How Vitamin E Works: An interview with Dr. Maret G. Traber
Part II: Various forms of Vitamin E
Richard A. Passwater, Ph.D.
This is the second of a three-part discussion with vitamin E expert, Dr. Maret G. Traber of the University of California at Berkeley. Here, we chat about the many differences between natural vitamin E and synthetic vitamin E, and the different ester forms of vitamin E. In Part I, we discussed the chemical structure of vitamin E and how its chemical structure determines how vitamin E works to quench free-radical reactions. We also discussed how vitamin E is absorbed and stored in the body. In Part III, we will discuss Dr. Trabers award-winning research on how vitamin E is transported and why the body preferentially transports only natural vitamin E.
Passwater: As a reminder, it may be useful for readers to refer to the glossary published along with Part I in the November issue of Whole Foods; this section will help explain some of the more technical terms included in this article. Further, be aware that the numbering of figures (illustration) included with this article represents a continuation of the numbering system begun in Part I in the November issue.
Also, please note that various remarks are followed by bracketed numbers. These are keyed to a list of scholarly references that will be provided when Part III is published in the January issue of Whole Foods.
Passwater: In Part I, we talked about how vitamin E is absorbed, but absorption is only a small part of the story of bioavailability. Vitamin E has to be delivered to body components in order to protect them. Your research has focused on how this transport occurs, and which form -- and basically only one form -- is transported to body components.
OK, so lets discuss the structural differences of the various forms of vitamin E and why these differences are so significant. Most of our readers know that vitamin E is available as alpha-tocopherol or "mixed"- tocopherols. Until recently, there hasnt been a great deal of interest at the consumer level in understanding the differences between these forms.
Part of the reason is that there are few studies showing important differences between the various forms of vitamin E, and when such studies do appear, they are often obfuscated by improper interpretations or questions concerning whether or not these differences apply to humans.
Another reason for the lack of interest by the consumer is that distinctions have to be made between the forms that involve some confusing technical-sounding names. When we use the name "vitamin E," we are describing what the compounds are. They are vitamins. When we use the common chemical names, we are describing more details about the structure of each kind of vitamin E molecule so that we can compare the biological differences with chemical structural differences. Would you please lead our readers through the basic nomenclature of the various vitamer forms of vitamin E?
Traber: D-tocopherols (alpha-tocopherol, gamma-tocopherol, beta-tocopherol and delta-tocopherols) and d-tocotrienols (alpha-tocotrienol, gamma-tocotrienol, beta-tocotrienol and delta-tocotrienol) are the eight compounds that occur in nature that have vitamin E activity. Their relative potencies are listed in Table 1. The form of vitamin E that the body preferentially transports and stores is the d-alpha-tocopherol.
Scientists traditionally refer to this natural source alpha-tocopherol as RRR-alpha-tocopherol. Although this name may sound confusing to the non-chemist, the name is short compared to the formal name. Chemists usually use the shorter forms because they are adequate to describe much of the chemical structures for comparisons. Greater chemical detail is given by the formal names, which for natural-source alpha-tocopherol is 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl-tridecyl)-6-chromanol.
To complicate matters, humans have learned to manufacture vitamin E from petrochemicals. However, this synthetic vitamin E is a racemic (from glossary) mixture of the natural vitamin E (RRR-alpha-tocopherol), and seven other alpha-tocopherol isomers. (See table 2). This synthetic form of vitamin E is commonly called "dl-alpha-tocopherol" and is to be listed on labels as such. (If the label lists only "alpha" and doesnt include either the "d-" or "dl-" designation, suspect that it is the synthetic dl-alpha-tocopherol." However, its more correct for scientists to call this mixture "all-rac-alpha-tocopherol," which means that the mixture is racemic.
Table 1. The various vitamers of natural vitamin E and their relative potencies.
Vitamin E Vitamer
Compared to d-alpha-tocopherol
Passwater: Most people, even most scientists dont realize that synthetic vitamin E is an equal mixture of eight isomers, containing 12.5 percent of each isomer. This means that it contains only 12.5 percent of the compound that the body preferentially transports and stores, as your studies have shown, and therefore contains 87.5 percent of molecules that have never been consumed by mankind until the manufacture of this synthetic vitamin E that as best I can estimate, was somewhere around 1968-1969.
I have always been concerned about the possible stereochemical or hindrance effects of the un-natural compounds in tocopherol receptors. This is why I usually call synthetic vitamin E "un-natural" vitamin E. We will discuss your research with the vitamin E transport protein later, but first I want to tell our readers about the change that occurred in the manufacture of vitamin E around 1968-1969 that has made an important difference in what is in the final mixture called "dl-alpha-tocopherol" or synthetic vitamin E.
