© Whole Foods magazine
January 2000Antioxidant Cocktail Update: Part 4: Newly discovered benefits of Pycnogenol. An Interview with Dr. Lester Packer
By Richard A. Passwater, Ph.D.
In this installment of our series on antioxidants, Dr. Lester Packer discusses new information about Pycnogenol, its role as a regulator of nitric. oxide in the body, and how this regulation is critical to our health.
In the three preceding installments, we chatted about the antioxidant network and various topics involving how antioxidants protect us from the harm of oxygen free radicals. We discussed how antioxidants can regenerate other antioxidants along the antioxidant network, how vitamin C was a crucial hub of the network in aqueous areas such as the cell cytosol, and how coenzyme Q-10 is a crucial hub in lipid areas such as the cell membrane. We mentioned how different balances of antioxidants give optimal protection against different diseases and how to adjust the "Packer Cocktail" for various lifestyles and risks. We elaborated on the critical role of glutathione, the "master antioxidant," in overall health and longevity, and the fact that lipoic acid and Pycnogenol improve cellular glutathione status better than ingesting glutathione itself. We also mentioned that anyone taking one of the cholesterol-lowering statin drugs should take coenzyme Q-10 supplements. All in all, we've covered a lot of ground about antioxidant nutrients and how they affect our health.
Passwater: Dr. Packer, there is something new to talk about every time we run into each other, and this has been happening for more years than either of us might want to realize, about four decades now. Most of our readers know of your brilliant research in antioxidants, but few know why you became interested in antioxidants, nor do they know the ."vitamin E Story" that started 76 years ago in the same building` the Packer Lab now occupies. This laboratory has been extremely fruitful over the years, especially in terms of antioxidant research, but other areas as well.
If memory serves. me correctly, I believe we first crossed paths when you were a young researcher in Dr. Briton Chance's laboratory at the University of Pennsylvania. I was visiting him to learn about the new technique for utilizing his invention-the Dual-Wavelength Spectrophotometer-to measure absorbance through turbid biological solutions. I've run into Dr. Chance twice this year and he still is an active researcher.
Packer: Yes, in my early days I was at Dr. Chance's Laboratories. I was doing my postdoctoral work there. And, that's where I met a young man who was a professor at the University of California at Davis. Dr. Al Tappel came to this laboratory on a six-month sabbatical leave, and he and I began a productive working relationship.
In those years-the 1950s-Dr. Tappel already had done very important work demonstrating how vitamin E acted as an antioxidant. Some of the most important Concepts in this field were initiated by him.
Passwater: I was at the FASEB meeting in Atlantic City in the mid-1970s when he was presented with the Borden Award for his research in vitamin E. In those days, scientists had to be very quiet about whether or not they took dietary supplements. An open admission would lead to their being considered radical and possibly unworthy of receiving grants to conduct research.
After his acceptance of the Borden Award,' Dr. Tappel was asked if he took vitamin E supplements and he, evaded the question. Afterward, at the "back of the room; I overheard one scientist remark to another that "Maybe Carlton Fredericks is right after all." Later, when I told this story to Carlton, one of the best known early advocates of supplementation, he was delighted.
Packer: When he came to Dr. Chance's laboratory,-Dr. Tappel was offered the opportunity, of choosing the Individual with whom he would like to be associated. Since he was going to be there for only a short time, it made sense that he should work with a partner rather than start an individual research program. He made the rounds, and we mutually chose to work together.
Although we didn't work together on E we used to work very late and, as we walked home together we used to talk about vitamin E. I developed a real interest in this nutrient, but I wasn't in a position to do any research on it at that time. Later on, however; I was recruited by the University of California at Berkeley and, shortly after I arrived, I was made aware that Drs. Catherine Bishop and Herbert Evans had discovered vitamin E in 1923 at Berkeley. In fact, they had worked for most of their lives in the same building in which I was working.
I started some of my own experiments on vitamin E, and it became my hobby for quite a number of years. I worked with various people at the laboratory. I collaborated with Dr. Tappel on many projects and, eventually, the tail wagged the dog and I decided to completely focus on antioxidant research
Passwater: Dr. Packer, I have my own list of achievements for which I think you should be honored, but I would like to know your opinion of your "greatest hits." If you had to create a top 10 list of Packer contributions, what would your choices be?
Packer: Through the years I have been fortunate to work with many talented students and post- doctoral students, scholars and visiting professors.
Passwater: This is not by accident. They seek you out.
