Vitamin E Works: An interview with Dr. Maret G. Traber
Richard Passwater, Ph.D.
To say that vitamin E is very important to our health is an understatement: it is protective against approximately 80 diseases. Vitamin E is a vitamin that everyone in the health moment should be more than casually familiar. Also, it is extremely important to understand the many differences between natural vitamin E and synthetic vitamin E. In the months to come, there is going to be more research discussing the differences between various natural forms of vitamin E, such as between the tocopherols and tocotrienols and between alpha-tocopherol and gamma-tocopherol. Now is a good time to review the fundamentals.
No matter what level of interest in vitamin E, there is a lot to learn from experts such as Maret G. Traber, Ph.D. who's work has been honored by the LaGrange, IL -based Vitamin E Research Information Service. This organization, which is funded by Henkel Corporation, presented Dr. Traber with its VERIS Award for her research with vitamin E.
In this series of columns, we will try to bring out points of interest to the novice as well as to those with more advanced knowledge. If you are a novice, we understand that you won't be interested in a lot of technical reading. Not to worry! Although there will be an occasional biochemistry or advanced organic chemistry nomenclature and definition given, please don't be discouraged with this as they are helpful in differentiating between the various forms of natural and synthetic vitamin E. You can still develop an understanding that there are important differences as well as "get the flavor" of why the body prefers only the natural vitamin E.
Although all forms of vitamin E are absorbed by the body, only one form is preferentially retained in large quantities and transported to body components. If you are willing to put up with an occasional technical discussions, there will be much to reward your effort. Consumers ask many questions about the various forms of vitamin E. This series of three chats with Dr. Traber is intended to provide those answers. It is not important that the novice learn all of the scientific jargon, but that the novice gains the insight that there are large fundamental differences between real vitamin E and synthetic. Synthetic vitamin E is good, but natural vitamin E is better.
Maret G. Traber, Ph.D.
Dr. Maret G. Traber has been conducting basic research concerning the absorption and transport of vitamin E in the body since 1983, and is fondly called "The Vitamin E Goddess" by those of us who conduct research with vitamin E. Prior to conducting vitamin research, she conducted basic research on cholesterol absorption, transport, turnover and excretion since 1976.
Dr. Traber has conducted basic research at the New York University School of Medicine, and currently, both the University of California - Berkeley and the University of California-Davis. She is now with the Packer Lab research group in the Department of Molecular and Cell Biology at the University of California- Berkeley. In addition, she has taught nutrition classes at Rutgers University and Columbia University College of Physicians and Surgeons. Her vitamin E research has resulted in her being awarded the VERIS vitamin E Award in 1993 and being the Chair of the Vitamin E Task Force of the Food and Nutrition Sciences Associations (FANSA).
She has published over 60 original research studies involving vitamin E and has contributed over 31 book chapters, conference proceedings, editorials and review articles on vitamin E. She is an Associate Editor for LIPIDS, a primary journal for the study of lipids (fats).
Passwater: Major scientific contributions just don't happen. They're the result of long training and hard work. Your award-winning research is a prime example of dedicated hard work as well as intelligent inspiration. What led you into Biochemistry.
Traber: We could start way back in the good old days when I was a child growing up during the "cold war" and the Russians beat us into space with their Sputnik. This so incensed my father that when I had a choice between taking music classes or a science class, he said, "absolutely you're taking science." At a very tender age, I was encouraged that science was a good thing and girls should do math and all those kinds of serious things like physics; lucky for me, I was fascinated.
Passwater: What piqued your interest about vitamin E?
Traber: I was in Dr. Herbert J. Kayden's lab at the New York University School
of Medicine studying lipoprotein receptors and macrophages and why 45-year old men die of
heart disease. We were doing all kinds of very interesting research very successfully but
it was really hard to get NIH grant money because in charge of allotting NIH grants said
our lab was too small to be doing the things we were doing.
Passwater: Well, we know a lot more about that thanks to your award-winning research. Before we talk about your biochemical detective story, let's review some of the vitamin E basics that involve many of the questions that we get from consumers over the decades.
Let's start with the absorption process. Taking vitamin E supplements won't help unless they are absorbed. Let's look at the absorption process as you have presented in figure 1. What is going on here?
Traber: I would like to especially emphasize to people who have decided taking vitamin E supplements is a good idea, they should absolutely not take their vitamin E supplement with a just a cup of coffee in the morning as they run out the door off to work. Fat is needed to involve all of the digestive processes for fat absorption as vitamin E is fat-soluble and not water-soluble.