Synthetic vitamin E was the first large-scale commercial source of vitamin E. It became available in the 1940's (US 2,411,969 Karrer and Isler, 1941). From the early 19404s until the late 1960s, synthetic vitamin E was basically manufactured from just two compounds trimethylhydroquinone and natural, 2-ambo-phytol from lemon grass. They would be joined together to make alpha-tocopherol. However, unlike the way in which nature makes natural RRR-alpha-tocopherol, the two components of the old synthetic vitamin E could join together in two ways. One way being the natural RRR-alpha-tocopherol but the other way involved having the phytyl "tail" join the chromane head in a different position on the joining carbon atom.
Carbon atoms have four bonding points that can result in additional atoms, if they include atoms of different elements or groups of atoms, being added in either a "symmetrical" or "asymmetrical" manner. In other words, carbon atoms that have two different groups attached to them plus two bonds to other carbon atoms, such as in vitamin E, are asymmetric. This means that there can be isomers that are mirror images of each other and can not be superimposed on each other. In vitamin E molecules there are three such carbons that become "chiral" centers [2,4' and 8'] and thus have non-superimposable mirror images.
Asymmetrical carbon atoms have the property of rotating light beams. This is called optical rotation. Natural vitamin E is a single enantiomer (an "optically active" stereoisomer that rotates light) and rotates light only one way clockwise. Formerly, this was described as rotating light to the "right." Thus, originally natural vitamin E was given the designation "d," which is an abbreviation of the Latin word "dextro" meaning right.
During the synthesis of vitamin E from just two starting materials, there is an equal probability that they can join together in one of two positions. The result of the "old" synthetic vitamin E was a 50-50 mixture of molecules that rotated light either clockwise (right) or counter-clockwise (left). This ambogenic mixture was called dl-alpha-tocopherol because it was half d-alpha-tocopherol and half l-alpha-tocopherol. The designation "l" is an abbreviation for the Latin word "levo" for left. Figure 12 illustrates this point. We will compare this to the present synthetic vitamin E later.
Thus, one can put natural vitamin E into an instrument called a polarimeter and measure the degree of the rotation of a polarized light beam clockwise (right). The "old" synthetic vitamin E did not rotate light because it was a 50-50 mixture of the two "d" and "l" enantiomers.
Today, synthetic vitamin E is still called dl-alpha tocopherol by most people in the nutrition field, and dl-alpha-tocopherol is still the official designation used on labels to denote synthetic vitamin E. However, synthetic vitamin E is made a new way using natural, optically inactive isophytol that produces eight stereoisomers (enantiomers). Figure 13 illustrates the stereoisomers of the present-day synthetic vitamin E. This mixture is called all-rac-alpha-tocopherol by chemists, but the commercial name was never changed when the process was changed. Synthetic vitamin E is still listed on labels as dl-alpha-tocopherol, which was the old synthetic "ambo" vitamin E containing just two stereoisomers, but this is mis-leading because it is now a mixture of eight stereoisomers. You can even see a difference in color between natural vitamin E and synthetic vitamin E. Natural source vitamin E is a reddish brown oil while synthetic vitamin E is yellow to amber. Natural source d-alpha-tocopheryl acetate is a golden oil, while synthetic dl-alpha-tocopheryl acetate is a nearly colorless pale yellow oil.
Traber: Another interesting difference that we see in the laboratory is that samples of pure RRR-alpha-tocopherol crystalize, while the all-rac-alpha-tocopherol doesnt. This is because the RRR-alpha-tocopherol contains only one kind of molecule and identical molecules can align to form a crystal, demonstrating the purity. In contrast, the all rac-alpha-tocopherol, with its eight different kinds of molecules remains an oil! You seldom see this difference in the vitamin E you buy in the store because that is usually diluted with oil so that it is more liquid and can be handled by the machinery that puts it into capsules.
Passwater: An interesting observation. And you bring up another question concerning any effect an oil may have on the vitamin E. Im going to bring that up again later, but now lets get back to the differences between natural-source and synthetic vitamin E.
Figure 15 illustrates the different quantities of natural vitamin E (RRR-alpha-tocopherol) in the three forms discussed. Natural-source vitamin E is essentially all RRR-alpha-tocopherol (less any of the other natural vitamin E vitamers that may be present); the old synthetic vitamin E -- the "dl" or "ambo" mixture was 50 percent RRR-alpha-tocopherol, however, the present-day synthetic vitamin E -- "the all racemic" mixture -- is only 12.5 percent RRR-alpha-tocopherol. To me, this is a significant and meaningful difference. I feel that any study performed on the "old" synthetic vitamin E should be repeated using the "present-day" vitamin E to see what, if any, difference there is.
I dont want to imply that the "present-day" synthetic vitamin E is useless or ineffective. We know that it too helps protect against free-radical damage, but I dont believe it is as effective as the tables suggest.
Table 2 lists these eight stereoisomers (enantiomers) and their "official" vitamin E activities. However, Dr. Traber, you and others have shown that these values may be incorrect when one considers their antioxidant and other than rat-resorption bioassay.
