Bioflavonoids, "Vitamin P" and Inflammation: An interview with Dr. Miklos Gabor.
by Richard A. Passwater, Ph.D.
In October, I was privileged to meet Professor Miklos Gabor of the Albert Szent-Gyorgyi Medical University of Szeged, Hungary. Dr. Gabor has published more than 200 research reports and five books on flavonoids. He has also served as the scientific editor of other books on bioflavonoids. In 1990, Dr. Gabor received the Jancso Medal and Award for his outstanding results and scientific work of high quality, and in 1993, he received the Novicardin Prize awarded by the Hungarian Academy of Sciences.
Professor Gabor and I had a common interest besides Pycnogenol(R) research. We had a common friend, the late Nobel Laureate, Dr. Albert Szent-Gyorgyi (1893-1986). Professor Gabor was now carrying on bioflavonoid research at the University named in honor of Dr. Szent-Gyorgyi (Americanized pronunciation is Saint Jor'-jee).
Before I share what I learned about bioflavonoids from Dr. Gabor with you, let me tell you a little about Dr. Szent-Gyorgyi, who discovered the biological importance of bioflavonoids. Dr. Szent-Gyorgyi was born in Budapest, but was claimed by the U. S. and Hungary alike, and he conducted his research while spending time in Cambridge, England; the Mayo Clinic, Minnesota; Woods Hole, Massachusetts and Hungary.
Dr. Szent-Gyorgyi was more than a pioneer of biochemistry -- he was a "father" of biochemistry. He was awarded the Nobel Prize in Medicine in 1937 for his discovery of the biological oxidation process with special regard to vitamin C and fumaric acid catalysis. In 1928 he isolated what he at first called "hexuronic acid," but is now called "ascorbic acid" or vitamin C. He also "discovered" the muscle protein actin, actomyosin and their relationship to ATP. He discovered the C4 dicarboxylic acid catalysis that forms the basis of the Krebs cycle which was pioneering research on how food is converted into energy. His keen mind and bright ideas opened the doors to many areas of biochemical research. He taught us so much, yet he was often labeled a "maverick" because of his new ideas.
Dr. Szent-Gyorgyi always professed that his discovery of the biological function of bioflavonoids was serendipitous. He found something he did not seek. While he was trying to isolate vitamin C, his colleague Professor I. (St.) Rusznyak had a patient with subcutaneous capillary bleedings. They thought that vitamin C might help, so they gave the patient an impure preparation that contained vitamin C plus other compounds. They achieved a rapid success. Later, a similar patient was treated with a pure solution of vitamin C expecting quicker success, but instead, the pure solution had no effect. So they went back to the impure solution. Dr Szent-Gyorgyi suspected that a flavone might be the key factor.
In 1935, Dr. Szent-Gyorgyi and his associate Dr. I. (St.) Rusznyak, isolated a "factor" from lemon juice that decreased the permeability and increased the resistance of the capillary wall. At first, chemical analysis indicated that this factor was a single flavonoid compound and it was named "citrin." Because of the effect on capillary health, Dr. Szent-Gyorgyi also called this factor "vitamin P." [Nature 138:798;1936, Nature 137:27;1936]
He chose "a letter on the far unoccupied side of the ABC" letters already being used to designate vitamins in case that bioflavonoids were not found to be true vitamins "correction could be made without confusion." The letter "P" was convenient because it could stand for "permeability," "purpura" or "petechiae." The "vitamin P" normalized the low capillary resistance of vascular purpura patients. In 1936, Dr. Szent-Gyorgyi and his associate, Dr. V. Bruckner found that citrin was actually a mixture of the flavone hesperidin and eriodictiol glycoside, a flavonol glucoside. [Nature 138:1057;1936]
By 1936, studies by Dr. Szent-Gyorgyi and associates with guinea pigs indicated bioflavonoids and vitamin C were synergistic and interdependent. In 1936, Dr. Janey reported the favorable effects of flavonoids on intact and poisoned frog hearts. In 1937, Dr. Huszak reported on the biochemistry of parenterally administered "citrin." Other researchers such as Zemplen, Bognar, and Farkas actively researched the biochemistry of flavonoids. However, in 1938, Dr. Szent-Gyorgyi reported that he could not substantiate that bioflavonoids were truly essential nutrients.