Passwater: But "fat" is a bad word these days. True, as a rule most Americans are eating more fat than they should, but some fat is needed; the right fat at the right time. Since an important role of vitamin E is to protect fat - especially in cell membranes - and fat transporters against oxidation. Let's go back to the fundamentals of some fats and fat-like compounds that are important to cell membranes.
Traber: All fats are not alike. I am sure our readers have heard much about the problem with cholesterol deposits in arteries, but this multi-ring structure is a fat-soluble-sterol that is important in cell membranes. That's why it's in egg yolk-so that the dividing cells of the chick have a good supply of cholesterol for their cell membranes.
I am also sure our readers are familiar with saturated and polyunsaturated fats. Generally, these are both triglycerides. Triglyceride means three fatty acids esterified (joined together via an oxygen linkage) to a glycerol backbone as shown in figure 2. Saturated and polyunsaturated fats have different kinds of fatty acids. Saturated fatty acids are solid at room temperature while polyunsaturated fatty acids are liquid. This difference is simply illustrated by comparing butter with corn oil. They both contain fat, but their fatty acids are very different.
A more complex example involves phospholipids. These are lipids (fats) that contain, in addition to fatty acids and an alcohol, a phosphoric acid group. Phospholipids are the main lipid constituents of membranes. Lecithin is an example of a phospholipid. It often is an ingredient in foods because it offers the property of linking both water and fat. Other examples of phospholipids are phosphatidylcholine and phosphatidylserine. Figure 3 shows the structure of a typical phospholipid. Note that phospholipids have a "head" that has an affinity for water and two "tails" that have an affinity for fats.
Passwater: Aha! You mention that because it's going to be important later when we talk about the shape of vitamin E and how it fits into cell membranes to protect these phospholipids against free radicals.
Traber: Right. And it's also interesting to know how these "head and tail" shapes facilitate the transport of fats in a water based system such as the bloodstream. Oil (fat) and water don't mix, so the body has to develop a system to transport its fatty materials, such as cholesterol, vitamin E and nutrient fats in blood. Phospholipids are a good illustration of the system used. They can spontaneously arrange themselves into micelles as shown in figure 4.
Now, let's consider what happens when someone eats food containing fat: the fat causes the secretion of bile and the secretion of pancreatic enzymes. They mix together so that you have the release of a whole bunch of components that are necessary to make an emulsion. This is almost kind of like making mayonnaise in some sense. We have to have oil and water mixing so that enzymes can get in there and start chewing away and releasing the fatty acids.
The enzymes come in and start taking the fatty acids off the triglyceride molecules one fatty acid at a time. These fatty acids, along with bile acids, continue to make what are called micelles which arrange the molecules so that there is a fat droplet in the middle with these nice emulsifying (amphipathic) groups on the outside that like both oil and water as shown in figure 4 . The fat in the triglyceride can stay with the fat in the center of the droplet, and the water on the outside can stay with the water soluble-forms on the surface. It is thought that small micelles containing bile, fatty acids and cholesterol are the transport vehicles to move vitamin E to the intestinal cells for absorption.
I recently attended a conference in Vermont where we were talking about intestinal absorption of nutrients. Scientists still don't know how a nutrient crosses the brush border of the intestinal cell and get inside for packaging. It does. Once it gets inside the cell the cell has to make a lipoprotein as shown in figure 5. A lipoprotein can be thought of simply as a conjugated protein in which lipids form an integral part of the complex particle. A lipoprotein contains varying amounts of triglycerides, cholesterol, phospholipids and protein. Lipoproteins are classified according to their composition and density. The lipoprotein gets packaged with triglycerides that have reformed from the free fatty acids moved from inside the intestinal lumen to inside the cell. They are put back into a triglyceride so we are back to our three fatty acids glued to a glycerol backbone.
Chylomicrons are large lipoproteins consisting of about 90 percent triglycerides, with small amounts of cholesterol, phospholipids and protein. They are largely fat-rich in the center with a few phospholipids and proteins on the surface to help direct it to where its going. Chylomicrons are formed in the intestinal tract and carry dietary fats from the intestinal mucosa into the plasma. One may think of the chylomicron as a big truck. It is moving fat from the intestinal cell into the circulation. It actually moves through the circulation and scientists using radioactive labels have shown that a chylomicron stays in the circulation only five minutes. It moves very quickly from the intestine to the liver and during that process, lipoprotein lipase is on the walls of the capillaries. You can almost think of them as beach balls flying past. They get captured by the lipoprotein lipase; it hangs onto the chylomicron for a little bit of time, again hydrolyzing the triglyceride inside and releasing the fatty acids.
