More Than Just Beta-Carotene:
by Richard A. Passwater, Ph.D.
Dr. James P. Clark is the Director of Technology at Henkel Corporation and Lance Schlipalius is the Technical Manager at Betatene Limited of Australia.
Dr. Clark received his Ph.D. degree from the University of Colorado in Physical Chemistry in 1967. He has spent his entire professional career investigating vitamin E and phytosterols for General Mills Chemicals and Henkel Corporation. He became interested in beta-carotene about three years ago.
Mr. Schlipalius received his Science degree from Melbourne University in 1968 where he majored in Microbiology and Nutrition. In 1973, he received his Food, Science and Technology degree from the Royal Melbourne Institute of Technology.
It is interesting to see that the time has come when cereals and mass-market children's vitamins advertise that they contain beta-carotene. Although the health food industry introduced beta-carotene to the public many years ago, I can still remember asking the audience attending my lecture in 1983, "How many of you are familiar with beta-carotene?" In an audience of several hundred people, only four or five hands went up. That prompted me to write the booklet, "Beta-carotene" which was published in 1984.
Recently, the New York academy of Sciences conducted a conference entitled, "Carotenoids in Human Health," to review the progress of our rapidly expanding understanding of the roles of beta-carotene and other carotenoids in health. The major sponsor of the conference was provided by the Henkel Corporation. During the conference, I had the opportunity to chat with Dr. Clark and Lance Schlipalius.
Originally, we were interested in beta-carotene, just one of the more than 600 members of the carotenoid family, because we were interested in vitamin A. Then we became interested in beta-carotene because it has it's own actions in preventing cancer. Beta-carotene is a stronger antioxidant than vitamin A and it also can quench the radical producer, singlet oxygen, which vitamin A does not do.
We have been interested in beta-carotene because it:
Now we are interested in many members of the carotenoid family because they may have cancer preventing and additional properties.
Passwater: Dr. Clark, what new research was presented at this conference?
Clark: New research was presented in many different areas. Research has a tendency to grow by leaps and bounds. There is a leap forward and then there is a filling in of the gap. Much of the information presented here was supportive to the fact that beta-carotene reduces the risk of heart disease. There was also evidence presented showing the protective effect of beta carotene in people who are photosensitive, i. e. have skin problems that are caused by even brief exposure to sunlight. However, the most exciting research presented here was evidence of a special carotenoid, halocynthiaxanthin, that protects against the AIDS virus by preventing replication of the virus. There is a suggestion that the carotenoids may inhibit tumor development via gap junction communication and not by anti-radical action alone.
In addition there was evidence presented that beta-carotene can enhance the immune system and improve our body's ability to protect us against disease and foreign invaders.
Passwater: OK, you mentioned another carotenoid. Let's back up and start at the beginning. The carotenoids are a family of colored, fat-soluble chemical compounds with limited solubility in water that have similar chemical and physical properties, but somewhat different biological properties. Their chemical structures having 40 carbon atomes including a "backbone" chain of 9 conjugated double bonds flanked by 6-carbon member ring structures or near-ring structures on each end, with ten single-carbon side chains or substitutions. However, these subtle differences in molecular structures translate into important differences in electronic configurations and the dynamics of intramolecular processes.
The carotenoid family consists of smaller families of pigments called carotenes and xanthophylls. Carotenes are hydrocarbons (contain only carbon and hydrogen atoms), whereas, xanthophylls also contain atoms of oxygen.
Clark: Carotenoids are characterized by having a long "backbone" of conjugated double bonds. This chemical structure makes them very highly colored because the double bonds absorb parts of the light spectrum. The yellow, orange, and many red pigments in plants are usually carotenoids. These pigments are made by plants, and can accumulate -- or be modified -- in some animals to produce their protective coloration and sexual attraction.
Our diet contains hundreds of carotenoids. Nineteen different carotenoids have been identified in human blood so far. The carotenoids that are of most interest currently are beta-carotene, of course, alpha-carotene, gamma-carotene, canthaxanthin, lycopene, lutein, and zeaxanthin.
