwater: What was your conclusion in your first dietary study?

Bierenbaum: We published our first report on the study in 1962 with a follow-up in 1967. [6] The final report which was in Lancet in 1973, showed very clearly that after ten years of being on that diet resulted in a statistically significant improved survival rate. [7] The longer one was on the diet, the better the result.

 

Passwater: I have read many of your research reports on nutrition and health. They cover many nutritional aspects; different fats; calcium, and vitamin E, among others. You started out looking at the role of diet. What took you from the macro approach of looking at total fats, etc., to some of the micro nutrients?

Bierenbaum: When we started our research, cholesterol research was still in its infancy. The whole approach to dietary management was an entirely new concept to medicine. We started off by looking at projects that could be funded and that was types of diet without any ultra refinements. We also learned very quickly that to keep patients on any kind of a markedly altered diet for a protracted period of time is virtually impossible. Even after having had a myocardial infarction, in about six months to a year’s time, patients diets slip. Even when reporting their diets to us, we find what they report poorly resembles what they eat. When we compared the reported diet histories to our analysis of triglyceride fatty acids and red blood cell fatty acids, they were completely divergent and dichotomous. [8]

After a couple of years we stopped doing diet histories and just stayed with the triglyceride fatty acid and red blood cell fatty acid analysis which gave us at least the lipid profile that they were eating. We also did some subcutaneous tissue aspiration and after about 18 months without any diet change, you could really pick that up too. So that is how we got involved with some of the more basic biochemistry that was involved. Since we learned the hard way how difficult it was for the average American at that time to stay on a diet, we looked for other ways of reducing heart disease.

We got involved with calcium because a friend of mine, Dr. Hal Yacowitz from Farleigh Dickinson University came up to me one day and said, "You complain about people not following the diet, but if you give them supplements of calcium, you can lower their cholesterol and triglycerides in four days." I said, "Baloney, that’s impossible because it takes us a month to six weeks to get cholesterol reductions with diet." He said, "Why don’t you try it, Big Mouth?" So, I did. As a matter of fact, I took four grams of calcium carbonate a day for four days and my cholesterol level went down ten percent. My triglycerides went down twelve percent. Of course, I couldn’t move my bowels because the calcium and fats in the colon had formed such hard soaps. We were just preventing the absorption of dietary cholesterol and triglycerides. So that was one of the options and we published fairly extensively on calcium supplements. [9 - 15]

 

Passwater: Did you look at calcium and blood pressure?

Bierenbaum: We did. We published the results in 1988 [15 ] The Canadian Dairy Association supported a fairly large study. Calcium in patients who do not have elevated serum renin levels will have a significant effect at reducing blood pressure levels, particularly in those which are slightly or markedly elevated. People with normal blood pressure will have a minor reduction in pressure but not very outstanding. That work really confirmed what was coming out of Oregon and other places around the country. A gram of calcium helps lower cholesterol, triglycerides, also lowering blood pressure, all in one pill. Very exciting stuff for just one nutrient.

 

Passwater: Well, fortunately you’re devoting even more time to research. You’ve come up with some very interesting results in your tocotrienol - arteriosclerosis study. What did you see that made you want to look at tocotrienols or even vitamin E and arteriosclerosis?

Bierenbaum: Well, in the meantime, I had teamed up with Dr. Tom Watkins in 1987. We were intensively studying how to improve blood platelet aggregation.

 

Passwater: Blood platelets are small cells that are critical to the blood-clotting process. If the platelets become damaged through oxidation their aggregation increases and the blood is said to become "stickier." The "slipperiness" or "stickiness" of blood is measured as the blood platelet adhesion index.

Dr. Watkins, weren’t you previously doing research with Dr. Lester Packer at the University of California at Berkeley?

Watkins: Yes, Drs. Mary Williams, Alec Keith, Lester Packer and I worked on some biomembrane problems there.

 

Passwater: What led to your interest in platelet aggregation?