Traber: Yes, now synthetic vitamin E is made from different starting materials, this is more like "starting from scratch" when you cook. Instead of having two possible configurations when the two former starting materials were joined together, there are three carbon atoms that have chemical groups joining asymmetrically and having the possibility that the carbon could rotate light in the right direction or the left direction. This makes the total number of different configurations eight -- multiply two times two times two you end up with eight different possibilities for having right or left rotations.
I often use the left and right hand as an analogy in explaining the differences because people understand you cannot put the right glove on the left hand! Although the right hand looks much like the left hand, they are different. One is the mirror image of the other. The "R" configurations can be represented by the right hand and the "S" by the left hand.
The older designation of "d" and "l" do not apply because we are dealing with eight combinations of right and left -- not simply two. So, instead of calling it right or left we now designate each chiral carbon as either "R" from the Latin word for right "rectus" or "S" from the Latin word for left "Sinister." It actually turns out that synthetic "S" forms may be sinister indeed because they do not work very well in the body. So, whenever one sees "S" in the description of vitamin E, it refers to a synthetic form not found in nature. Although the "S" forms are mirror images of the "R" forms, they are much less active, and they are not transported in the body by the tocopherol transfer protein.
Natural vitamin E -- the "old" d-alpha-tocopherol -- is now designated as RRR-alpha-tocopherol [(2R,4'R,8'R)-alpha-tocopherol]. Synthetic vitamin E is all-rac-alpha-tocopherol, but it still will commonly be called dl-alpha-tocopherol.
Passwater: When Drs. Herbert Evans and Katherine Bishop were discovering this "factor X" in 1922, the inadequacy of which resulted in fetal death and resorption in the laboratory rat, the only property of this fat-soluble factor that was later named vitamin E was its relationship to fertility. The common chemical name for vitamin E -- tocopherol -- was coined in 1924 from the Greek words "tokos" meaning childbirth and "pherin" meaning to bring forth. The "ol" was added to show that it was a member of the alcohol family. It was not known that vitamin E was an antioxidant or had any other properties. Yet, the ability to prevent fetal death and resorption is the standard by which vitamin E is still measured. The results of this bioassay had been expressed as "International Units of vitamin E" by the USP since 1965, and now we are using "milligrams of alpha-tocopherol equivalents" (mg alpha-TE). In this system, one milligram of dl-alpha-tocopherol was assigned a value of 1 IU, and other forms were weighted according to their relative potencies in the rat resorption bioassay. Table 3 lists these comparative ratings. How were the relative values of vitamin E determined?
Table 3. "Official" potencies for common forms of Vitamin E. These 1965 era ratings need to be re-examined in light of recent findings as described herein.
Relative Potency, IU/mg
Relative Potency compared to d-alpha-tocopherol.
Traber: Thats the horrible fetal resorption assay. A virgin rat is made vitamin E- deficient and then is impregnated. Then the number of fetuses that are resorbed is determined. Then you take other rats that have been fed various amounts of the form (vitamer) of vitamin E you are testing and do the same thing to see what is the lowest dose needed to prevent fetal resorption. In this day and age, I wish we could say we have some great molecular biology answer but thats the standard for determining bioavailability, believe it or not.
Passwater: This bioassay developed by Drs. M. Joffe and P. L. Harris in 1943 is relative only to fertility, not all of the functions that we are looking for when we take vitamin E supplements. Is rat resorption a relative indicator of what we are looking for when we take vitamin E as an antioxidant? Is rat resorption strictly an antioxidant function?
Traber: Absolutely not. I think we want only an indication of how bioavailable--whatever that word means a form of vitamin E is, what does it do? Thats what we are still trying to figure out 75 years after the discovery of vitamin E -- what does vitamin E do?
We know in a test tube it is an antioxidant. The various antioxidant capabilities of these forms of vitamin E arent that different, and in fact in some systems you can nicely show that gamma tocopherol or alpha tocotrienol are better antioxidants than alpha tocopherol.  The bioassay says that in the body, alpha tocopherol is the most effective. It doesnt say what it is the most effective at doing. Scientists are still trying to answer the question, "why do we need only alpha tocopherol?"
Thats where the tocopherol transfer protein (TTP) story comes in. It looks as if the liver has a mechanism for salvaging alpha-tocopherol and putting it back in the plasma so it can be delivered to tissues. What we havent figured out is why do the tissues preferentially need only alpha-tocopherol. Is there some special function that only alpha tocopherol can serve?
The hot news right now - Dr. Angelo Azzis group in Switzerland is showing that alpha tocopherol can in fact regulate signal transduction and this is how the whole cell is regulated. How applicable that is to the whole body? Is this just really something you can do in the test tube or in tissue culture cells? Can we prove it to be an important thing in vivo? Thats yet to be shown. But Dr. Azzi has several reports that suggest that alpha-tocopherol will regulate protein kinase C. Protein kinase C is an important enzyme that turns on and off other signaling molecules which ultimately changes which genes are turned on and off and, therefore, which proteins are expressed and how a cell responds. Now we are finding that vitamin E is sitting sort of at the core of how every cell is working.
