Troxerutin is a semisynthesis compounds based on rutin.

It could prevent forming of thrombus by inhibiting platelet aggregation. Also with Vitamin P
like activity troxerutin could protect blood vessel from damaging by 5-hydroxytryptamine and
bradykinin. It could enhance vascular resistance, reduce vasopermeability and prevent edemas
symptoms incurred by abnormally rise of vascular permeability.
Troxerutin have obvious effect on protecting brain from acute cerebral ischemia injury. It could
applied to various symptoms incurred by cerebral thrombosis and cerebral embolism.
Troxerutin could be used in dietary supplements and pharmaceutical products.
Troxerutin is a derivative of the natural bioflavonoid rutin.
Troxerutin is found in many plants, and can be easily extracted from Sophora japonica
(Japanese pagoda tree). Troxerutin is an antioxidant and has beneficial effects on venous health.
Troxerutin is used in the treatment of varicose veins and hemorrhoids.
Brain cell protection
Chronic administration of troxerutin protects mouse brain against d-galactose-induced
impairment of cholinergic system. Neurobiol Learn Mem. 2009. Key Laboratory for Biotechnology on
Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou,
Jiangsu Province, PR China.
Previous evidence showed that administration of d-galactose (d-gal) increased ROS production
and resulted in impairment of cholinergic system. Troxerutin, a natural bioflavonoid, has been reported
to have many benefits and medicinal properties. In this study, we evaluated the protective effect of
troxerutin against d-gal-induced impairment of cholinergic system, and explored the potential
mechanism of its action. Our results displayed that troxerutin administration significantly improved
behavioral performance of d-gal-treated mice in step-through test and morris water maze task. One of
the potential mechanisms of this action was decreased AGEs, ROS and protein carbonyl levels in the
basal forebrain, hippocampus and front cortex of d-gal-treated mice. Furthermore, our results also
showed that troxerutin significantly inhibited cholinesterase (AchE) activity, increased the expression
of nicotinic acetylcholine receptor alpha 7 (nAchRalpha7) and enhanced interactions between
nAchRalpha7 and either postsynaptic density protein 95 (PSD95) or N-methyl-d-aspartate receptors
subunit 1 (NMDAR1) in the basal forebrain, hippocampus and front cortex of d-gal-treated mice,
which could help restore impairment of brain function.
Troxerutin for ear disorder
Aescin and troxerutin as a successful combination for the treatment of inner ear perfusion
disturbances.
1

Phytomedicine. 2008. Siegers CP, Syed Ali S. Institute of Experimental and Clinical Pharmacology
and Toxicology, University of Luebeck, Ratzeburger Allee Luebeck, Germany.
A fixed combination of aescin and troxerutin has been developed for treating inner ear perfusion
problems of different etiology. The efficacy of this combination is tested versus pentoxyfyllin in a
randomized clinical study as group comparison with 34 patients for each group. The improvement of
hearing after 40-44 days of treatment is determined as end point of treatment. Hearing was measured
by threshold, whereby a difference of more than 10dB is judged as a significant improvement. After
the treatment with the combination of aescin and troxerutin hearing is significantly improved, in 23 of
34 patients the threshold is changed more than 10dB. With pentoxyfyllin hearing is also improved,
although to a lesser degree. Both drugs are well tolerated, major adverse drug effects are not observed
with either treatment.
Troxerutin for diabetic nephropathy
Efficacy of troxerutin on streptozotocin-induced rat model in the early stage of diabetic retinopathy.
Arzneimittelforschung. 2005. Research Institutes of Dong-A Pharmaceutical Company, Kyunggi,
Republic of Korea.
The vascular changes associated with early diabetic retinopathy, which include the formation of
microaneurysms and acellular capillaries, vessel dilation, vascular endothelial growth factor
expression, were investigated experimentally in streptozotocin-induced diabetic rats treated with
antioxidants: troxerutin (trihydroxy-ethylrutoside, CAS 7085-55-4), Vaccinium myrtillus, and calcium
dobesilate (hydroquinone calcium sulfonate, CAS 20123-80-2). Oxidative stress might be involved in
the upregulation of retinal VEGF during early diabetes, and it is likely that troxerutin has
comparatively effective antioxidant properties. Therefore, troxerutin might be a useful treatment for
attenuating diabetic retinopathy.
Troxerutin for renal injury
Troxerutin protects the mouse kidney from d-galactose-caused injury through anti-inflammation and
anti-oxidation.
Int Immunopharmacol. 2009; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu
Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, PR China.
This study was carried out to investigate the protective effect of troxerutin against D-galactose (D-gal)induced renal injury in mice. Our results indicate that troxerutin has significantly inhibitory effects on
the NF-kappaB-mediated inflammatory response. These findings suggest troxerutin could attenuate
renal injury induced by D-gal probably through its antioxidant and anti-inflammation properties.
Int J Mol Med. 2014 April. Altered miRNA expression profiles are involved in the protective effects of
troxerutin against ultraviolet B radiation in normal human dermal fibroblasts.
2

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
4

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.
5

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. SzentGyorgyi?
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.
6

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 Antiinflammatory 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
7

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]
8

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
9

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
10

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 dosedependent 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.