Watkins: In one of the studies we had used Canola Oil. We had noticed that the ingestion of canola oil on a daily basis resulted in wasting antioxidant resources. We had also seen that patients who had hyper-aggregable platelets, in general had lower levels of antioxidants in the serum, so we decided to examine that further. We did some studies looking at the effect in animals and then we did some studies using some human subjects, as well. We looked at fish oils and the effects that they have; those, in other words that are very rich in polyunsaturates, fish oil being one example. These oils would depress the serum levels of the antioxidants when fed, and when that happened, we noticed that there was a corresponding increase in thrombogenic risk associated with platelet hyper- aggregation. We were concerned about that and wanted a fish oil study, in fact, to show very clearly that that was what we had done. Then we turned toward terrestrial sources of omega-3 fatty acids, like flaxseed, and that’s when we started some of the bread studies.

Bierenbaum: We had started looking at antioxidants, I guess, in the late 1970's and early 1980's.

The main reason we had done that was because we were involved in studies using an apparatus called a filtragrometer which gave a sort of ex vivo technique of measuring platelet aggregation. We were looking for agents that might be able to improve aggregability, particularly in patients with hyper-aggregation and patients with coronary disease. It was during that period, I guess that we were one of the first groups to look and see that smoking exerted a pro-aggregatory effect in at least some of the coronary patients by increasing platelet aggregation. In addition to that, we were able to show that aspirin was able to interfere with platelet aggregation, even though we weren’t sure at that time about the cyclooxygenase pathway that was being interfered with.

 

Passwater: Does smoking interfere with platelet aggregation before the cyclooxygenase involvement?

Bierenbaum: Yes, before the cyclooxygenase. We noted that and that there was a pronounced smoking effect.

 

Passwater: Then you weren’t surprised by the recent study by Dr. Ron Watson of the University of Arizona showing that the powerful antioxidants in Pycnogenol(R) help reduce the platelet aggregation caused by smoking since you found this effect in the first place.

Bierenbaum: That’s correct.

 

Passwater: Please tell us more about your studies with antioxidants and diabetics in the late 1970's.

Bierenbaum: We had done some work subsequent to Dr. Watkins arrival in the area of omega-3 fatty acids of flaxseed. We have done a lot with flaxseed. Also, it became obvious to me that patients with diabetes developed arteriosclerosis differently than patients who did not have diabetes. In the early days of the filtragrometer, we had not only what we call the aggregation time we also had dis-aggregation time. Normally when you switch back to citrate from heparin that we were using to stabilize the platelet aggregation, you would have dis-aggregation that would result in a decrease in the pressure. We measured that phenomenon. The patients who have diabetes, once they aggregated their platelets, they would not dis-aggregate, no matter how much pressure you pulled on the apparatus filters. This was an outstanding finding, so we published it, but nobody paid very much attention to it. It became fairly obvious to me that this was one of the areas that we knew we would have to get into further studies with. We published, that subsequently, in the Nutrition Reports International in the 70's and 80's.

In the 80's, we gave diabetic patients supplements of vitamin E to see its effect on aggregation. We showed that, in fact, you can improve aggregation rather substantially when you use supplements of vitamin E. That study showed something that was very interesting. Nobody paid much attention to it either but if you use large doses of vitamin E in the range of 2,000 IU a day, or even as low as 800 IU a day, the diabetics have a normalization of their blood sugar. We think that may be mediated through better insulin utilization.

 

Passwater: Today, a lot of research is being conducted with the antioxidant lipoic acid and diabetes.

Bierenbaum: Lester Packer is our alpha-lipoic acid expert.

 

Passwater: You were talking about canola oil feeding and excessive consumption of the antioxidants? Were you looking directly at individual antioxidants or were you indirectly looking at the products of reactive oxygen species, such as TBARS.

Watkins: In the canola oil study, we were looking at alpha-tocopherol and beta-carotene. We also looked at retinol and ascorbic acid. There wasn’t much effect with retinol or ascorbic acid but there was a very large, significant effect with alpha-tocopherol and beta-carotene.