Passwater: Well, we have known for a long time that vitamin E helps regulate the biosynthesis of DNA, and now it is exciting to see that it is at the core of how every cell works. Lets go back to the antioxidant activity again. It seems that the in vitro (test tube) antioxidant power of the vitamin E vitamers is the reverse of the biological potencies. In chemical glassware, delta-tocopherol is a more powerful antioxidant than gamma-tocopherol, which in turn is more potent than beta-tocopherol, which is stronger than "real" vitamin E alpha-tocopherol. Perhaps nature has designed the vitamer antioxidant for different purposes than vitamin E function.
Traber: You have hit upon the heart of a current scientific controversy about vitamin E. For decades scientists argued that because alpha-tocopherol did not have the highest antioxidant activity of the various forms of vitamin E, thus, the function of vitamin E in the body must have nothing to do with its antioxidant activity. Now, keep in mind that this was in the days when the understanding of free radical chemistry was in its infancy. Research by Drs. Graham Burton and Keith Ingold demonstrated that in biological systems, alpha-tocopherol actually had the highest antioxidant activity of any of the vitamin E forms [4-7] This means that the tocopherol transfer protein is actually choosing the form of vitamin E with the highest antioxidant activity.
It is interesting that oil plants such as corn and soybean actually synthesize alpha-tocopherol as they are growing, but when they begin to make their polyunsaturated oil and store it as they ripen, they make gamma tocopherol. This was told to me by Ed Ostermeyer, one of the pioneers in vitamin E who worked for Eastman Chemical in Kingsport TN. The other plant that is interesting is the palm oil tree. It makes a relatively saturated oil, yet makes vitamin E forms with unsaturated tails, the tocotrienols. It seems to me that these oils have very different physical characteristics, so may need very different kinds of vitamin E for their antioxidant activities.
Passwater: Its fortunate that nature gives us several forms of vitamin E. We have different needs than the plants we are mainly concerned with protecting the widely distributed polyunsaturates in cell membranes and LDL from oxidation, not protecting oil concentrated in seeds. One of the advantages of having the different forms is that we get different compounds that may have benefits different than the "standard" vitamin E activity.
Well, nature gives us eight vitamers, that is "d" forms of alpha-, beta-, gamma-, and delta- tocopherols and tocotrienols. While man manufacturers eight isomers of alpha-tocopherol, and this is a different story. In review, it seems that if one takes a supplement of synthetic vitamin E, it is going to be absorbed and taken into the chylomicrons and then into the liver in a very short time. It is not going to circulate in the blood for a very long time before the liver removes it. Thus, the tocopherol transfer protein that we are going to discuss later, is not going to grab all those "sinister" molecules (SRR-alpha-tocopherol, etc.) and it is going to be excreted from the liver. So, whats going on here with the synthetic vitamin E in the overall picture? How effective can synthetic vitamin E be if seven out of eight molecules are filtered out by the liver?
Traber: This is partially compensated for by the way that vitamin E potency is measured. The International Units that were determined by means of the fetal resorption bioassay adjust -- or at least partially adjust -- the dosages of the various forms. As the relative potency conversions in Table 2 show, it takes only 67 milligrams of natural RRR-alpha-tocopherol to provide 100 IU while it takes 91 milligrams of synthetic all-rac-alpha-tocopherol to provide the same 100 IU of activity. So on the basis of the biologic activity according to this terrible fetal rat resorption assay we have talked about, vitamin E is measured by IU instead of weight. However, it may be much more involved that fetal resorption.
Basically what Dr. Robert Acuffs group and we have found in humans, using with our stable isotope, labeled deuterated tocopherol, is if you give equal weights of each, natural vitamin E is twice as effective as the synthetic. This is determined based on human data and human plasma kinetics, not rat fetal resorption. [8,9].
A more recent human study (eight women) estimates that natural vitamin E is three times more effective than synthetic vitamin E.  When the researchers measured the increase in blood levels and lipoprotein levels of vitamin E, they found that 100 milligrams of RRR-alpha-tocopherol was similar to 300 milligrams of all-rac-alpha-tocopherol. They concluded, "Because it is clear from our data that RRR-alpha-tocopherol has a bioavailability almost three times higher than that of all-rac-alpha-tocopherol, RRR-alpha-tocopherol is preferable for the treatment and prevention of disease."
Passwater: Thats really not surprising to anyone doing animal studies with vitamin E for a long time. Even some of the earlier crude rat resorption bioassays occasionally found that natural vitamin E was 1.8 times as effective as the synthetic, but the "average" result was about 1.36 times. Now how do we get everyone to throw away the old 1.36 value and use the newer, more meaningful values?
Table 4 reviews some of the differences between natural and synthetic vitamin E
Table 4. Some differences between natural and synthetic vitamin E.