It was the discovery in Szeged that called attention to the biological actions of flavonoids, and from 1940 onwards, researchers from many countries began studying the biochemical effects of flavonoids such as catechins, proanthocyanidins, rutin, etc. Hungarian researchers had started the research on the biochemistry of flavonoids, and today remain leaders in the field.
I had the pleasure of discussing vitamin C and the role of electron transport and the electronic desaturation of protein molecules in the cancer process with Dr. Szent-Gyorgyi many times during 1972 through 1979, as well as lecturing together. Dr. Szent-Gyorgyi would discuss my joint research with Dr. Keith Brewer on energy transfer in cell membranes via double bond excitation. This research was published in American Laboratory in a five-part series from 1974 through 1976. In a March 19, 1973 letter to me, Dr. Szent-Gyorgyi remarked, "I have not published anything on cancer in a long time, though I have been working very hard. I arrived at a new concept, but my ideas are not in disagreement with yours, they are complementary."
We were both working on our "electronic theory for cancer," or as Dr. Szent-Gyorgyi liked to call it, the "electronic dimension of life and cancer." Dr. Szent-Gyorgyi called our approaches complementary because we were both examining the participation of cellular structures -- not just the liquid-state compounds. Also, I was publishing on the free-radical initiation of cancer and he was investigating the electron transfer system within structural proteins that allowed them to become semiconductors by oscillating between two states -- one of which was a free radical state.
He had observed that structural proteins in cells are the color of "a good Swiss chocolate." The color is due to the presence of an electron transfer system in structural proteins which transforms them into free radicals. However, the structural proteins in cancer cells are colorless, indicating that their electron acceptors are missing or have been damaged.
Dr. Szent-Gyorgyi also found that dicarbonyls produced by the electron transfer process were capable of stopping cell division. He reasoned that the defective electron transfer system in cellular proteins allowed the cells to engage in uncontrolled cell division, thus become cancer cells.
Cancer cells have lost their ability to be semiconductors. Their structural proteins can no longer accept the single electrons of free radicals, and thus in turn temporarily become free radicals themselves, and then cause the formation of cell-regulating by-products such as dicarbonyls.
Dr. Szent-Gyorgyi was a fascinating man with many brilliant concepts, and provided much encouragement for my research. He often shared his views on true discovery and how it must by nature seem radical and wrong to everyone -- or it wouldn't be a true discovery. Occasionally, Dr. Szent-Gyorgyi and I would discuss the role of bioflavonoids as nutrients, and that Dr. Szent-Gyorgyi still thought that some good modern research would clarify the "essential or nearly essential" importance of bioflavonoids. You can see that my meeting Dr. Gabor has brought back many fond memories of Dr. Szent-Gyorgyi and that Dr. Gabor and I had some long chats about our mutual friend.
In the foreword to one of Professor Miklos Gabor's books, Dr. Szent-Gyorgyi remarked in 1972, "American science did not take in a friendly spirit to vitamin P and the name "vitamin" was dropped. More than that, discussions have been going on to strike the flavones altogether from the lists of (nutrients and) drugs, since no therapeutic action has been found. I think the contradiction is due to the fact that in the USA, citrus fruits belong to people's regular daily diet. They are rich in flavones, so a (total) lack in flavones is very rare, and if there is no deficiency, a vitamin has no action. In contrast to this, in countries where citrus fruits are expensive, the lack of flavones may cause trouble and their medication may show favorable effects. While these discussions were going on, important experimental material was collected in Hungary which, in my mind, leaves no doubt about the vitamin nature and the biological activity of flavones."
However, others do not share this conclusion. In Dr. Gabor's 1986 book, Dr. Middleton writes in the foreword, "There seems to be a resurgence of interest in flavonoid research in recent years after the vitamin P era had come to its proper conclusion." Dr. Middleton also remarks, "For many years one worker and his colleagues in the "flavonoid fields" persistently has kept our attention focused on the relevance of flavonoid research. This individual, Professor Miklos Gabor, deserves great credit for his insight and perseverance."
In October 1993, I had the chance to chat with Dr Gabor who is the world's leading expert on the role of bioflavonoids and capillary health and also to compare stories about Dr. Szent-Gyorgyi. I will try to share some of his knowledge of bioflavonoids and capillary health with you.
Passwater: Dr. Gabor, did you have the opportunity to do research with Dr. Szent-Gyorgyi?
Gabor: No, during the stay of Dr. Szent-Gyorgyi at Szeged, I was a student. However, I did attend his lectures and have the opportunity to know him then, and of course, we had a continuing scientific dialog through the years.