 

Passwater: So you were relating this to the polyunsaturated fatty acids in the canola oil?

Watkins: Yes, that’s what we related it to and that’s particularly important because there has been a lot of promotion of canola oil said to contain omega-3 fat, for example, and it has often been advertised as being "lowest in saturates," either one which is true. It is, of course, low in saturates. Also, the fact is that with most all vegetable oils many of the antioxidants are removed in processing, going out with the "bottoms." We feel that the public ought to know about that.

 

Passwater: You were looking at oils and their effects on antioxidants. What attracted your attention to tocotrienols? Few researchers seem to be paying attention to them? Tocotrienols are usually just considered secondary forms of vitamin E, but they are unique nutrients.

Watkins: Tocotrienols are members of the vitamin E family, but they seem to be nutrients emerging in their own right, in addition to their action as "vitamin E" Here, I am referring to the fact that we classically measure vitamin E in a bioassay that measures how much is needed to prevent resorption of the fetus in the rat. Yes, tocotrienols share that function, although they are weaker in this function than tocopherols. But, maybe the unique structure of the tocotrienols with their shorter "tails" enables them to do other things better than tocopherols with their longer, straight tails can.

 

Passwater: I call the thinking that a given molecule performs only one function "functional fixidity." An analogy is that it’s like a screwdriver. A screwdriver is used to turn a screw, but it also can be used to open a can of paint or to scratch a mark on a board. It has lots of functions. We tend to think of only one. It’s similar with tocotrienols and other nutrients. We tend to think of tocotrienols, "oh yes, they’re rarer forms of vitamin E," but they may be more than that.

We used to look at "vitamin A" alone. Then we looked at "beta-carotene" as a source of vitamin A. Later, we began to look at both beta-carotene as beta-carotene and vitamin A as vitamin A.. This might be a similar situation with tocopherols and tocotrienols.

Bierenbaum: It’s not only that but you have some of those other carotenoids which seem to be very much more important than the beta carotene.

 

Passwater: As research progressed, we learned lycopene is a better singlet oxygen quencher than the other carotenoids, zeaxanthin has greater affinity for the macula, as does lutein.

Bierenbaum: Mixed carotenoids protect against retinal degeneration all the way around.

Maybe our results and the research by Dr. Ames’ group indicates that there are a whole series of actions for the gamma vitamers of vitamin E which are different than those of alpha-vitamers of vitamin E. I am not sure that there is any hard evidence yet, but I think there will be a lot of people looking at that within the next few years.

Our vitamin E studies attracted the attention of PORIM, the Palm Oil Research Institute of Malaysia. They approached us to do some animal studies with a tocotrienol/tocopherol mixture from palm oils. They supported us both through the animal study and with the tocotrienol study that we reported in the Asian Pacific Nutrition Society Journal. [16]

That’s the reason we got involved with a mixture of the vitamin E’s instead of alpha- tocopherol alone, which is what we had been looking at until then. This was a preparation that had both gamma-tocotrienol and other tocotrienols, but it also had tocopherols, mainly alpha-tocopherol in it. After we did the animal studies, which we reported in Lipids [17 ], we decided this might be a very good preparation to study in patients with arteriosclerosis to see if we could produce some regression (improvement) or slow up the progress of the disease.

 

Passwater: Rats don’t usually develop arteriosclerosis. What did you see in the animal study that made you think you would see regression in humans?

Watkins: We had seen a really powerful hypocholesterolemic effect. Also, the tocols (tocotrienols and tocopherols) really cooled down the platelets. It had a very powerful antioxidant effect and so we thought "Wow! We’ve got two or three benefits here, so let’s test it in humans.

 

Passwater: What could make a plaque regress? What’s going on? Are we affecting the cell adhesion molecules (CAMs), the cell surface proteins involved in the binding of leukocytes and oxidized-LDL to endothelial cells or extracellular matrices?