Natural Vitamin E
Synthetic Vitamin E
turpentine or petrochemical
Only one form
More than twice as active,
mg per mg
Is retained longer in tissues
Earlier you mentioned that there is a difference between natural and synthetic vitamin E in regards to how long they can stay in cell membranes. Please elaborate.
Traber: Once again, we come back to "R" versus "S." It turns out that "S" configurations make the tail of vitamin E kink. So the tail is bent in "S-" containing enantiomers, whereas the "R" form matches all of the other "R" forms of the fatty acid tails. So this is how natural RRR-alpha-tocopherol nicely lines up in the membranes, whereas the synthetic form because of this little kink in the tail -- comes out of the membrane faster because it has the wrong stereochemistry.
Passwater: What do we know about possible inhibition of the synthetic vitamin E molecule from going into the membrane in the first place.
Traber: Drs. Burton and Ingold did some studies with the red cell membrane showing the natural and synthetic vitamin E molecules went into the red cell membrane with an equal rate but the "S" form came out faster. 
Passwater: How about the effect of the shorter tails of the tocotrienols. The triple unsaturation shortens the tail length. Would this give tocotrienols more mobility in membranes which could help account for tocotrienols being more effective biological antioxidants?
Traber: It was Dr. Valerian Kagan here at the Packer Lab who showed tocotrienols have shorter tails. [12, 13] The shorter tails possibly allow tocotrienols to move faster in membranes. I think he showed that if tocotrienols were added to a membrane they were more effective antioxidants than alpha-tocopherol because they could move faster in the membrane. However, the tocotrienols are filtered out from the plasma during the first pass through the liver and they dont very readily get transported back into the plasma again.
Passwater: Well talk about that some more in part three when you tell us about your exciting research with the tocopherol transfer protein
What forms of vitamin E are mostly in the diet and does this distribution have any practical biochemical significance? Your research shows that alpha-tocopherol is the one that the body retains. Yet gamma-tocopherol is the form of vitamin E most prominent in the North American diet. Does whats in the diet really have any relevance?
Traber: I suppose it has relevance in the idea that Dr. Stephen Christen in Dr. Bruce Ames group was quite adamant that gamma tocopherol might have a special role in protecting against nitration by peroxyl nitrate, and thats a newly discovered radical that many scientists are excited about.  Nitric oxide reacts with superoxide to produce peroxy nitrate and that can cause all kinds of damage. One way to analyze it is to measure nitrotyrosine. What the Ames group has shown in a PNAS report in the last few months is that in fact gamma tocopherol can prevent that reaction or rather gamma-tocopherol gets nitrated more readily and so has a role separate than that of alpha-tocopherol. Alpha-tocopherol has three methyl groups and no open spaces on that first ring in the chromane head. Gamma tocopherol has only two methyl groups on that ring, and thus, a place where the nitration reaction can happen.
Dr. Bruce Ames group has suggested that a detrimental effect of vitamin E supplements is that they cause plasma gamma concentrations to go down. They are correct, Dr. Garry Handelman showed that vitamin E supplements cause plasma gamma tocopherol concentrations to decrease, but, I personally do not believe that this is an important phenomenon. I think the Ames group data works fine in the test tube but I havent seen anything to show that vitamin E supplements are any way toxic.
They also suggested that people should take gamma tocopherol supplements. I know that there are mixed vitamin E supplements on the market. What I know is that most Americans eat polyunsaturated margarines made from corn oil or soybean oils and these have roughly 6 to 10 times more gamma tocopherol than alpha tocopherol and I think that the gamma tocopherol intake is really quite high in the United States. Now that was before the demand for vitamin E increased so dramatically with all of the media reporting on the good effects of vitamin E. Now, I understand that vegetable oil manufacturers are more aggressively removing vitamin E from their oil to sell to the vitamin E manufacturers. I should go back to the lab and measure the current gamma-tocopherol contents of some oils.
I think, yes, there is potential significance to their claims; we dont know enough about the various forms of vitamin E and so these kinds of issues become controversial and make headlines.
One thing is for sure, that is that vitamin E supplements have the advantage of providing the 200 IU or so of vitamin E needed to produce the protection against heart disease as reported in the Harvard studies (NEJM 1993) without adding more than a hundred grams of fat and 1,000 calories. If you consider that vegetable oils at best might have 60 IU of alpha-tocopherol per 100 grams of fat, it would take at least 167 grams of fat having 1,500 calories to get 200 IU of vitamin E in the diet. This is why I advocate vitamin E supplements for people on low-fat diets they may be getting only five milligrams of alpha tocopherol per day.
Passwater: Another thing for sure is that we know vitamin E supplements do provide many important benefits and have been found safe and without adverse effects at daily intakes exceeding 2,000 IU.
Since smokers have lots of nitrates in their cigarette smoke, would gamma-tocopherol be of interest to smokers?