Packer: We have been associated with a number of important discoveries. The biological sciences have been moving forward very rapidly, and our laboratory has been right in the thick of things. We started working in a big way with antioxidants very early on. My appreciation for this area came from my background in biological oxidations, how they occurred and how they were used to Dr. Lester Packer harness biological energy. I was working on energy production mechanisms and attempting to elucidate how mitochondria and chloroplasts worked in terms of basic mechanisms of biological energy conversion.
We worked in these areas for many years and chronic made a lot of contributions to this body of knowledge. Today, this is the focal point of the work we do in our laboratory. We work on bioflavonoid antioxidants, particularly Pycnogenol and ginkgo biloba, as well as purified bioflavonoids for controls. Also, we continue to work on vitamin E-and when I say vitamin E, I mean tocopherols and tocotrienols. And we work on lipoic acid, too. These are the major antioxidants we currently are working with. Of course, we do some studies that relate to vitamin C, as well.
Passwater: Dr. Packer, I'd like to set the scene of this interview for our readers. First, they should understand that our hectic schedules make it difficult to get together unless we both are at a scientific meeting. Right now, we are in a corner in the main restaurant of the Hotel de Palais in Biarritz, France where we are attending an International Pycnogenol Conference. You are here to present the results of your latest research on how Pycnogenol protects against Reactive Nitrogen Species (RNS).
This may be a case of me twisting my arm to pat myself on the back, but I feel at least partly responsible for stimulating your interest in Pycnogenol. I recall having an earlier discussion with you in Hawaii at a Conference on Antioxidants and Genetic Expression. I informed you that Professor Antti Arstila, chairman of the Department of Cell Biology at the University of Jyvaskyla in Finland, had given a lecture just two weeks before, at the 2nd International Pycnogenol Conference in 1995. Dr. Arstila described how Pycnogenol affected the action of Nuclear Factor-kappa B (NF-kB), quoting extensively from your 1993 research with Dr. Yuichiro Suzuki on NF-kB and vitamin E derivatives and lipoic acid.
As I remember it, you were surprised that Pycnogenol would have such an effect in the cell nucleus, as flavonoids were relatively large molecules. I reminded you that Pycnogenol was not merely oligomeric proanthocyanidins (OPC), but a synergistic mixture of more than 40 different bioflavonoids of various molecular sizes. I saw the gleam in your eye, and I knew that you would be looking further into this mechanism. Now, I am holding an inch thick collection of papers that you have published or submitted on Pycnogenol and nitrogen monoxide (nitric oxide, NO). This should not be confused with nitrous oxide (N2O) the anesthetic better known as laughing gas.
In an earlier installment, we discussed your research showing that Pycnogenol regenerates vitamin C. Now, please tell us a little about your research with Pycnogenol and the nitrogen free radical, nitric oxide, and other RNS.
Packer: The biological effects of the bioflavonoids of Pycnogenol are thought to result mainly from the most widely studied property, their antioxidant activity regarding oxygen free radicals and other reactive oxygen species (ROS). However, little is known about interactions between plant-derived antioxidants and reactive nitrogen species. The free radical nature of nitric oxide (NO) renders NO as a potent prooxidant molecule, and chronic NO overproduction can become self-destructive as occurs in inflammatory diseases. 'thus, a tight regulation of NO production is important for cellular integrity, and a significant effort has been focused on developing therapeutic agents that regulate NO synthesis.
Passwater: OK, NO was the molecule of the year in 1993 and the cover-molecule in Science magazine. In 1998, the Nobel Prize in Medicine was awarded to Drs. Robert Furchgott, Louis Ignarro and Fetid Murad for their research involving the elucidation of the vasodilation caused by N0. It's a very sexy molecule for many reasons. It was all around us, inside us, in side our cells, but largely ignored and ids missed solely as a pollutant. In 1987, the compound that scientists had been calling endothelium-dependent relaxing factor (EDRF), the active compound that migrates to the muscle cells in the artery and relaxes the arteries, was found to actually be N0, the same compound that is released from nitroglycerin that dilates the coronary arteries when taken by angina patients. Eventually, the role of NO in dilating penile arteries to facilitate blood flow to achieve erection was discovered. But NO's formation in the body and its role in immune function receives the most attention today.
In arteries, NO is produced in the endothelial cells regulation of that line the arteries. NO is formed there by the action of the enzyme, nitric oxide synthase (NOS) on the amino acid arginine. It is not a shortage of arginine that normally is the limiting factor, but ineffective NOS. Pycnogenol regulates NO levels in the proper places by stimulating the nitric oxide synthase enzyme to produce more NO in the arteries where it increases blood flow and has a moderately beneficial effect on blood pressure. Where NO is not desired, or too much has been made, Pycnogenol destroys the excess NO. There is another enzyme that increases NO under periods of stress. Thus, Pycnogenol also helps protect us against the harmful effects of stress.