Passwater: You are the world's leading authority on bioflavonoids and capillary health. You have published many research reports and have written several books on bioflavonoids, capillary permeability edema and inflammation. What originally aroused your interest in this field, and what continues to hold your interest?
Gabor: During the period from 1950 to 1954 in the Department of Pharmacology of the Szeged University Medical School, I began my research with some naturally occurring compounds -- haematoxylin, haematein, brasilin and brasilein -- which can be broadly considered as members of the bioflavonoid family. Our research group demonstrated that these natural dyestuffs can decrease the increased vascular permeability in guinea pig eyes and skin capillaries of rats.
After we demonstrated the permeability-decreasing action of haematoxylin compounds, we examined their ability to normalize lowered capillary resistance. The permeability of capillaries is quite important to health, and the effect of various nutrients on capillary permeability fascinates me. My first book deals with the pharmacology of capillary resistance, including the effects of bioflavonoids. This book "Die Pharmakologische Beeinflussung der Kapillarresistenz und Ihrer Regulationsmechahanismen" was published by the Hungarian Academy of Sciences (Akademiai Kiado, Budapest) in 1960.
In 1965, the Hungarian Academy of Sciences founded a Committee for Flavonoid research. In 1965 and 1967, I was privileged to organize the first and second international symposia on bioflavonoids. Since then, these symposia have been held every four-to-five years. The next international bioflavonoid symposium entitled the "Ninth Hungarian Bioflavonoid Symposium" will be held in Wien (Austria) in 1995. However, I have to emphasize that a conference more limited in scope was the conference on "Bioflavonoids and the Capillary," which was organized by the New York Academy of Sciences and held on February 11, 1955.
In 1972, Dr. Szent-Gyorgyi wrote the foreword for my English-language book, "The Anti-inflammatory Action of Flavonoids." The foreword to my 1986 English-language book, "The Pharmacology of Benzopyrone Derivatives (Flavonoids) and Related Compounds" was written by Professor Elliott Middleton, Jr. of the State University of New York at Buffalo. So you can see that my interest in bioflavonoids is very strong.
Passwater: Yes, and so is the interest of Professor Middleton. I have co-authored a book on Pycnogenol(R) [Keats Publ., 1993] with a colleague of Professor Middleton at Buffalo, Dr. Chithan Kandaswami. We discuss Drs. Middleton's and Kandaswami's research on cancer and bioflavonoids in this new book and in upcoming Health Connection columns continuing the interview series with Dr. Kandaswami.
I also note that Dr. Hans Selye wrote a foreword to your 1974 book, "Pathophysiology and Pharmacology of Capillary Resistance."
Evidence is lacking that bioflavonoids are essential nutrients. Is that because they are not essential or is it merely because that no diets have been developed that are totally free of bioflavonoids? I note that in the scientific literature you have studied the blood brain barrier and aorta structural abnormalities produced by what you call "P avitaminosis" (a deficiency of "vitamin P") produced by flavonoid-free diets. Would you please elaborate a little for us on "P avitaminosis? Do humans and other animals get enough bioflavonoids in their experimental or normal diets to prevent a recognized bioflavonoid deficiency from being observed?
Gabor: Many experimental "fragilizing" diets have now been developed that are totally free of bioflavonoids. Humans and other animals get enough bioflavonoids in their normal or experimental diets to prevent a frank bioflavonoid deficiency.
I should like to mention here that the estimated daily dietary intake of flavonoids in the United States is about one gram. This originates from cereals, potatoes, bulbs, roots, peanuts, nuts, vegetables, herbs, fruits, fruit juices, cocoa, cola, coffee, beer and wine. Flavonoids may be present in amounts up to a hundred milligrams per kilogram of fresh weight in soft fruits and their juices. Anthocyanin may be present in rich amounts in some foods such as raspberry, which can contain hundreds of milligrams per hundred grams of fresh weight. Notable sources of anthocyanins are red cabbage, onion, beans, radishes, and rhubarb sticks.
The concentration of catechins in ripe fruits is about five -to-twenty milligrams per hundred grams of fresh weight. Dimeric proanthocyanidins occur in unripe berries and the leaves of soft fruit plants in amounts ranging between fifty and five hundred milligrams per hundred grams of fresh weight. Some proanthocyanidins are present in apples and grapes. Flavonoids are in tea, cocoa, wine and beer.