Bierenbaum: We’re not absolutely sure. We are now envisioning there are both a labile pool of LDL which is oxidized and a stable pool of LDL which is oxidized. HDL serves as an antioxidant in itself. We think that what happens is that the HDL which has the antioxidant attached to it neutralizes the oxidized effect on the LDL cholesterol in the labile pool and helps move it out of the plaque before it gets firmly fixed. We really feel that this is a viable mechanism and may be the mechanism, because we saw such dramatic effects so quickly after the patients started on the tocotrienol. We saw a major effect after six months. So we think that this is a very rapid action and we think that it results because of the two pools — the stable pool, which is calcified and obviously not going to be very mobile, and you would have the labile pool. I guess in the early 60's Dr. Jules Hirsch of Rockefeller University also postulated, and later proved, that there is a stable and a labile fat pool, so we think that the LDL particularly in the oxidized form behaves exactly the same way.

Watkins: This was also consistent with studies we had done about twenty years ago when we were using model membranes and we were also looking at mitochondrial membranes and we looked at structures that are similar to this polyunsaturated form of vitamin E and we noticed that we could actually change the performance of the associated enzymes by varying the nature of those chains. When we gave a tocol mixture, it changed the polyunsaturated forms – the tocotrienol forms along with the tocopherols, so that we had that factor in there which had this big effect that Dr. Bierenbaum was just describing on that labile pool. We saw that in animal studies too.

 

Passwater: Why tocotrienols and not just a couple more grams or tons of tocopherol?

Bierenbaum: We thought you would never ask that question.

Watkins: It is basically because of the difference in the length of the so-called "tails" in these two vitamin E family members, and perhaps also due to the differences in electron cloud distribution in the tails. The phytyl chain in the "tail" of the vitamin E molecule is saturated in tocopherols, but not so in tocotrienols. The bond lengths in the saturated tocopherol tails are longer than the double-bonds in the unsaturated tocotrienol tails, and the differences in unsaturated (double bonds) and saturated (single bonds) are reflected in different cloud densities. The double bonds give the tail a little "wag" or zig-zag in their stereochemical shape.

 

Passwater: The double bonds in the tail of the tocotrienols makes their tails shorter, and thus, they have more mobility in cell membranes. [18] Many of our readers will be familiar with this as being the difference between tocopherols and tocotrienols as was discussed in the December 1997 issue with Dr. Maret Traber. There is a nautical analogy that seems to apply nicely. Tocopherols have longer, stickier tails, like anchors on a boat. They also tend to cluster together in fixed positions like boats in anchorage. Tocotrienols have shorter, stubbier, slipperier tails that are more like keels than anchors, so tocotrienols slip around more in cell membranes. As discussed with Dr. Traber in the December issue of Whole Foods, this is very different from the seven un-natural stereoisomers present in synthetic vitamin E. These isomers containing an "S" configuration have pronounced "kinks" in their tails and are removed rapidly from membranes. While the "S" configurations of synthetic vitamin E do temporarily reside in membranes, their kinky tails are twisted out of the plane which is disruptive to the membrane. The "kinks" also prevent the "S" configurations from lying close together. Natural vitamin E (RRR-tocopherols and tocotrienols) can stack close together like a pile of spoons, as well as fit in nicely with the membrane phospholipids.

Watkins: Yes, the unsaturation in the "tail" of the tocotrienol molecule leads to chaos and facilitates the removal process that was just described.

 

Passwater: Chaos is a biophysical concept that may be new to many of our readers. Would you be kind enough to further explain the importance of chaos?