11

P-vitamin (rutin, bioflavoidok)

TpusVitamin
Alapvet tudnivalkA P-vitamin vagy rutin tulajdonkppen a bioflavonoidok kz tartoz anyag,
amely a C vitamin ksrjeknt fordul el, megvdve a C-vitamint az oxidcitl s elsegtve a
felszvdst. A bioflavonoid, ill. flavonoid kifejezs hasonl felpts antioxidnsok ezreit
takarja. A flavonoidokat 1936-ban a Nobel-djas Szent-Gyrgyi Albert professzor fedezte fel, amikor
rjtt, hogy segtsgkkel megelzhet a hajszlerek teresztse vagy trkenysge, gy
megelzhet a vralfuts s az dma kialakulsa is. Szent-Gyrgyi P-vitaminnak nevezte a
bioflavonoidokat. Br ksbb mr nem hasznlta ezt a kifejezst, a flavonoidok vitamin-szerepet is
betltenek.
Miben jtszik szerepet?A rutin vdfaktorknt szksges a szervezet szmra a C-vitamin
mellkanyagaknt. Ersti a hajszlereket, mrskli a koleszterinszintet, lasstja az regedsi
folyamatokat, j az dma s a herpesz kezelsre. Antioxidcis tulajdonsga rvn gtolja a
tumor nvekedst.
Hinya esetnHinyban gyengl az rfal, elpattanhatnak a hajszlerek, rugalmatlann vlnak az
rfalak. Mivel a P-vitamin ksranyag, tovbbi hinytneteit ltalban nem klntik el a C-vitamin
hinyban kialakul panaszoktl.
TladagolsaA P-vitamin tladagolsbl kvetkez toxikus hatsok nem ismertek, csak enyhe
hasmenst okozhat a tl nagy mrtk bevitel.
Mekkora mennyisgben van r szksgnk?Pontos szksglete nem ismert, megfelel C-vitamin
bevitel mellett nem szksges kln ptlsa. Mestersges C-vitamin ptls esetn minden bevitt
500 mg C-vitamint clszer kiegszteni 100 mg bioflavonoiddal.