Traber: Its possible but I havent seen any data that anybody can find nitrated gamma tocopherol in smokers. The other interesting thing about gamma tocopherol is that there is a new metabolite that is called LLU-alpha (that was described by Dr. William Wechters group in a PNAS paper a year ago).  LLU-alpha is a hormone and it turns out to be gamma tocopherol with the tail mostly cut off and LLU alpha turns out to be a natriuretic factor, it causes increased sodium excretion. One possibility is that smokers could cause more nitration of their gamma tocopherol so less is available for making LLU alpha and so they have increased blood pressure and so have more heart disease because they have too high blood pressure.
All this is wild speculation, but it should let our readers know that there are all kinds of new and interesting facts about vitamin E that we still have to discover.
Passwater: It certainly should be investigated.
Heres another question that comes up frequently. Im sure that store personnel hear it more than once throughout the course of a year. Many consumers and possibly some in the industry as well -- are confused by the usage of "ol" such as in tocopherol and "yl" such as in tocopheryl. Both natural and synthetic vitamin E are available in ester forms, so the "ol" and "yl" designations have nothing to do with telling natural-source vitamin E from synthetic. Tocopherol or tocotrienol with an "ol" suffix -- designates the free "active" alcohol form of vitamin E. This is the form that is an active antioxidant and stored in the body. Tocopheryl with a "yl" suffix designates that it is an ester form.
Whenever the "yl" suffix is used, it is followed by another name to indicate the organic acid used to form the ester. The ester forms of vitamin E are protected from oxidation until the organic acid portions are cleaved in the digestive system.
Traber: The reason vitamin E supplements are sold as tocopheryl acetate or tocopheryl succinate or even sometimes tocopheryl nicotinate or tocopheryl linoleate is because the forms of vitamin E found in plants and stored in the body is an antioxidant and that means it will react with oxygen.
So if you had free tocopherol sitting on the store shelf before you know it you wouldnt have any more vitamin E there; it would be all oxidized away and you would be a very unhappy soul paying money for something that was garbage. Because they understand this, manufacturers make it into a form by reacting free vitamin E with naturally occurring organic acids such as acetic acid or succinic acid to form esters that are absolutely stable on the shelf. Yet, when you ingest tocopheryl esters, they readily hydrolyze to release the active antioxidant tocopherol form of vitamin E again and you get the full potency antioxidant absorbed.
The esters are formed by replacing the electron-donating, free-radical quenching hydroxyl group in the chromane head with the organic acid. Acetic acid is the organic acid that gives the sour taste and much of the aroma to vinegar. Succinic acid is a slightly large molecule than acetic acid that is produced in the citric acid cycle (Krebs cycle) that body uses to help convert food into energy. Tocopheryl acetate, an oil, is generally used for capsules and tocopheryl succinate, a solid, is generally used in tablets. The structures of alpha-tocopheryl acetate and alpha-tocopheryl succinate are shown in figure 15.
In rats, the esterified forms may be more bioavailable, but in humans, the "free" form and acetate ester are equally bioavailable.  Table 3 lists the "official" potencies for "free" tocopherol and various tocopheryl esters.
Passwater: I believe that these "official" relative potencies are based on pre-1967 studies using rat-fetal-resorption studies. In 1980, Dr. Max Horwitt re-examined the biological potencies of RRR-alpha-tocopheryl acetate and all-rac-alpha-tocopheryl acetate. He concluded that"the evaluations showed that all-rac-alpha-tocopheryl acetate may have no more than half the biological potency of RRR-alpha-tocopheryl acetate when used as a supplement for vitamin E-depleted adult subjects." 
Later, in 1984, Dr. Horwitt and colleagues again confirmed that rat-fetal-resorption assays underestimate the potency of free RRR-alpha-tocopherol and to RRR-alpha-tocopheryl acetate relative to all-rac-alpha-tocopheryl acetate.  By studying the increase in tocopherol content of the blood at different points in time after taking 800 IU of vitamin E supplements, under their experimental conditions, they found that the mean increase in alpha-tocopherols (mg/g lipid) in 24 hours was 71.2% after RRR-alpha-tocopherol, 60.9% after RRR-alpha-tocopheryl acetate, 41.2% after RRR-alpha-tocopheryl succinate, and only 31.6% after all-rac-alpha-acetate. Their experimental conditions were much better than those of a rat-fetal-resorption bioassay. They concluded that "animal assay data do not correlate with data from studies of absorption and retention in the blood of vitamin E ingested by humans."
However, these 1984 results are still quoted by many as evidence that tocopheryl acetate is better absorbed than tocopheryl succinate. Since this is a frequently asked question and you are involved in this type of study, let me ask you directly. Of the vitamin E esters, is there a meaningful difference between vitamin E acetate (tocopheryl acetate) and vitamin E succinate (tocopheryl succinate) in the human?