Beta-carotene is the most well known and studied member of the carotenoids. Carotenoids are synthesized by plants, and as a result they have been in the human diet for as long as we have been on earth, however, the roles of carotenoids in nutrition are just now being investigated. Beta-carotene has been recognized as a source of vitamin A for several decades. But, only recently, have scientists started investigating the functions of beta-carotene itself.
So far, the hydrocarbon carotenoids -- the carotenes -- have been studied more than the other carotenoids. The carotenes are commonly found in carrots, algae, orange fruits and green vegetables. The carotenoids that have been most often studied include lycopene, lutein, zeaxanthin and canthaxanthin. Lycopene (lie-co-pene) can be found in tomatoes, watermelon, and many plant oils. Lutein (lew-te-en or lew-teen) is found in many leafy green vegetables, alfalfa, and egg yolks. Zeaxanthin (sea-zan-thin) can be found in corn. Canthaxanthin (can-tha-zan-thin) can be found in some seafood and fungi. Capsanthin gives the bright red color to paprika.
Beta-carotene, and to a lesser extent, alpha-carotene, are precursors of vitamin A. Although the others are not converted into vitamin A in our bodies, they are antioxidants, antiradicals, and singlet oxygen quenchers, and may participate in gap junction communication.
Passwater: Gap junction communication may be a new concept to many of our readers. Some scientists believe that carotenoids achieve their cancer protection by improving the chem,ical communication between cells which helps cells that are being transformed into cancer cells, revert back to normal.
I mentioned that more than 600 members of the carotenoid family have been characterized, and you point out that perhaps only a relatively few will turn out to be biochemically significant to humans. But, aren't there important differences in the function of the isomers of each carotenoid?
Clark: Each carotenoid can have many isomers. An isomer is a molecule that has the same number of identical atoms as another molecule but arranges these same atoms differently to produce a different molecular shape.
The molecular shape is very important because the body chemistry is facilitated by enzymes that function as biological catalysts. Enzymes recognize their substrates (the compounds they act upon) by their shape to a large extent as well as their chemical functionality and their electrical polarity (charge distribution). The net result is that a molecule can have the same number of identical atoms as another one -- but have a different shape -- and can have an entirely different response or function in the body.
The molecular shape is important because enzymes and their substrates -- the molecules that they act upon -- must fit together like a key in a lock. Note the differences in the shape of some of the cis isomers and the all trans isomer of beta-carotene shown in figure 1.
Passwater: Then if someone is taking a supplement of beta-carotene, they may be taking one single compound -- a specific isomer -- or they may be taking a mixture of compounds -- various isomers of beta-carotene. You mentioned that the body recognizes these isomers differently. How can we be sure that when we take a beta-carotene supplement, that we are taking the form of beta-carotene that our body uses best?
Clark: The safest way to be sure of that is to take beta-carotene from natural sources. The beta-carotene that is produced synthetically is a single isomer -- a very straight molecule called "all-trans" beta-carotene. Beta-carotene that is found in nature frequently consists of both the straight "all-trans" molecule and a variety of bent molecules that contain what are called "cis" double bonds. Since these molecules are found in nature and are part of our normal diet, it certainly seems prudent to include them in a supplement.
Passwater: So, we have gone from simply vitamin A to beta-carotene and vitamin A, and now it is not only alpha-, beta- and gamma- carotenes and other carotenoids, but various cis- and trans- isomers of each one of them. Things are getting a little complex. Have we been guilty of over-simplification or tunnel vision looking at beta-carotene only?
Clark: Probably. Scientists have focused on beta-carotene for a couple of different reasons. It is the easiest to manufacture, so it is an item of commerce, and secondly, it is the most potent precursor vitamin A. If you are using beta-carotene strictly as a source of vitamin A, then beta-carotene is the carotenoid of choice because one molecule of beta-carotene produces two molecules of vitamin A in your body.
But, there are other functions which are just being uncovered, where other carotenoids, including other isomers of beta-carotene, also contribute.
Passwater: Please elaborate -- what are some of these other functions and which carotenoids are involved?
Clark: Science is really just starting to answer those questions. However, alpha-carotene may turn out to be just as important to our long term health.
