Whole Foods magazine

November 1999

Antioxidant Cocktail Update: Part 2 Lesser known antioxidant are very important. An Interview with Dr. Lester Packer

By Richard A. Passwater, Ph.D.


We are continuing our chat with Dr. Lester Packer who is updating us on his antioxidant research. As we discussed in Part 1, Dr. Packer's book, The Antioxidant Miracle, which is written for general readers, offered recommendations about a daily "antioxidant cocktail" that could improve the health of everyone who tried it. In this session, we will focus more on some of the lesser known antioxidants and why they are so important to your health.

Dr. Packer is a professor in the Department of Molecular and Cell Biology at the University of California at Berkeley: He received a Ph.D. in microbiology and biochemistry from Yale University in 1956. At Berkeley, he has been professor of physiology since 1961 as well as director of the Membrane Bioenergetics Group and a senior scientist at the Lawrence Berkeley Laboratory since 1972. His research, in the area of biological oxidation and bioenergetics, has emphasized studies on the role of oxidants and antioxidants in biological systems.

Dr. Packer is one of the world's leading researchers on vitamin E and other biological antioxidants. His recent work has elucidated new areas in the biochemistry of vitamin E, the vitamin E cycle and the antioxidant network This is relevant to the understanding of new enzymic reactions of vitamin E, the vitamin E radical, and the biological consequences of the action of vitamin E. Recent work concerns the prevention of oxidatively induced injury in biological systems by antioxidants and how vitamins E, C, and lipoic acid affect other antioxidants-particularly bioflavonoids--through the antioxidant network, gene expression and cell regulation. These investigations are helping to develop a new, broader understanding of biological antioxidant defense mechanisms.

Dr. Packer has published over 700 articles and written or edited more than 70 books on every aspect of antioxidants and health, including the standard references Vitamin E in Health and Disease, Vitamin C in Health and Disease, 711e Handbook of Natural Antioxidants and Understanding the Process of Aging: 771e Roles of Mitochondria, Free Radicals, and Antioxidants

Dr. Packer is a member of eight professional societies and six editorial boards of scientific journals, and has organized numerous conferences in the area of his research interests. He is the executive editor of Archives of Biochemistry and Biophysics, and serves on the editorial advisory boards of Free Radical Biology and Medicine, The Journal of Applied Nutrition, and The Journal of Optimal Nutrition. He is a member of eight professional societies and is president of the International Society for Free Radical Research, and vice president of UNESCO's Global Network of Molecular and Cell Biology. Currently, he is president of The Oxygen Club of California (OCC), immediate past president and chair, International Committee of the International Society for Free

Radical Research (ISFRR), and vice president of UNESCO's Global Network on Molecular and Cell Biology (UNESCOMCBN)

Passwater: We left off with a description of -Me Packer Plan" in which you offered your best educated guess about what antioxidants to take to prevent and/or combat various diseases. A key component of your basic Antioxidant Cocktail is lipoic acid. Let's chat for a moment about the importance of lipoic acid and Pycnogenol and how they increase the body's glutathione production. Glutathione has been called the "master antioxidant" by researchers such as our friend, the late Dr. Al Meister.

Packer: lipoic acid, which is essential to healthful functioning and is, in fact, made in the body in trace amounts, is a substance that is a co-factor of enzymes.

In the early 1950s, lipoic acid was thought to be a vitamin, but now we realize that small amounts are made by the body. The lipoic acid formed in the body usually is bound to enzymes in the mitochondria that are involved in energy metabolism. If extra lipoic acid is supplied exogenously as a nutritional supplement, however, the additional lipoic acid can be reduced by body enzymes and can be a very potent antioxidant

Not only will lipoic acid share its reducing power with all the other key components of the antioxidant network, it also will increase the net amount of glutathione that is in tissues. We actually have carried out experiments that demonstrate the mechanism whereby lipoic acid is able to do this and it is a very interesting story.

The body needs the sulfur-containing amino acids, cystine and cysteine. Cystine and cysteine are not dietary essentials as the body can make them out of methionine. Cystine is essentially two molecules of cysteine joined together, minus a couple of hydrogen atoms where the molecules have been joined.

Passwater: Figure 1 shows that two molecules of cysteine each can lose a hydrogen atom and link their sulfur atoms together to form cystine. With the help of the enzyme cystine reductase, the linked sulfur atoms can be separated and a hydrogen atom added to each to form two molecules of cysteine. The important point is that the ease of joining the sulfur atoms together and breaking them apart again allows these compounds to cycle between each form.

Packer: This loss of hydrogen is termed an oxidation reaction. When conditions favor adding the hydrogen back and breaking the molecule apart, a molecule of cystine reverts to two molecules of cysteine. Thus, the oxidation of cysteine yields cystine and the reduction of cystine yields cysteine. The body cycles the two forms back and forth as the oxidation - reduction status changes. The enzyme cystine reductase aids in the reduction of cystine to cysteine.

Passwater: Cysteine is one of the three amino acids that is incorporated into glutathione when it is produced in the body. But, cysteine by itself is not the most effective means to markedly increase cellular glutathione levels. This is for two reasons. First, there is a limit to one's tolerance of cysteine, and second, cysteine is quickly changed into the larger molecule cystine.