Perhaps, Dr. Szent-Gyorgyi was technically correct in saying that certain bioflavonoids, as a group, should have vitamin status. However, frank bioflavonoid deficiency is not a major problem. Today we don't seem to eat enough bioflavonoids for optimal health, but we do seem to get enough to prevent "P avitaminosis." Keep in mind that bioflavonoids are important to blood vessel health and even protection from heart disease, and there is a definite benefit to be obtained by optimizing dietary bioflavonoid intake. We should do more research on the benefits of bioflavonoids and not be distracted by the question of whether or not bioflavonoids should have vitamin status.
Keep in mind that Dr. Szent-Gyorgyi's experiments indicated that at least a trace of vitamin C must be present to observe the vitamin-like effect of the bioflavonoids. In his experiments, guinea pigs were kept on the scorbutic Sherman - La Mer - Campbell deficiency diet. One group, the untreated controls, died in an average of 28.5 days. The group given one milligram of citrin daily for six weeks lived an average of 44 days. All of the animals in both groups showed the typical symptoms of scurvy. Dr. Szent-Gyorgyi and his colleagues concluded, "these results suggest that experimental scurvy, as commonly known, is a deficiency disease caused by the combined lack of vitamins C and P."
Dr. Szent-Gyorgyi asked other scientists to repeat his studies. The results were partly corroborative and partly negative. In 1937, Drs. Szent-Gyorgyi and Bentsath stated, "vitamin P requires for its activity the presence of ascorbic acid. A scurvy diet frequently contains traces which in themselves have no influence on the development of scurvy, but enable vitamin P to act. In the total absence of ascorbic acid, vitamin P is inactive." [Nature 140:426;1937]
Passwater: There certainly is a synergism between vitamin C and the bioflavonoids. They protect each other against oxidation and have other interactions. Let's move on to the importance of bioflavonoids to health. Capillaries are important because they carry nutrients to cells and carry away waste. Capillaries must be permeable enough to allow fluids to seep out of the capillaries, mix with the fluid that surrounds all of the cells, and then reenter the capillaries. If the capillaries are too permeable, too much fluid and protein seep out resulting in edema, and even red blood cells may also seep out causing bruising and red spots. You have even designed a simple portable petechiometer to measure the degree of petechiae (small hemorrhages appearing as red spots) formation permitted by weak capillaries. If capillaries are too permeable, they are no longer a barrier to infection. Dr. Gabor, what has your research shown regarding Pycnogenol(R) and capillary permeability.?
Gabor: I have studied the effect of water-soluble flavone derivatives including proanthocyanidins and hesperidin-methylchalcone on the vascular wall resistance in rats with spontaneous hypertension (high blood pressure). My investigation revealed that the pathologically low capillary resistance in rats with spontaneous hypertension was normalized by treatment with oligomeric proanthocyanidin. This research will be published this year in Scripta Phlebologica.
Thus, Pycnogenol(R) increases pathologically low capillary resistance, decreases undesirably high capillary permeability and improves circulation. As I explain in my upcoming Scripta Phlebologica report, the anti-inflammatory action of proanthocyanidins may be based on increasing the capillary resistance, but additional factors should be considered. The antioxidant action of Pycnogenol(R) has been reported; it can scavenge superoxide radicals, it reduces UV-B radiation-induced cytotoxicity of fibroblasts and inhibits lipid peroxidation.
Free radicals and other reactive oxygen species are formed at the sites of inflammation and contribute to tissue damage. The scavenging effect of Pycnogenol(R) for radicals correlates with its anti-inflammatory activity. Pycnogenol(R) may also act by inhibiting lipoxygenase and cyclooxygenase.
Passwater: Aha! Most people assume that it's the high blood pressure alone that bursts the blood vessels, but it is the decreased capillary resistance and increased permeability that cause the blood vessel to bleed and weaken enough to burst.
So, if low capillary resistance is common in people with high blood pressure, and this is a major factor that leads to stroke and retinal hemorrhage, your study is of major importance to the millions of people with high blood pressure. Your findings could drastically reduce the incidence of strokes. Please elaborate on your study.
Gabor: It has long been known that the capillary resistance is pathologically decreased in a considerable proportion of hypertensive persons [Griffith and Lindauer, 1944; Kuchmeister and Scharfe, 1950; Gough, 1962; Davis and Landau, 1970; etc.]