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Flavonoids
Phytochemistry
Flavonoids are extremely common and widespread in the plant kingdom. They function as plant
pigments and are responsible for the colours of many flowers and fruits. Being abundant in plants,
flavonoids are commonly consumed in the human diet, especially if it is rich in fruits and vegetables.
The word flavonoid is derived from the Latin word flavus meaning yellow and many flavonoids are
indeed yellow in colour. However, many others are white and the special flavonoid-related
anthocyanins are red, blue or purple. (For a discussion of the pharmacological properties of
anthocyanins, see the bilberry monograph.) Flavonoids are also present in leaves, where they are said
to protect the plant tissue against the damaging effects of ultraviolet radiation.
Flavonoids consist of a single benzene ring joined to a benzo-gamma-pyrone structure. They are
formed from three acetate units and a phenylpropane unit (via the shikimic acid pathway). More than
2000 are known with nearly 500 occurring in the free (aglycone) state and the rest as O- or Cglycosides. Flavonoid glycosides are generally water-soluble.
There are three main types, classified according to the state of oxygenation at carbon 3. These are
flavones, flavonols and flavonones.
The properties of isoflavonoids are discussed in the phyto-oestrogen section.
Flavones
Unfortunately, the term flavonoid is used rather loosely in the pharmacological literature. It is
often applied as a collectiveterm to describe any plant polyphenolic compounds, including
anthocyanins, green tea polyphenolics, the flavonolignans in St Marys (milk) thistle and oligomeric
procyanidins and catechins, by way of example. None of these phytochemicals is actually flavonoids,
and their bundling with flavonoids only serves to confuse any meaningful conclusions that can be
drawn about the pharmacological properties of true flavonoids.
Pharmacodynamics
Most of the studies conducted on flavonoids have used in vitro models, often employing
isolated enzyme systems. The findings of these studies need to be interpreted with caution, since it is
uncertain that oral doses of flavonoid glycosides or even their aglycones can reach sufficient
concentrations in living organisms to reproduce these effects. This reservation applies even more for
oral doses of herbs containing flavonoids, since the flavonoid dose will be commensurately lower in
the plant matrix. The issue was well illustrated by one early clinical pharmacology study that found,
while quercetin and
apigenin inhibited platelet aggregation in vitro, no significant effect was found in human
volunteers.172 Fortunately, clinical studies involving flavonoids (albeit at doses typically much higher
than can be achieved by phytotherapy) and flavonoidcontaining herbs are on the increase. (For a
further discussion on the bioavailability of flavonoids, see the Pharmacokinetics section.) There are
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now tens of thousands of published studies on flavonoids. Hence, the brief section in this chapter
serves only as a primer to this vast body of literature. The original pharmacological interest in
flavonoids arose during vitamin C research in the 1930s. Studies by Hungarian workers indicated that
a number of vegetables and fruits (notably citrus) contained substances capable of correcting certain
abnormalities associated with scurvy.
In particular, this new factor, designated as vitamin P, corrected the capillary fragility
associated with ascorbic acid deficiency. Vitamin P was subsequently found to be a mixture of
flavonoids. Additional research disputed that vitamin P was essential to maintain human life and the
term was dropped in the 1950s. However, research did confirm the therapeutic value of flavonoids for
fragile capillaries (actually fragile connective tissue surrounding capillaries) and as extenders of
vitamin C activity, possibly through improved absorption and protection from oxidation, and by
partially substituting for some of its biological functions.
Decreased capillary fragility denotes improved connective tissue tone and a reduced tendency
for capillary contents to leak into surrounding tissue. This implies that flavonoids will prevent oedema
associated with inflammation and stasis. Such effects from flavonoids are reasonably well established
from clinical trials.
A proprietary mixture of micronised flavonoids consisting of 90% diosmin and 10% hesperidin,
usually administered at a dose of 1000 mg/day, has been investigated in several clinical trials. Such
double blind, placebo-controlled trials have shown that this flavonoid combination improves venous
tone in normal volunteers, enhances microcirculation in patients with venous insufficiency, assists
healing of venous ulcers and relieves symptoms of acute haemorrhoids.
A recent critical review confirmed the benefits of this combination in patients with advanced
venous disease. A meta-analysis of clinical trials also supported its benefit in the treatment of
haemorrhoids. Of course, this is more a nutraceutical therapy and it is arguable whether these doses
have any relevance to phytotherapy, as they could not be realistically achieved by the administration of
plant extracts.
Flavonoids are polyphenolic compounds (they contain several phenolic hydroxyl groups), some
more so than others.
The chemical properties that flow from this feature underlie many of the impressive in vitro
pharmacological effects of these compounds. In particular, they are able to complex metal ions, act as
antioxidants and bind to proteins such as enzymes and structural proteins (this last feature could also
explain the ability of flavonoids to enhance the integrity of connective tissue).
The in vitro antioxidant properties of flavonoids were the focus of much early research. The
ability of flavonoids to complex pro-oxidant metallic ions such as iron probably augments their
antioxidant effects in specific circumstances.

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Of particular interest is the capacity of flavonoids to inhibit macrophage-mediated oxidation of

LDL * Macrophage-mediated oxidation of LDL, a hallmark in early atherosclerosis, depends on the oxidative state of the
LDL, and that of the macrophages. The LDL oxidative state is determined by the balance between the LDL polyunsaturated
fatty acids and cholesterol, which are prone to oxidation, and the LDL associated antioxidants. Dietary consumption of
nutrients rich in polyphenols, such as red wine or liquorice results in LDL enrichment with these polyphenolic flavonoids,
and hence, subsequent LDL oxidation is reduced. In addition, enrichment of LDL with polyphenols results in a marked
decrease in the susceptibility of the lipoprotein to aggregation (another lipoprotein atherogenic modification). The
oxidative status of the macrophages depends on the balance between cellular oxygenases and antioxidants. Macrophage
enrichment with polyphenolic flavonoids in vitro or in vivo also reduce macrophage oxidative state, and subsequently cellmediated oxidation of LDL. The present review article summarizes our current data on these aspects of the antiatherogenic
potential of polyphenolic flavonoids.