Cysteine is thought to be the rate-limiting amino acid for glutathione production in the body. In order for cysteine to be readily taken up by cells, it has to be as cysteine in its reduced form, which is the smaller of the two molecules, but usually it is the larger oxidized form, cystine, that is found in the body. The rate at which cystine is taken up by cells is very slow, much slower than cysteine. And, it is the cysteine form that is incorporated into the glutathione molecule.

Packer: Lipoic fits into the story here. Lipoic acid comes into cells and is reduced to dihydrolipoic acid. The reduced form, dihydrolipoic acid, is readily exported outside the cell, where it can reduce cystine to cysteine. This is important because cysteine is taken up by an amino acid transport system 10 times faster than the system that works for cystine In this way, the limited supply of the rate-limiting amino acid for glutathione synthesis is overcome. This is the major way in which lipoic acid increases the tissue content of glutathione.

N-acetyl-cysteine (NAC), which itself is a good antioxidant, often is used with the intention of increasing glutathione levels in the cell. NAC works differently. IL basically is a precursor of cysteine that has to be de-acelylated in the liver, and then it can supply greater amounts of cysteine for glutathione synthesis. So the two nutrients are interesting in terms of the different ways in which they work. They both can increase glutathione levels, but NAC is not nearly as effective as lipoic acid in doing this. One has to take much higher doses of NAC to achieve the same result in terms of increasing glutathione levels. In addition, NAC does not offer all of the other benefits of lipoic acid.

People can increase their glutathione levels best by eating a diet rich in the amino acid precursors of glutathione and then taking 100 mg of lipoic acid as a supplement.

Passwater: This brings up the point that glutathione itself is not absorbed intact very well. As I frequently have discussed in this column, the old research indicating that glutathione was absorbed intact turned out to be an experimental artifact. Taking glutathione supplements does not directly increase blood levels of glutathione to any appreciable extent. But when dietary glutathione is broken down in the digestive system, some of the component compounds are absorbed and the body can put some of these precursors back together as glutathione. This is an inefficient process, however, and is much more costly than eating a diet containing adequate protein and sulfur compounds.

But you also have said that Pycnogenol results in increased cellular glutathione levels.

Packer: Yes, indeed. Pycnogenol does increase cellular glutathione levels, but it is not as effective for this purpose as lipoic acid. Keep in mind, however, that Pycnogenol is the strongest antioxidant nutrient that we have measured in our laboratory, and it has many other health benefits as well.

Pycnogenol increases cellular glutathione, but it does this not by overcoming the tale limitation. The increased glutathione levels have been measured, but since Pycnogenol is a mixture of about 40 different antioxidants, it's difficult to determine the precise mechanism(s) involved. As you know, Pycnogenol increases the levels of vitamin C and vitamin I? as well, and this is duo in part, at least, to its sparing effect of other antioxidants. One reason drat Pycnogenol increases cellular glutathione levels is that it is such a powerful antioxidant that it effectively destroys free radicals that otherwise would consume glutathione.

Another remarkable experiment that we performed was a model of a cerebral ischemia In this case, we cut off the blood flow to the brain by restricting the flow of blood through the carotid arteries for a period for 30 minutes, and then the blood flow was restored. Normally, in the following 24 hours, 80% of the animals would die if given this kind of cerebral ischemia. However, if lipoic acid had been injected into the animals just before the carotid artery occlusion was released, only 25% of the animals died.

We then looked at three different brain regions. In all of these brain regions, if lipoic acid had not been administered, the glutathione levels fell to very low levels. Normally, the lipid oxidation products measured by thiobarbituric acid assay (MARS) was much increased in these three different brain regions. However, if lipoic acid had been administered to the animals, these molecular markers of lipid oxidation damage and of loss of antioxidants were normalized. Lipoic acid exerted a remarkable effect in protecting the brain, in addition to protecting against mortality in these animals. Very few animals died when protected by lipoic acid.

I could mention one other experiment that we found to be interesting. We took mice that were adults-that were seven weeks old-and we placed them on a diet that was deficient completely in vitamin E. As we did this, these animals began to lose weight and many of them died. However, when we added lipoic acid to the diets of some of these animals, they lived-even though they continued to be deficient in vitamin E. They did not lose weight, they looked normal, and, in a sense, we could say that lipoic acid seemed to be taking over for the missing vitamin E.

Actually, when we looked into the tissues of these animals, we found that the vitamin E levels had dropped to very, very low levels as a result of the induced vitamin E deficiency. Still, all tissues always showed residual levels of vitamin E. We could never completely eliminate vitamin E, and we think it is because this network antioxidant system always is working and keeping vitamin E regenerated so it doesn't get lost in the system. It is very difficult in an adult to generate a vitamin E deficiency if adequate amounts of the other antioxidants are present.

It was remarkable that lipoic acid could exert these effects on keeping the animals healthy. 'Me implication, of course, is that these kinds of things will also happen in people but we just don't do these kinds of experiments in people. 'Me weight of the evidence is getting stronger and stronger that supplementing your normal diet with antioxidants is a good way to get some insurance for healthy aging.

Passwater: Dr. Packer, I know we've barely scratched the surface in our discussion so far. You have proven that the study of antioxidants can be a very challenging, very fulfilling life's work. In any event, this series of articles is far from over. In Part 3, we'll go more deeply into the roles played by glutathione and vitamins C and E, as well as considering in depth the importance of coenzyme Q-10. Thank you, and I look forward to picking up our conversation next month. WF

1999 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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