The fatty acids then go to the tissue, mostly adipose tissue I am sad to tell you, so as soon as someone eats chocolate cake, that chocolate fat goes directly to their adipose tissue. Now you know why the body is so efficient in converting dietary fat to body fat. At the same time, the vitamin E is getting delivered along with that fat, and then the chylomicron remnant moves to the liver.
Passwater: It sounds as if the vitamin E that you've just eaten can get to your adipose tissue fairly quickly also. Yet, it takes a long time for tissue stores of vitamin E to increase. It seems some tissues are harder to load then others. Aside from storage in adipose tissue and membranes, is vitamin E significantly preferentially retained or accumulated by certain organs?
Traber: No. There are no one or two primary storage organs or sites other than adipose tissue. About 90 percent of the vitamin E stored in the body is in adipose tissue and most of the rest is stored in virtually every membrane in every tissue.
Passwater: How quickly can tissues or organs be loaded with vitamin E? As an example, vitamin E offers some protection from damage from the UV in sunlight, can one expect to take a vitamin E supplement and then have a little extra UV protection an hour later? Can one start taking vitamin E supplements today and have reduced risk of heart disease tomorrow?
Traber: No one knows. The epidemiologic studies suggest that 100 IU vitamin E for 2 years or longer are beneficial. There are some research studies suggesting that adipose tissue stores also require at least 2 years before changes in tocopherol concentrations can be identified. Thus, taking one pill and expecting it to prevent heart disease is unrealistic. Vitamin E supplementation should be a daily habit, done in a consistent manner along with a good diet. The news from the best experts is just like your mother told you!
Passwater: Is vitamin E stored or transported in the body in any form other than the free alcohol (tocopherol) form?
Traber: No. Unlike vitamin A, for example, vitamin E is transported and stored only in the free tocopherol form.
Passwater: Let's talk about what you have discovered about what happens to vitamin E in the liver and why essentially only one form of vitamin E -- the natural form that chemists normally call d-alpha-tocopherol or RRR-alpha-tocopherol - is put back into the bloodstream later. For now, let's focus on the absorption of vitamin E. You mentioned the role of bile. People who have had their gallbladders removed don't store a large amount of bile, so a large amount of bile is not available to get released at once when stimulated by fat in the intestine. Would somebody who has had gallbladder surgery need to take any special precautions? Would they need extra fat to efficiently absorb vitamin E? Do people who have fat malabsorption syndrome have special problems with vitamin E absorption?
Traber: I think that in both the case of fat malabsorption patient as well as the gallbladder patient, they actually want to try to avoid fat. Large fatty meals can strain their system, so the fat doesn't get digested and instead can cause intestinal upset or diarrhea. I think one can still take vitamin E supplements with food and achieve good absorption. It is surprising how much fat there is in food. The person who drinks just a cup of coffee, clearly, there is no fat there. If you even eat a piece of bread, if you have some skim milk with that, there is enough fat there to aid digestion and absorption of vitamin E.
Passwater: Is there anything that would interfere with the absorption of vitamin E besides the lack of fat? You were talking about dietary lipids - fats and oils. That reminds me of the non-dietary, non-lipid oil called mineral oil. It is a liquid petroleum distillate. Mineral oil is not absorbed and is sometimes used as a laxative and is often part of laxative formulations.
Traber: Anything that solublizes vitamin E and then is not absorbed or even causes diarrhea would take away the vitamin E without it having much chance to be absorbed. This is the case with mineral oil and a new product called Olestra. Olestra is a fake fat that doesn't get absorbed. Also, the drug Cholestyramine interferes with fat absorption. So if one is taking Cholestyramine they shouldn't take vitamin E supplements at the same time. Those kinds of things that are intentionally preventing fat absorption present problems with vitamin E absorption.. There is a new drug that is being discussed that is a lipase inhibitor. This prevents some fat from being absorbed. Again it would be important to take one's vitamin E supplement not at the same time as a lipase inhibitor because you want to absorb the vitamin E but not the fat.
Passwater: This applies to vitamin E absorption regardless if it's in food or taken as a supplement. Is that correct?