Watkins: Now we’re talking about the physical importance of food, not its chemical composition, but the importance of it in delivering a physical effect. In this case, we are actually talking about chaos that’s needed. If we have too much cholesterol in the diet, to use the example that the public knows, we have membranes that "turn to cement practically." Then the big discovery was made, the observation with the big feeding study that was done right here, as a matter of fact, about the importance of oils in the diet because they can introduce enough local chaos so that the cholesterol can move out of the bloodstream and through those liver membranes and other membranes and out of the circulation into other cells so that they don’t cause circulatory problems. That kind of effect is what we are seeing in a local domain that is introduced by substances like the tocotrienols because their distribution in the membranes is different from the distribution of tocopherol, as we just discussed.

 

Passwater: Your description to me is more of a biophysicist’s approach of introducing chaos. Do you think typically this is analogous to something like membrane fluidity or some other description?

Watkins: Right. Let me use a different analogy, sprinkling salt on the stoop in the winter. A small amount of salt will lead to the eventual melting of a large amount of ice.

 

Passwater: What advantage does increasing the chaos in membranes have?

Watkins: In humans we have carotid stenosis. Stenosis is a narrowing or constriction of the opening in the artery through which the blood flows. Within six month’s time, as we have published, the tocotrienol mixture was able to mobilize lipids in the labile pool, thereby improving the blood flow through the carotid arteries. [19]

 

Passwater: That in itself is extremely significant. If no other arteries were involved than the carotid arteries in the neck that are the main blood supply for the brain, it would significantly reduce stroke. There are about 500,000 strokes annually in the U. S., with about 150,000 stroke deaths. About one-third of these victims show significant carotid stenosis. Prior to your discovery, the only treatment for carotid stenosis was a dangerous surgery procedure, if the condition was detected in time.

This mixture contains more than just tocotrienols, but you emphasize that it is the tocotrienols that have increased mobility in the membranes and ability to go through the cytosol.

Bierenbaum: Yes. There is also a suggestion by Dr. Bruce Ames’ group that gamma-tocopherol or gamma-tocotrienol could be a factor, because they can better react with nitric oxide. The mixture we fed provided generous amounts of gamma-tocotrienol.

Watkins: We haven’t been able yet to get sufficient quantities of pure gamma-tocotrienol to test its full biochemical potential in humans.

 

Passwater: But, your experience leads you to consider the regression of arteriosclerosis to be an effect of the membrane mobility of the tocotrienols, rather than an enhanced antioxidant activity. Tocotrienols have a greater in vivo recycling efficiency under conditions of oxidative stress..

Watkins: If it were just an antioxidant effect, then we ought to be able to address the issue by feeding people more and more alpha-tocopherol or gamma-tocopherol, but that’s not the problem once we develop this kind of lesion in the artery that Dr. Bierenbaum was talking about. In there, we have to do something to dislodge that labile LDL pool and so we have to have something

that will introduce chaos and that’s what this change in shape of the tocotrienols does. That’s the kind of effect that we showed about twenty years ago in Berkeley in some of our other fat studies.

 

Passwater: You have what I consider amazing results — you gave a group of people a tocotrienol mixture and monitored their health over time. Your study is a randomly-assigned, double-blind, placebo-controlled, clinical trial with the subjects in both groups fairly well matched in terms of confounding characteristics.

You periodically publish showing progress which is a regression of carotid artherosclerosis. You monitored atherosclerosis as carotid stenosis. How did you measure this, and what does this actually measure and how reliable is this measurement?

Bierenbaum: Doppler [Bilateral Duplex Ultrasonography] studies were utilized to measure regression and progression. In skilled hands, this is a very reliable technique measuring degree of obstruction to blood flow. An independent neurologist graded the stenosis (and/or lesions) without knowing which patients were from which group.

 

Passwater: Are you measuring the width of the lumen, rather than indirectly measuring the blood flowing through the artery? The reason I bring this point out is that it might be possible to increase blood flow through an artery without affecting the amount of plaque deposited in the lumen. In animal studies as done by Dr. Tony Verlangieri, the artery can be opened and directly examined. I doubt if many of your patients would want their carotid arteries sliced open, especially since the tocotrienols have already decreased the stenosis.