We once were concerned only with oxygen free radicals and ROS. Now a whole new avenue of concerns has been opened up. Antioxidants are needed to regulate NO. Please tell our readers more about NO, which you often call "the Jekyll and Hyde of molecules."
Packer: NO is an important signaling molecule that turns genes on and off.
Passwater: This is important, but it is a new area for many of our readers, so let's hold off on gene regulation for just a few moments.
Packer: Well. NO also controls the muscular tone of blood vessels, which regulates circulation. NO additionally modulates communication between brain cells. And helps us concentrate, learn and maintain memory.
When produced by cells in the immune system, NO fights infection, kills tumor cells, and promotes wound healing. NO also aids in the digestion of food by helping peristalsis (gastric movements). And, as you mentioned, NO is essential for perceiving pleasure and pain, and it helps translate sexual excitement into penile erections.
Passwater: Of course, that's the good news. Now give us the bad news.
Packer: As I point out in "The Antioxidant Miracle," NO can be very harmful. NO can restrict blood flow and contribute to heart disease and stroke. When excess NO is produced, it can trigger inflammation, which can cause arthritis, colitis, inflammatory bowel disease, and possibly even cancer.
In the brain, excess NO can hamper mental function, cause memory loss and accelerate brain aging. NO also promotes the production of more free radicals. When NO encounters the superoxide free radical, it goes from bad to worse. It then becomes peroxynitrite, which is a powerful free radical that destroys antioxidants and damages proteins.
Pycnogenol can regulate N0, keeping its friendly functions while preventing its toxic functions.
Passwater: I have a research summary from a year ago that describes 16 of the Pycnogenol reports and studies conducted in the Packer Lab. Now, you are going to report on even more. What type of studies have you been doing with Pycnogenol?
Packer: Our research indicates that RNS, generated by activated macrophages or by direct administration of peroxynitrite, lead to significant loss of vitamin E and glutathione (GSH) in human endothelial cells, and preincubation with Pycnogenol protects endothelial cells against vitamin E and GSH depletion.
Ongoing studies in our laboratory have shown that Pycnogenol modulates NO metabolism inactivated macrophages due to its ability to quench NO radicals and to inhibit both iNOS STERNA expression and iNOS activity
Moreover, we have observed that Pycnogenol significantly inhibits the inducible expression of the cellular adhesion molecule ]CAM-] in endothelial cells. ICAM-1 plays an important rule in the infiltration of activated lymphocytes through the endothelial barrier and in transformed cell infiltration during tumor progression. Thus, the inhibitory effect of Pycnogenol on ICAM-1 expression may be one of the mechanisms by which these plant extracts provide beneficial effects in different human pathologies such as chronic inflammation and cardiovascular diseases.
Our research team has looked at the antioxidant power of several extracts from fruits and vegetables, including ginkgo biloba, green tea and other flavonoids, all of which boosted vitamin C levels by recycling oxidized vitamin C back into its active antioxidant form. But none worked as well as Pycnogenol. We also have found that Pycnogenol can indirectly increase the level of other antioxidants such as vitamin E and glutathione. Of all the antioxidants tested in the Packer Lab, we have found Pycnogenol to be the strongest. It quenches the most damaging radicals including the superoxide anion radical, NO and the hydroxyl radical. Of all the free radicals formed in the body, the hydroxyl radical is the most dangerous because it can attack DNA directly.
Passwater: Dr. Packer, there are many different bioflavonoids in Pycnogenol and they, in turn, have many metabolites. This makes the work of researchers highly complex. Given these circumstances, have you studied the bioavailability of Pycnogenol in humans?
Packer: Studies in vivo are fundamental to assess the real efficacy of ingested flavonoids as antioxidants and to understand if these kinds of extracts are bioavailable -or at least whether oral administration results in a detectable outcome. To directly address this question, a controlled study on human subjects was performed in our laboratory in collaboration with Professor C. Rice Evans and colleagues at the University of London. Results indicate that Pycnogenol components such as ferulic acid and other hydroxy cinnamates are rapidly and readily bioavailable in all subjects.
Passwater: Dr. Packer, once again you have given our readers a generous helping of both theory and scientific proof of the efficacy of antioxidant nutrients. In the final part of the series, we will be exploring the most exciting and important discovery about these extraordinary nutritional compounds-namely, the way in which they are involved in genetic expression and their relevance to aging, cancer. heart disease, arthritis and many other non-germ diseases. WF
© 2000 Whole Foods Magazine and Richard A. Passwater, Ph.D.
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