Other carotenoids may be the more efficient in singlet oxygen quenching. Lycopene may be the most efficient of all of the common dietary carotenoids in quenching singlet oxygen, and capsanthin, a less common dietary carotenoid, may be almost as efficient at singlet oxygen quenching as lycopene. Singlet oxygen can be harmful because it leads to depletion of the carotenoids and to the formation of significant amounts of harmful oxidation products which can mutate DNA and damage cell membranes.
Canthaxanthin, which is not a precursor of vitamin A, has been demonstrated in cell culture studies to inhibit tumor growth, so it may have a protective role against cancer. It may be that each carotenoid has a different efficiency in protecting against cancer depending upon the particular mechanism of carcinogenesis involved.
Remember that these are all early scientific investigations. But what is clear is that these carotenoids are part of our diet and they are components of human blood and tissues.
Passwater: In other words, we should trust nature more than we trust our evolving and limited understanding of how nature works. These complexes in foods are varied and may have varied uses. To me, it seems very likely that natural food concentrates, such as D. salina, which have several naturally occuring carotenoids,may well have synergistic effects beneficial to humans as well as the plants that they protect. It seem important that we get adequate amounts of various carotenoids and avoid concentrating on any one carotenoid as that may inhibit the absorption of others.
Mr. Schlipalius, do we have any evidence that some carotene isomers are transported by the blood preferentially over others, or are stored in tissues preferentially? Do we see any differences that might give us a clue?
Schlipalius: There is some diversity of transport through the body and into the tissues, but it is still very early in these studies to try to understand what they mean and how important transport is.
Passwater: We may not know why at this time, but we do know that cis-beta-carotene is transported preferentially in the blood and that cis-beta-carotene is preferentially stored in the tissues. Doesn't this imply that the body notices a difference between the various isomers?
Schlipalius: The blood is only a transport mechanism and is not where the real action happens. We don't know why there is a difference in carotene transport, but there is. There are relatively few carotenoids -- about 15 or so -- that are actively transported in the blood in detectable quantities.
Most of the human studies, however, are performed on blood samples because it's easier to sample. People don't like to have you sample their livers, hearts or tissues taken just for analysis. This is understandable.
Passwater: How about carotenoid receptors? Dr. Clark, do the various carotenes and other carotenoids have specific receptors in cellular membranes to take up the carotenoids from the blood and bring them into the cells?
Clark: That is something we don't really have a good answer to yet. It's clear that vitamin A -- the retinoids -- do have proteins that carry them and act as receptors Dietary carotenoids and their transport and deposition in tissues are just at our frontiers of understanding in biochemistry.
Passwater: If we take pure beta-carotene as a supplement, can that hinder the absorption of other carotenoids?
Clark: It might as was described by Dr. John Erdman here at this conference. Beta-carotene reduced the absorption of canthaxanthin, one of the other important natural carotenoids. There have also been reports that trans beta-carotene may reduce the absorption of lycopene. This is another area that scientists are just beginning to investigate and understand.
Passwater: Again, that seems to be justification for taking mixed carotenoids from natural food concentrates. Does beta-carotene reduce the absorption, transport or storage of vitamin E?
Clark: There is one report in the literature that suggests that beta-carotene can reduce the vitamin E concentration in blood, but there are many more and very substantial studies that show it doesn't. My opinion is that beta-carotene ingestion does not reduce the absorption of vitamin E, and that was more or less the consensus of this meeting.
Passwater: We place great emphasis on reducing dietary fats. Carotenoids are fat-soluble compounds that need fats to help in their absorption process. How do we ensure that our effort to lower dietary fat will not decrease our carotenoid absorption?
Clark: As long as you replace the fat with foods such as fruits and vegetables, you make up for the decreased efficiency of absorption due to less fat being present to carry the carotenoids into the bloodstream by increasing the amount of carotenoids available for absorption. Even though the carotenoids in vegetables and fruits are difficult to extract from their fiber matrix, by choosing carotenoid-rich foods, you will come out ahead.
Carotenoid supplements are readily assimilated. What is important is if you take a carotenoid supplement, is that you take it with your highest fat-content meal of the day to optimize absorption. That is true of vitamin E and vitamin A also.