Special mention should be made of the observation that, if hypertension is associated with a low capillary resistance, the incidence of cerebral insults (apoplexy, stroke) and retinal hemorrhage is essentially higher [Griffith and Lindauer, 1944]. It was established by Paterson in 1940 that capillary rupture accompanied by intimal bleeding plays a role in the mechanism of cerebral arterial thrombosis. He assumed that, at the intracapillary pressure resulting from the high blood pressure, the capillary fragility (which is enhanced for various reasons) is responsible for the intimal rupture of the cerebral arterial capillaries.
These data stimulated us to carry out capillary resistance determinations in spontaneous hypertension rats. As the results reveal, pathologically low values were observed in the large majority of the experimental animals.
In connection with the flavonoids used, it may be mentioned that oligomeric proanthocyanidin, isolated from Pinus maritima, was selected because its indications are to increase pathologically low capillary resistance, to decrease an enhanced capillary permeability, and to improve the circulation.
My study revealed that the pathologically low vascular wall resistance of spontaneous hypertension rats can be elevated by treatment with oligomeric proanthocyanidin.
Passwater: Does your research indicate that Pycnogenol(R) would be of help to people having fragile capillaries that might result in problems such as bleeding gums, floaters caused by bleeding into the retina, glaucoma, bleeding kidneys, and stroke? Also, I have seen European studies that show that Pycnogenol(R) is a nutritional adjunct that helps against varicose veins, heavy menstrual bleeding, hemorrhoids and the complications of diabetes.
Gabor: I have not personally conducted clinical trials on these conditions per se, however, capillary health is compromised in all of these conditions, and Pycnogenol(R) acts to improve capillary health by improving their bioflavonoid nourishment.
Passwater: For many years you have been studying the effects of flavonoids on the capillary resistance of psoriatic patients. A friend of mine in Manchester, England, Dennis Gore, has reported anecdotal data to me that proanthocyanidins seem to be effective against psoriasis itself. Have you noticed this in your studies?
Gabor: Proanthocyanidins are used successfully against diseases characterized by capillary bleeding associated with increased capillary fragility. The capillary resistance of psoriatic patients is significantly lower than that of healthy persons. Pycnogenol(R) tends to restore normal capillary resistance in these psoriatic patients. However, I have not conducted a clinical trial of the effect of Pycnogenol(R) on psoriasis as a disease state. I have studied what may be the causative component of the disease and I have shown that bioflavonoids can correct this factor.
Passwater: How do the bioflavonoids help capillaries maintain their proper resistance and permeability?
Gabor: As you know, I have been studying the actions of the flavonoids in elevating capillary resistance since the early 1950's and in 1974 I published a detailed survey of the results of all of the relevant research up to that date. However, just as with inflammation, we still have a lot to learn about the "how" part. Even though we need to learn more about the mechanism involved, we do know that the effects are real. I have observed that Pycnogenol(R) improves the capillary resistance within two hours and maintains it longer than eight hours.
Passwater: What has your research shown about bioflavonoids and inflammation?
Gabor: I earlier reported that proanthocyanidin significantly decreased the inflammation and edema induced by serotonin, prostaglandin or carrageenin. The decrease is dose-dependent and statistically significant. [Gabor & Razga, Acta Physiol. Hung. 77:197-207 (1991)] Pycnogenol(R), sophoricoside and fisetin are the most effective flavonoids against inflammation that I have tested, and Pycnogenol(R) has the advantage of being very water soluble and bioavailable.
The mechanisms at play involve the inhibition of several chemical mediators including histamine, prostaglandins, 5-hydroxytryptamine and kinins. Also, these flavonoids can block undesirable actions of lipoxygenase and cyclooxygenase.
The actions of Pycnogenol(R) against inflammation are different than those of rutin, hesperidin and the citroflavonoids.
Passwater: What are your interests for future research?
Gabor: Sixty years after the pioneering research by Rusznyak and Szent-Gyorgyi, the question naturally arises as to the explanation of the renaissance in flavonoid research. The answer is clear: chemists have synthesized new flavonoid derivatives with previously unknown biological effects; phytochemists have isolated numerous new flavonoids from many plants; biochemists have demonstrated the most varied effects on different enzymes; and an ever increasing number of pharmacologic effects have become known through variations of the chemical structures of the flavonoids and related compounds. This research has led to the discovery of many new drugs that can be applied for therapeutic purposes. In these words you can find the future of the research of bioflavonoids. Personally, I am working now with experimentally induced edema and with the effects of various drugs on this phenomenon.
Thank you, Dr. Gabor.
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