Traber: That's right. As long as you are eating it with food there is no problem.
However, if one takes huge amounts of vitamin E, say a couple of grams, or if they decide to take their month's supply of vitamin E in a handful all at once, it's likely that it won't all be absorbed very well. It might even cause diarrhea because vitamin E itself is an oil. Vitamin E needs to really dissolve in oil and that's why it's important not to take too much at once. In fact, it would be a smarter thing to take smaller doses with each meal rather than one big fat capsule once a day.
Passwater: That's the same advice we have been giving out for years. I know that this begs the question of what are effective dosages of vitamin E, but we have to let that question wait until Part III when we chat about your research with the tocopherol transfer protein (TTP).
How about iron? Many people have read that it is not a good idea to take iron and vitamin E at the same time. Yet food contains both. Wheat germ is rich in both vitamin E and iron. If the iron is chelated or naturally bound or compartmentalized, it does not react with vitamin E. In the body, they are transported by separate systems that keep them apart. Most multivitamins contain vitamin E and iron together, and the vitamin E strength is maintained for months and even years as proven by assays. Is there any problem concerning vitamin E and iron?
Traber: That is a tough question. Under certain conditions in a test tube, you can mix vitamin E, vitamin C and iron and you can create free radicals that will deteriorate vitamin E. However, in the body, the acid in the stomach lowers the pH which prevents vitamin E from being oxidized by reactions involving iron. In the small intestine, there is a lack of oxygen that precludes much oxidation.
Passwater: Changing the subject a bit, the media have caused a lot of confusion about vitamin supplements recently. One of the things that the public became confused about was the safety of taking large amounts of vitamin E supplements. There is no question that vitamin E supplements are safe and effective. Several scientific articles review vitamin E safety. However, suddenly people who had to take very large amounts of vitamin E supplements because they had absorption problems became alarmed. What can you tell them?
Traber: I received a phone call from somebody who has a fat malabsorption syndrome and what they told me was they had been taking large vitamin E supplements because they don't absorb fats very well and they were concerned that maybe they were taking too much and this was actually not healthy. I would like to emphasize to all the people who have fat malabsorption where their physician has said to them, "you have a problem with vitamin E deficiency"-that those people take large vitamin E doses. We're talking grams of vitamin E a day. These are people who have serious malabsorption of vitamin E and it should be emphasized that if you are in that category you should absolutely take the large dose of vitamin E like you have been recommended to do; there is no data suggesting that vitamin E is toxic and in this case where you can actually develop neurologic abnormalities it is essential that they not decrease their vitamin E intake.
Passwater: The functions of vitamin E are due to the chemical structures of its vitamers. Vitamers are different chemical forms that have the same vitamin activity. These various vitamers cause a great deal of confusion in lay people when they try to read through the jargon of organic chemists and biochemists. I have put a technical glossary in Box 1 for reader reference, but I am sure that the readers would like a simpler description from you. Would you please describe the basic structure common to all of the vitamin E vitamers?
Traber: The vitamin E vitamers are classified as quinoid alcohols because they have a hydroxyl group. They can also be considered monophenols for the very same reason. The tocopherols basically consist of a "ring" portion called a chromane "head" or "ring" and a "tail" portion called a "phytyl" group. A chromane (also called chroman or chromanol) head has two rings which are essentially naphthalene with one carbon atom substituted with an oxygen atom, thus a cyclic ether, and a pyhtyl group consists of a saturated 16-carbon isoprenoid. The tocotrienols are essentially identical to the tocopherols, except that they have three double bonds in the tail at 3', 7' and 11'. This can "loosely" be called an unsaturated phytyl group or isoprenoid. The simplified structure can be drawn as in figure 6. Figure 7 shows the formal structure representations for natural alpha-tocopherol and natural alpha-tocotrienol.
Vitamin E nomenclature is difficult, but I think I can simplify it some. Vitamin E occurs in nature in 8 different forms: alpha-, beta-, gamma- and delta- tocopherols and alpha-, beta-, gamma-, and delta- tocotrienols (Figure 8). Tocotrienols differ from tocopherols in that tocotrienols have an unsaturated side chain, while tocopherols have a phytyl tail. Chemically synthesized dl-alpha-tocopherol is not identical to the naturally occurring d-alpha-tocopherol because the synthetic contains 8 different stereoisomers arising from these three chiral centers at carbons 2,4' and 8' in the tail. RRR-alpha-tocopherol, the naturally occurring form, is only one of the eight stereoisomers present in all rac-alpha-tocopherol (see figure 9).