Passwater: Do tissue levels of carotenoids build up rapidly? For example, if you needed to build up the carotenoid levels in your skin to help protect against sun-induced damage, you couldn't simply take extra beta-carotene in the morning and have it help protect your skin appreciably that day.
Clark: The carotenoids are stored in the fatty tissues in various organs. Any increased build-up will normally take 2-4 weeks of added carotenoids in the diet to increase significantly in the fat beneath the skin.
Schlipalius: Yes, the carotenoids tend to accumulate where the fat is, in particular in the liver, and to some extent, the kidneys, in the genital organs, and also in the skin. The carotenoids find their way to the extremities of the body through the circulatory system, but since there are considerable amounts of many fatty tissues, a slow build-up occurs in any area.
Passwater: How about building up beta-carotene in low-density lipoprotein?
Clark: It will occur in the LDL faster than in the skin, because the LDL transports the carotenoids through the circulatory system. Since LDL are the transporting mechanism, they will become enriched in carotenoids faster. But, it still will take a couple of weeks to fully optimize the carotenoid levels in your LDL -- depending of course, on how depleted they are to begin with.
Passwater: Let's go back to the skin. It is widely known that excess carotene can build up in the fatty tissue beneath the skin and in caucasians, appears to give the skin a yellowish-orange tone. Is this a sign of toxicity, a benefit or what? Clark: To start with, there is no indication that there is a toxic effect at all. People might worry that it appears that a person is jaundiced. However, the yellowing due to carotene accumulation never occurs in the whites of the eyes, unlike jaundice caused by disease, which does occur in the whites of the eyes. The skin coloring is considered a nuisance by some, while others like it. In any event, it can be controlled by the amount you take in your diet.
There is some indication that the added carotene stored in the skin may have additional protective effect, but that is not well substantiated. I see no need to over do the intake, even though it is not toxic. There is a sensible limit to everything.
Passwater: Speaking of toxicity -- or the lack thereof -- and speaking about the benefits of carotene, I believe that today, most people are taking beta-carotene simply because it is a non-toxic source of vitamin A. So the major question for most people is still, is beta-carotene really a non-toxic way to get all of the vitamin A that they need?
Clark: Yes. beta-carotene is very safe. That is one of the reasons that beta-carotene is being used in large-scale human trials to reduce the risks of cancer and atherosclerosis. It is so safe that there is no risk in dispensing beta-carotene without prescription.
Passwater: Let's expand on that. It is well-known that high doses of vitamin A can be toxic. Since beta-carotene can be converted into vitamin A, are high doses of beta-carotene dangerous?
Clark: You are certainly correct about the toxicity of vitamin A. High doses will cause a variety of toxic effects, even resulting in death at very high levels. Many health authorities recommend a maximum daily intake of no more than 10,000 International Units, and only 6,000 IU per day for pregnant women. By comparison, beta-carotene doses of more than 180 milligrams per day (equivalent to about 300,000 IU of vitamin A) have been consumed for several years with no apparent adverse effect.
Passwater: That's remarkable, especially considering that one molecule of beta-carotene can be split into two molecules of vitamin A. Can you explain why beta-carotene is not toxic at these levels?
Clark: The answer is simple, although the biochemical mechanism is not absolutely clear. The body doesn't convert excess beta-carotene into vitamin A. When we are deficient in vitamin A, the intestine converts more beta-carotene into vitamin A as it is being absorbed. Excess beta-carotene is either not absorbed or is stored in various body tissues. The liver only converts a limited amount of beta-carotene into vitamin A as needed, so vitamin A never reaches toxic levels.
As for beta-carotene itself, although it is structurally very similar to vitamin A -- essentially being two vitamin A molecules joined together -- it is not concentrated in the liver. The liver packages the carotenoids into VLDL, LDL and HDL particles and ships them out to other tissues. Beta-carotene is stored in a variety of tissues. The liver, adrenals, and testes are particularly high in beta-carotene, but kidney, ovaries and adipose (fat) tissue also contain significant concentrations. By comparison, the liver contains about 95 percent of the body's total supply of vitamin A.