Traber: There is a nice study done by Dr. Burton and several of his colleagues in 1995.  They looked at the relative availability of free tocopherol compared to these various ester forms and they found that by using deuterated material they could compare the absorption and plasma transport of all three different kinds and what they found is basically the esters were as available as the free form so if people are looking for a nice form of vitamin E to take I dont think they have to buy the free tocopherol and I personally think they are better off buying the acetate or succinate because they are readily available yet they are stable on the shelf and you dont have to worry about being oxidized before you eat it.
Passwater: OK, so the 1995 Burton et al. study using deuterated tocopheryl esters which is a most-exacting, high-precision method -- shows no difference in absorption or bioavailability of the esters, and your research with the tocopherol-binding protein shows that only the free RRR-alpha-tocopherol is preferentially transported and stored in the body, there shouldnt be any difference in the performance of the esters. Yet, there are reports claiming superiority for the succinate ester. As an example, there is a published report claiming that the succinate ester is more effective against cancer. What is going on?
If the bioavailability of the acetate and succinate is the SAME based on IUs taken orally, and they are both cleaved at the same rate in the digestive tract, and then the free tocopherol is absorbed from both equally, and transported equally, how can the succinate ester be better? Are the studies merely cell culture or in vitro studies?
Traber: I am sure that if you eat it, it gets hydrolyzed and thats the end of that. In tissue culture it does something very different. Most of this work is done by Dr. Kimberly Kline and her colleagues. [19-24] Then there is research from Dr. K. Cheeseman's lab: [25,26] They show that the tocopheryl succinate gets taken up and is better hydrolyzed and delivered to the right part of the cell to prevent oxidation.
Then just when I think I understand what is going on. A report from Dr. Mark Fariss adds to the confusion.  This research by Dr. Mark Fariss demonstrates that tocopheryl succinyl ETHERS, which are non-hydrolyzable prevent cancerous growth! But it looks like his latest research in rats has to do with availability.  In this case, the succinate can make a micelle of sorts because its an amphipathic molecule, so maybe its better "absorbed" in rats eating a 5% fat chow diet.
Passwater: Researchers are often confused by animal studies using the various esters of vitamin E because many do not realize that there is an apparent difference in vitamin E absorption between rats and humans. One study by researchers at the University of Western Ontario gave diabetic rats large amounts of vitamin E esters in their diets and then compared the effectiveness as determined their ability to reduce leakage into the vitreous humor of the rats eyes. They found that alpha-tocopherol and alpha-tocopheryl succinate were effective, whereas, at least in this study with diabetic rats, alpha-tocopheryl acetate was not. 
Im sure that there will be more studies into just what is going on and how important or unimportant that may be. Now lets go back to the simpler stuff. What form is vitamin E found in food? Is it the unprotected "free" alcohol form or is it esterified or tied up in some way as to protect it?
Traber: Vitamin E in foods can be in any of the eight naturally occurring forms. I think it is in food as a natural antioxidant, so it is in the free form (tocopherol or tocotrienol with "ol" at the end) ready to be oxidized.
There are various published tables of vitamin E contents of foods. One nice description is by Dr. A. Sheppard et al.  Here you can see that virtually every food has a little vitamin E in it. However, most of the vitamin E in the American diet comes from fat-rich foods, like margarine, mayonnaise, shortening, salad dressings and peanut butter. Surprisingly, now a major source of vitamin E is potato chips because the vitamin E is sprayed on the chips to prevent them from going rancid.
Passwater: Thats ironic. In the 1970's, our industry made a big point of the fact that junk foods were full of artificial preservatives such as BHT and BHA and that this was not good. The message was well received by the public and sales of "foods" containing artificial preservatives and colors decreased. So the snack food industry went to natural preservatives such as vitamin E and vitamin C, and some health food retailers started selling bottles of BHT.
A second irony is that natural vegetable oils have to be refined and made clear and pretty for the American public to buy. In this refining process, several natural sterols and vitamin E are stripped out. The vitamin E is sold to those who make pills for those who dont get enough vitamin E in their diet because they eat refined foods.
Im sorry to interrupt, but these ironies have always puzzled me. You were making some points about vitamin E in foods.
Traber: I was making two important points. One is that virtually every food has some vitamin E, but the major sources are fat-rich foods. The second point is that if you decreases your intake of fat, you substantially decrease your intake of vitamin E.
Passwater: How reliable of a source of vitamin E is food? Does the vitamin E in food degrade rapidly after harvesting because of exposure of to light and the oxygen in air and/or lipid peroxides that form?
Traber: This is a hard question because its not easy to generalize. Certainly, oxidation could occur due to all of those factors, but most food handlers are in the business of providing wholesome food. If butter, meat or fish turn "rancid" the consumer wouldnt buy them. Rancidity is evidence of rampant lipid peroxidation. If you look at meat in the store, it is generally dark red, if it is very dark or even greenish, the consumer wouldnt buy it; the greenish color is evidence of oxidation.