 

Passwater: You are measuring this in the carotid artery because its practical to measure the blood flow through these large arteries in the neck -- do you have any reason to believe that the regression is confined to the carotids?

Bierenbaum: I have no reason to believe that the regression is limited to any artery or arteries. I only have evidence that the tocotrienol mixture regresses plaque in the carotid arteries.

 

Passwater: After six months, what changes did you observe in carotid stenosis?

Bierenbaum: After just six months, 24 percent of the subjects taking the tocotrienol mixture had a regression of their stenosis. However, during this time, 20% of the controls had progression of their stenosis. [19]

 

Passwater: And after two years?

Bierenbaum: After two years, 32 percent of those receiving the tocotrienol mixture had a regression of their stenosis ( 4 % had marked regression), while none receiving the placebo experienced any regression. Comparatively, 44 percent of the controls showed a progression of their stenosis with 16 % having a marked progression, as opposed to mild progression in 8% of those receiving the tocotrienol mixture.

 

Passwater: And three years?

Watkins: Now, 32 percent of the tocotrienol group have regression of their carotid stenosis, with four percent showing marked regression. This compares to 48 percent of the control group receiving the placebo having progression of their stenosis, with 16 percent having marked progression. In the three-year period, only eight percent of the tocotrienol group had progression of their stenosis. [5]

 

Passwater: Did you detect other changes such as blood lipids, platelet adhesion or oxidant levels?

Watkins: Neither blood cholesterol nor triglycerides changed. Blood flow improved as the antioxidant levels rose in the blood. Platelet aggregation increased somewhat. This carotid blood flow improvement, independent of and separate from blood lipids per se, was attributed to the antioxidants and their effect in lowering peroxidation. TBARS, a measure of peroxidation, decreased as serum antioxidants rose with supplementation.

 

Passwater: Well, that certainly says a lot for the tocotrienol mixture, tell us more about it and how much did they take?

Bierenbaum: At the start, the patients were given four capsules a day, but after six months, we increased the dosage to six capsules a day. The dose is given as a total of six capsules for a total of 324 milligrams per day of mixed tocotrienols.

 

Passwater: I would think people would be breaking your doors down saying "Tell us more." What kind of reaction are you getting in the medical and scientific communities?

Bierenbaum: We are reluctant to make any glaring comments or claims because of the limited number of subjects in the study. We have only fifty patients in the study and that number was restricted by the available funding. When you have that small a group, we really think you have to wait about five years to accumulate enough data to make a big statement. I have been to a number of meetings so far and everybody seems to be very much impressed. The comments are always the same. We are in the era of the "mega study" now. When the mega and meta analyses are done — meta analysis on top of meta analysis, so for us to report and make a big furor on fifty patients, I think now would be a little too early. We are now running in on the third and fourth year of data collection, and we will start making some noise pretty soon.

 

Passwater: Let’s talk more about tocotrienols. Being that they are so desirable, are they in our diet?

Bierenbaum: We’re not sure. We know they are in the liver. We have had some trouble measuring them in the blood, despite the fact that we are giving them to the patients. Occasionally, we will get a little peak showing up in the serum. We have a suspicion that the tocotrienols are hiding in the endothelium and in other places in subcutaneous tissues and not making themselves available to us to literally measure them.

 

Passwater: Looking at any dietary source of tocotrienols, let’s say somebody were eating palm oil. I would assume diets in the Pacific Rim countries are richer in tocotrienols than U. S. diets.

Watkins: Right.

Bierenbaum: One of the things you have to pay attention to when you are looking at the diet in different parts of the world is the amount of fat that they have in the diet. I think this whole process that we are seeing is a combination of the amount of fat in the diet, the amount of hypercholesteremias produced by the diet, and the amount of cholesterol they are eating. For instance, the use of tocotrienols to lower serum cholesterol levels is really only effective when you are on a low-fat diet. We think it has to be much less than a 30-percent fat diet.