Passwater: At the conference, Dr. Hans Biesalski of the University of Mainz reported that beta-carotene supplementation would not satisfy the vitamin A needs of animals depleted in vitamin A. Evidently, beta-carotene supplements repleted the amount of vitamin A stored in the livers of vitamin A deficient rats, but failed to restore desired vitamin A levels in the tissues. Will beta-carotene supply all of a person's needs for vitamin A, or should people get both vitamin A and beta-carotene in their daily diets?
Clark: We can't really answer that question yet. There are at least a couple of studies with small laboratory animals -- rats -- that suggest some vitamin A is necessary in their diet because they cannot obtain all of their vitamin A requirements from beta-carotene. This may also be true for humans, but that hasn't been proven yet. If it is proven for humans, then strict vegetarians should consider taking a low-potency vitamin A supplement because preformed vitamin A is found only in foods of animal origin.
My own personal feeling is that you should not rely solely on carotenoids for your entire vitamin A requirement.
Passwater: With so many clinical studies underway at various "dosages" of beta-carotene, please help our readers transpose back and forth between "mg," "RE," and "IU."
Clark: Vitamin A activity was originally measured in International Units (IU), where 1 IU of vitamin A activity was defined as 0.3 micrograms of all-trans retinol or 0.6 micrograms of all-trans-beta-carotene. Today, vitamin A activity is normally expressed as retinol equivalents (RE), where 1 RE is defined as 1 microgram of all-trans retinol or 6 micrograms of all-trans-beta-carotene (other provitamin A carotenoids require 12 micrograms to equal one RE of vitamin A activity.)
Consequently, one milligram of beta-carotene has a vitamin A activity equivalent to 1,667 IU or 167 RE.
Passwater: Most people are confused by the use of both an "RDA" and an "USRDA." The RDA is the recommended dietary allowance for a nutrient that is established by a scientific body for the purpose of evaluating diets. The USRDA is established by the Food and Drug Administration as a consumer convenience for labeling purposes to simplify the many categories of age and sex used in the RDA tables. When it comes to vitamin A and the carotenoids, there is even more confusion because one is using "RE" and the other is still using "IU." What are the RDA and USRDA for vitamin A and beta-carotene?
Clark: The current RDA (established by the National Research Council) for vitamin A is 1,000 RE for men and 800 RE for women. The current USRDA (established by the US Food and Drug Administration) for vitamin A is 5,000 IU per day. Beta-carotene does not yet have an RDA or USRDA, but has the following vitamin A equilalencies:
Passwater: One of the most interesting presentations at the symposium told of using carotenoids from algae to protect LDL from oxidation in a vitamin E deficient patient. Why is algae an important source for beta-carotene for supplements?
Schlipalius: There is one particular alga, Dunaliella salina, that produces by far, the highest concentration of beta-carotene of all plants -- producing some 10 to 100 times that of the next well-known source which is carrots. But, it's harder to remove the beta-carotene from carrots. The beta-carotene and carrot fiber are difficult to separate. This happens in the human body as only 20 to 25 percent of the beta-carotene is absorbed from the carrots in the diet due to the fiber. It also applies to the production of supplements. Poor separation means increased costs and that you can't produce convenient concentrations unless petrochemical solvents are used.
The concentration factor from D. salina means that beta-carotene supplements can be provided to the customer at lower prices. Thus, D. salina can be grown economically for beta-carotene supplements. Carrots are good for eating as a vegetable.
Passwater: How convenient for us to have D. salina as a carotenoid source. Why is D. salina so kind as to help us?
Schlipalius: All algae produce small amounts of beta-carotene to protect themselves during photosynthesis. Photosynthesis is the process plants use to convert sunlight and carbon dioxide into energy and carbohydrate, using chlorophyll, the green pigment in plants. D. salina grows in environments where the sunlight is very strong, the temperature is very high and the water is very salty. Those three factors greatly increase the amount of beta-carotene that the plant needs to protect itself from singlet oxygen, oxygen radicals and the strong light. D. salina owes its existence to its high beta-carotene content. It is a very rare thing indeed for a plant to survive all three extremes -- high sunlight, high temperature and high-salinity. Like most good foods, what is good for the plant is good for us.