I'd like to emphasize that food contains a variety of vitamin E forms. Most of it is alpha-tocopherol, but the American diet is unusual because it contains lots of gamma-tocopherol. This is a result of corn and soybean oils, which are polyunsaturated and have 6-10 times as much gamma-tocopherol as alpha-tocopherol. Wheat germ is basically alpha-tocopherol and beta-tocopherol.
Passwater: My laboratory research in the 1960's and early 1970's was empirically driven, rather than theory driven. In a series of studies with laboratory mice, I had obtained results showing the synergism of certain antioxidant nutrients including vitamin E, and these experiments became the basis for my 1970 and 1972 patents on antioxidant synergism. It was the teachings of Drs. Denham Harman [Whole Foods, March and April 1995] and William Pryor [Whole Foods, October and December 1994 and January 1995] that provided the theoretical explanation of my experimental results, but it was the teachings of Drs. Graham Burton and Keith Ingold of the National Research Council of Canada in Ottawa that provided the detailed theoretical explanations on how vitamin E terminated free radical reactions. As a colleague, you have published several reports and reviews with them. Would you mind telling our readers a little about what makes vitamin E unique - what makes vitamin E vitamin E? Why is vitamin E such a good biological antioxidant?
Traber: Drs. Keith Ingold and Graham Burton were the ones who did all that beautiful work. They showed that there can be electron delocalization in the vicinity of the hydroxyl group on carbon number 6 of the chromane head. Yes, there is something magical about the alpha- tocopherol structure. It has a hydroxyl group on the head along with the three methyl groups that allow alpha-tocopherol to become a very stable radical after it "donates" an electron to another radical to break the chain of free-radical reactions. It is exciting that when vitamin E functions as an antioxidant it becomes a radical by surrendering an electron, but it becomes a harmless radical. The vitamin E radical can sit happily as a radical for about 12 seconds. Dr. Ingold calculated that and I was quite startled with it.
Besides not having enough energy to harm other compounds it lasts long enough that it can be converted back into an antioxidant again. If there is a vitamin C molecule around, the vitamin E molecule takes an electron from it and the vitamin C molecule becomes a radical while the vitamin E molecule goes back to being the reduced form so it can be an antioxidant again. The vitamin C radical molecule then takes an electron from lipoic acid or glutathione and it too is regenerated back to its antioxidant form. Glutathione can be reduced too becoming an antioxidant again by the enzyme glutathione reductase. This system uses the "reducing equivalent" created when glucose is oxidized during energy production. The result is that we have the basic metabolism of the body is used to keep vitamin E reduced so that it can be an antioxidant.
Passwater: While vitamin E is sitting there for as long as 12 seconds, it has relatively low energy in regards to tissue and therefore does not generate free radical reactions.
Traber: It doesn't give that radical away readily. It really sits quietly; it doesn't oxidize things like your polyunsaturated fat and so it actually grabs the radical from polyunsaturated fats and prevents them from continuing lipid peroxidation. That is why vitamin E is called a "chain-breaking antioxidant."
Passwater: What is the function of the phytyl tail of the vitamin E molecule? Is it to hold vitamin E in the membrane, making vitamin E soluble and mobile in cell membranes?
Traber: I think Dr. Valerian Kagan or Dr. Graham Burton was the one who calculated this, that the phytyl tail is exactly long enough that it matches the tails of phospholipids in the membranes. Membranes have a lipid bi-layer consisting of phospholipids that are arranged so they have a polar head group that likes the water phase facing outwards towards the water-based cytosol or plasma, and tails that face into the membrane center. Then on the opposite side of the bi-layer, the tails are arranged in the same manner, only now they are going towards the tails from the other side of the bi-layer. So we have two sets of tails matching each other heads the other way and vitamin E exactly fits on one half of this. (See figure 11) Natural vitamin E just sits there nicely to be on guard on one side of the membrane.
Synthetic vitamin E though is a different story.
Passwater: So true. However, that's a more complex issue than generally recognized. Let's chat in the next installment about why the body prefers to hang on to natural alpha-tocopherol and why synthetic vitamin E doesn't dwell as long in cell membranes and is not transported out of the liver.
© 1997: Reprinted with permission of the Copyright owner, Whole Foods magazine, Whole Foods Incorporated.