 

Passwater: Tocotrienols are usually present in such low quantities that they are very difficult to measure.

Watkins: In summary, the richer sources in the diet such as barley, rice and palm, are not widely consumed in the United States, or whole grain rice isn’t consumed widely. And, palm oil products aren’t consumed, except as blended spreadable fats. The ones that they export into this area largely have those antioxidant fractions removed. So, we wouldn’t see them in the American diet. Wheat germ, for example, any of those that have oils that can go rancid easily, have been removed in food processing, as is the case with other fat-soluble vitamins. In nature, tocotrienols are "free" – in forms that readily oxidize. We wouldn’t expect to see the tocotrienols in the American diet. We don’t see them in amounts close to levels of the tocopherols, which themselves are present in very limited amounts relative to our need..

Bierenbaum: The preparation that we are using now is provided by Eastman Chemical Company and Rangsit Biotech Company Limited. It is extracted from rice bran and has a higher concentration of tocotrienols than did the previous preparation. It also has a higher amount of alpha-tocopherol by way of its almost 1:1 ratio in this new rice bran oil preparation which we have been using for about a year and a half. We have not really seen any significant difference in the amount of tocotrienol that shows up in the blood, when we study each of the patients as they come in for their continued evaluation.

 

Passwater: But your thesis is that they may be preferentially retained in the endothelium.

Bierenbaum: Yes, we think it’s in the endothelium and probably in the subcutaneous fat. I know it is certainly present in the liver in significant amounts.

 

Passwater: Do tocotrienols spread more evenly in membranes than tocopherols which tend to clump. Do you think this is a factor in what you are seeing?

Bierenbaum: Yes to the first question. I think it could be to the second question. I think that is about as much as we can say. We don’t have definitive substantiation of that. That would be a worthwhile piece of data to collect. I would really like to see the mechanism explained a little better beyond the postulate we have come up with, but I think for the time being that’s the best we’re going to do on the available evidence.

 

Passwater: How about the cellular adhesion molecules (VCAM and ICAM) which are the "glue" that hold oxidized-LDL and leucocytes to the endothelial cells in the artery walls? Or what about the possible effects of tocotrienols on genetic expression, such as the nuclear transcription factors NF-kappa B and AP- 1, or the COX enzyme which can produce thromboxanes?

Does the greater mobility of tocotrienols enable them to get through the cytosol and up against the mitochondrial membrane or the nuclear membrane? What do you think is happening to the carotid arteries -- and possibly all of the arteries -- of your patients?.

Watkins: Based on some of the studies done in Lester Packer’s lab by Dr. Serbinova and her associates where they used ESR and NMR spectrometry, their studies confirmed the kind of studies that we did twenty years ago for example with various unsaturated fats showing a membrane effect. [20] In other words, some effects are exerted on the nuclear membrane, presumably in which there is enough local loss of order so that access is granted to a protein or enzyme, for example like NF-kappa B, and that is probably physically similar to what we have seen in this labile LDL pool.

 

Passwater: What about the wider distribution of the tocotrienols in membranes as opposed to the tocopherols which tend to clump together in membranes? Do you think this has an effect?

Watkins: A very important effect because that is what allows them to exert such major changes that we are observing with such relatively minuscule amounts of material. That’s one of the main benefits in their not clustering like the tocopherols cluster.

Bierenbaum: I think we were very fortunate to have looked at palm oil and to see the extract of palm oil which incorporated both the gamma-tocopherol and the gamma-tocotrienols. Also, I think it was just dumb luck that we blundered onto that because we had been married and wedded throughout to the tocopherol synthetic form and had not really been exposed to any of the natural vitamin E family. As a result of blundering onto that, we are talking about two different kinds of mechanisms going on here. We have a feeling that the gamma family, which is much more prevalent in nature than the alpha family, was meant to be put there and is an important part of many of the metabolic processes going on in the body. The reason that it hasn’t shown up in the literature before this is that it has been so hard to measure in the serum. If it had been as easy to measure as the alpha-tocopherol, then I think it would have been just as notorious. As we learn more about the tocotrienols we are going to find that they do different things than the alpha- tocopherol does just like the other carotenoids do things differently from beta-carotene. I think this is going to show up and be very clear over the next couple of years.