Passwater: Not everybody realizes that algae are edible plants.
Schlipalius: Algae in fact are a basic source of food. If we go back a few steps in our food chain, they are our food supply. Algae are food for fish, big fish eat little fish, thus algae effectively end up on our tables in the form of fish. Some parts of the world as well, notably Japan and China, eat algae directly as seaweed which are just large algae.
Algae are simply plant cells only a little different from the cells in the vegetables grown in your garden. Botanists classify them as a group because they are microscopic single-cell plants. They undergo photosynthesis, take in sunlight, carbon dioxide and trace minerals and they produce all the essentials they need for their own sustenance, proteins,carbohydrates and beta-carotene. Humans can then utilize the algae components as food.
Passwater: Perhaps as the "green revolution" continues, more and more people will try to eat down the food chain a little bit and algae may not seem so strange to them. But, D. salina is a good source of carotenes, and other algae have major supplement uses.
Schlipalius: Yes, there is little real algae in the standard American diet, but there are algae that are consumed as other dietary supplements. There's Spirulina -- which is also a microscopic alga and which has some relationship to D. salina.
Passwater: Doesn't D. salina provide more of the carotenoid family members than the carrot?
Schlipalius: Yes, D. salina has a broader spectrum of carotenoids than the carrot. Carrots, in effect, only have two carotenoids of note; all-trans beta-carotene and alpha-carotene. Earlier, Dr. Clark mentioned that natural carotenes contain mixtures of all-trans beta-carotenes and cis-carotenes. The ratio in the carrot is about 95 percent trans to 5 percent cis, whereas the ratio in D. salina is about 50:50. The percentage of alpha-carotene in carrot carotenoids is about 30%, whereas D. salina carotenoids has about 6 - 10 % alpha-carotene.
D. salina has a combination of a number of cis-beta-carotene isomers, all-trans-beta-carotene, and 6 -10 % alpha-carotene. There are also small amounts of oxygenated carotenoids such as lutein and zeaxanthin to approximately 10% of the total carotenoid content.
Passwater: I try to remind everyone about the advantages of eating varied whole foods whenever possible, and I point out that in the early days of producing supplements, those who choose to take food concentrates such as brewers yeast and wheat germ oil were better off than those who took only the few purified vitamins that were identified at that time. If you took brewer's yeast vitamin B tablets, you also were unknowingly taking the undiscovered B-vitamins. If you were taking only a purified vitamin B-1, then that was the only B-vitamin that you were taking.
Nature still knows much, much more than we do, and it seems that we should try to get as many of the different nutrients that nature gives us as we can. Isn't this a case where we should trust nature and look beyond beta-carotene?
Schlipalius: When you don't know all of the answers, it's better to have a broad spectrum approach.
Passwater: Gentlemen, where do you see carotenoid research going from here?
Clark: I see it focusing much greater in the future on investigating the role of carotenoids as carotenoids. In the past, it's focused primarily on carotenoids as a source of vitamin A. Now researchers are truly trying to understand how carotenoids are absorbed, transported in the body and the function that each play at the biochemistry level. At the nutritional level, we will continue to look at the clinical features where carotenoids protect against diseases. There are large trials underway now to study the role of beta-carotene in preventing atherosclerosis and cancer, I think these trials will be expanded in terms of numbers of persons included in the studies, the numbers of different studies, the diseases included in the studies, and the carotenoids used.
Schlipalius: I think we are going to see new research in two areas; firstly, understanding how carotenoids work -- as carotenoids themselves and not as vitamin A. The other area is in the medical segment. The findings that carotenoids can prevent diseases which previously were thought to be due to other factors are very exciting. The latest example of which is the relationship between the deficiency of beta-carotene in the eye lens and the development of cataracts. Similar possibilities may be better immune protection and the alleviation of arthritis.
Passwater: Gentlemen, thank you for sharing your knowledge and experience with us.
All rights, including electronic and print media, to this article are copyrighted to Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.)