I think there is concern about how much of the nutrient quality remains after processing, but I think for vitamin E this is less of a problem because in foods, like in tissues, the water-soluble antioxidants protect it. Canning and freezing, as well as cooking, especially frying and roasting can destroy vitamin E. Dr. Jack Bauernfiend published some information on this in 1980 (see Table 5). 
Table 5. Storage and Processing losses of tocopherols.
% tocopherol loss
Peanut oil Frying at 347EF, 30 min.
Safflower oil Stored at room temperature (68EF), 3 months
Tortillas Stored at room temperature (68EF), 3 months
Chicken, Beef Canning process
Ground corn Storage at room temperature (68EF), 6 months
Wheat germ Storage at 39EF for 6 months
Passwater: Lets discuss the use of vitamin E as an antioxidant to protect oils from turning rancid (oxidizing) during storage in containers or pills. Sometimes people erroneously use vitamin E acetate (d-alpha-tocopheryl acetate) to oils thinking that they are adding an antioxidant to protect the oil. The acetate ester of vitamin E is not an antioxidant until the acetate portion is cleaved off in the digestive tract.
Traber: I think that is an important point. A lot of cosmetic products that are sold as "containing vitamin E" use tocopheryl acetate. From scant published scientific literature on the subject, hydrolases (hydrolytic enzymes) in the skin seem to be able to convert a small percentage, perhaps five percent or so, of tocopheryl acetate absorbed into the skin free tocopherol. Reports differ. Some suggest that this may increase the antioxidant protection in the skin and may be adequate for sunburn treatment, but I prefer that the vitamin E that I put on my skin already be in the tocopherol form. If someone intends to use vitamin E topically for improving wound healing or to help a burn heal faster, they may also wish to use lotions or capsules containing "free" non-esterified tocopherols. They are available. You just have to look a little harder. I think the topical use of free tocopherol is the only real reason I would purchase the free tocopherol.
Passwater: The digestive system is very efficient at converting tocopheryl acetates to free tocopherol, whereas skin doesnt cleave the organic acid portion off anywhere near as well. Also, you can promote healing and reduce scarring with vitamin E by puncturing a capsule and squeezing the contents onto the area of skin you wish to treat but the tocopherol form works much, much better than the tocopheryl form for this application. Cosmetic chemists seem to choose the tocopheryl esters because they provide some vitamin E activity while being more stable and having a longer period of potency. However, other antioxidants could be used to protect the more potent free tocopherol to give a more effective and stable formula. One of the problems in converting tocopheryl acetate to tocopherol by hydrolysis directly in the skin is that it produces skin irritation in as much as ten percent of those using it topically.
Now I want to go back to a point made earlier in this part. You mentioned that many, if not most, manufacturers dilute the vitamin E with a little oil to reduce the viscosity so as to make it easier to fill the capsules. The manufacturers of vitamin E do not sell 100 percent pure vitamin E. Depending on the blend selected, the product is very concentrated in terms of vitamin E potency. By the way, there is no such thing as a "first distillation" or any other distillation. Some marketers have occasionally made such claims to imply that they have a better form of vitamin E. In order to facilitate filling and to adjust to capsule volume, encapsulators may add soy or vegetable oil, typically at 10 percent of the volume. In a 400 IU capsule of natural vitamin E, this would be about 295 milligrams of RRR-alpha-tocopheryl acetate plus about 30 milligrams of oil. Manufacturers use fresh oils, but even if as much as a percent or two were rancid, this would be about one-quarter to one-half of a milligram of oxidized oil, far less than the amount in one potato chip. The product is sealed in an amber capsule to protect it from oxidation as well. If alpha-tocopherol capsules are stored in a cool, dark place (especially in amber or dark bottles), they will lose very little potency for up to three years, and alpha-tocopheryl acetate capsules for five years or more.
Dr. Traber, there is something else I wanted to ask you about: is vitamin E ever a pro-oxidant?
Traber: As long as you have water-soluble antioxidants around it is going to be an antioxidant. Its only in the test tube where you can get rid of all the water-soluble antioxidants that you can show vitamin E can be a pro-oxidant.
This of leaves you with an interesting observation however, our readers should know that vitamin E is generally regarded as non-toxic. You have to look long and hard to even find some little case report where anybody has a problem with vitamin E.
Passwater: This explains the antioxidant synergism that I discovered in vitro in 1963 and in-vivo in 1967. I was using a matrix of gelatin with lipids as substrate and UV-photons generated by a xenon lamp and diffracted with a grating to initiate lipid peroxidation. I then quenched the source of photons and allowed the free radicals to propagate in darkness. I measured the degree of propagation and lifetime of propagation by sampling the amount of cross-linking occurring in the gelatin over time. When I observed the same antioxidant synergism in laboratory animals, I applied for my patents on antioxidant synergism in 1970 and 1972. 
Well so much for the basics. In Part III well discuss Dr. Trabers exciting research with the tocopherol transfer protein and what it means for us.
© 1997 Reprinted by permission of the copyright owner Whole Foods magazine, Whole Foods Inc.