I sincerely hope we are going to give phytochemicals and nutraceuticals a little more attention than we have been giving them. The past six months I have been suffering horribly from what looks like arthritis in my right knee. That’s a personal offense to me because it has been interfering with my daily tennis activity. I went to a specialist who examined me. The MRI was not descriptive, except for some arthritis and perhaps a ligament or a cartilage injury. He decided to treat me with physiotherapy at a very fine institution. Nothing really helped. One of my good buddies, who also happens to be my stockbroker, said to me "I can’t stand to hear you complain about this knee of yours anymore." I am going to put you on some anti-arthritic medication and he prescribed for me glucosamine chondroitin sulfate. The darn stuff works wonderfully well. I’m back to playing tennis daily.

Passwater: It seems to work in about 80 percent of the people trying it.

 

Passwater: What supplements do you take?"

Bierenbaum: Vitamins C, beta-carotene, natural vitamin E, vitamin B-complex with folic acid, calcium, aspirin and glucosamine with chondroitin sulfate.

Watkins: Generous amounts of antioxidants including vitamin C, vitamin E, beta-carotene; B vitamins; about 30 in total. Since examining the literature and seeing the convincing results in our work, I take the vitamins and minerals faithfully each and every day. I’ve had fewer colds; I feel better.

 

Passwater: I can’t add anything to that except to thank you Dr Bierenbaum and Dr. Watkins for discussing your research with us. It may save many, many lives.

 

References

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2. Verlangieri, A.J. and Bush, M.K. (1992) Effects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J. Amer. Coll. Nutr. 11:131-138.

3. Hodis, H.N.; Mack, W.J.; LaBree, L.; Cashin-Hemphill, L.; Sevanian, A.; Johnson, R. and Azen, S.P. (1995) Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273(23):1849-1854.

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6. Fleischman, A.I.; Hayton, T. and Bierenbaum, M.L. (1967) Serum lipids and certain dietary factors in young men with coronary heart disease. J. Amer. Diet. Assoc. 50(2):112-115.

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8. Fleischman, A.I.; Hayton, T. and Bierenbaum, M.L. (1967) Objective biochemical determination of dietary adherence in the young coronary male. Amer. J. Clin. Nutr. 20(4):333-337.

9. Fleischman, A.I.; Yacowitz, H.; Hayton, T. and Bierenbaum, M.L. (1966) Effects of dietary calcium upon lipid metabolism in mature rats fed beef tallow. J. Nutr. 88(3):255-260.

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14. Bierenbaum, M.L.; Fleischman, A.I. and Raichelson, R.I. (1972) Long-term human studies on the lipid effects of oral calcium. Lipids 7(3):202-206.

15. Bierenbaum, ML; Wolf, E.; Bisgeier, G. and Maginnis, W.P. (1988) Dietary calcium. A method of lowering blood pressure. Amer. J. Hypertens. 1(3Pt3):149S-152S.

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17. Watkins, T.; Lenz, P.; Gapor, A.; Struck, M.: Tomeo, A. and Bierenbaum, M. (1993) Gamma- tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Lipids 28(12):1113-1118.

18. Suzuki, Y.J.; Tsuchiya, M.; Wassall, S.R.; Choo, Y.M.; Govil, G.; Kagan, V.E. and Packer, L. (1993) Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochem. 32:10692-10699.

19. Tomeo, A.C.; Geller, M.; Watkins, T.R.; Gapor, A. and Bierenbaum, M.L. (1995) Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 30(12):1179-1183.

20. Serbinova, E. and Packer, L. (1994) Antioxidant and biological activities of palm oil vitamin E. Food and Nutrition Bull. 15:138-143.

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