and thereby attenuate atherogenesis. The antioxidant properties of

flavonoids could also contribute to their observed antiinflammatory and antiplatelet effects, and are
related not only to their structural characteristics, but also to their ability to interact with and penetrate
the lipid bilayers of the cell membrane.
Flavonoids scavenge the nitric oxide radical, the superoxide anion and singlet oxygen. Like
most other antioxidants, flavonoids can also act as pro-oxidants in particular circumstances. The
molecular promiscuity conferred by the phenolic groups of flavonoids is well demonstrated by the
range of enzymes inhibited by them in vitro. Enzyme activities inhibited to varying degrees by
flavonoids in vitro include cyclooxygenase, lipoxygenase, lens aldose reductase, xanthine oxidase,
cGMP phosphodiesterase, cAMP phosphodiesterase, angiotensin-converting enzyme, aromatase,
thyroid peroxidase, hyaluronidase, phospholipases and protein phosphokinases. However, more
research is needed to determine which of these activities might realistically translate into clinical
effects. Since enzymeinhibiting activity depends on the structure of the flavonoid, some compounds
are more likely than others to be clinically active.
Using isolated cells or organs in vitro, the activities demonstrated for flavonoids include
antiviral activity, especially for the 3-methoxylated flavones, anti-inflammatory activity, antimicrobial
activity, inhibition of histamine release from mast cells, antiplatelet activity, tumour cell cytotoxicity,
especially for highly methoxylated flavones, and spasmolytic activity. The flavonoid 8isopentenylnaringenin (now 8-prenylnaringenin) isolated from the Thai herb Anaxagorea luzonensis
was found to be an oestrogen agonist with an activity about 10 times greater than genistein. This
flavonoid, which also occurs in hops (Humulus lupulus), has now been extensively studied as a phytooestrogen. It strongly activates oestrogen receptor alpha and at least partially accounts for the observed
clinical value of hops in menopausal women experiencing mild vasomotor symptoms.
Animal experiments (usually using high doses) have demonstrated a number of interesting
pharmacological effects for flavonoids. One study found antioxidant effects in vivo for dietary
flavonoids (quercetin and catechin), with reduced lipid peroxidation in rats.208 Flavonoids have also
demonstrated hepatoprotective, antiulcer (gastroprotective) and analgesic activity in vivo. Several
flavonoids tested showed
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anti-inflammatory effects in acute and chronic animal models. A favourable effect of quercitrin on
experimentally induced diarrhoea was probably related to anti-inflammatory effects.
Flavonoids have exhibited preventative activity against chemical carcinogens and tumour
promotion in animal models, although most of the speculation over their cancer preventative role is
based on in vitro studies.
Anxiolytic properties have been demonstrated for some flavonoids (including chrysin and
apigenin), which selectively bind with a high affinity to the central benzodiazepine receptor.
The relationship between dietary flavonoid intake and cardiovascular disease was tested in
several early epidemiological studies. The Zutphen Study in Holland found that flavonoid intake in
elderly men (largely via tea, onions and apples) was significantly inversely associated with mortality
and incidence of stroke.
A Finnish study also found that people with very low intakes of flavonoids had a higher risk of
coronary disease, but US studies found no significant association. These investigations are confounded
by the difficulties in isolating effects due to just the flavonoids and the loose use of the term, as
discussed above.This was well illustrated by another US study that found the observed non-significant
inverse associations for broccoli, apples and tea on cardiovascular disease incidence in women were
not mediated by flavonoids. The same researchers later detected no protection from dietary flavonoids
on incidences of insulin resistance, type 2 diabetes and cancer, all from epidemiological investigations
in women.
In another interesting Finnish study, the total dietary intakes of 10 054 men and women during
the year preceding the baseline examination were determined with a dietary history method.
Flavonoid intakes were estimated mainly on the basis of the flavonoid concentrations in
Finnish foods. Participants with higher quercetin intakes exhibited lower mortality from ischaemic
heart disease.
The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63 to 0.99:
p=0.02). The incidence of cerebrovascular disease was lower at higher kaempferol (0.70; p=0.003),
naringenin (0.79; p=0.06) and hesperetin (0.80; p=0.008) intakes. Men with higher quercetin intakes
had a lower lung cancer incidence (0.42; p=0.001), and men with higher myricetin intakes had a lower
prostate cancer risk (0.43; p=0.002). Asthma incidence was lower at higher quercetin (0.76; p=0.005),
naringenin (0.69; p=0.06) and hesperetin (0.64; p=0.03) intakes. A trend toward a reduction in risk of
type 2 diabetes was associated with higher quercetin (0.81; p=0.07) and myricetin (0.79; p=0.07)
ingestion.
Clinical studies of flavonoids (more as nutraceuticals than as herbal extracts) are yielding some
interesting results.
Citrus flavonoids have demonstrated promising results in patients with hypercholesterolaemia
and in combination appear to exert significant anti-inflammatory activity in patients with osteoarthritis.
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Hesperidin, also from citrus, lowered diastolic blood pressure in a randomised, controlled trial.
Flavopiridol, a flavonoid-derived drug, is being developed as a treatment for cancer and inflammation.
The flavonoid most widely studied as a clinical nutraceutical is quercetin, and doses of around
500 to 1000 mg/day are typical. Generally, the clinical findings are modest, possibly reflecting on its
low and variable bioavailability. Favourable effects were observed on endurance in a randomised,
controlled trial, although other trials have not been positive. It did reduce blood pressure and oxidised
LDL concentrations in overweight patients with a high cardiovascular disease risk phenotype at only
150 mg/day.
For more information about the pharmacology of flavonoids, see the monographs on
Astragalus, chamomile, Ginkgo, hawthorn, horsechestnut and licorice. In particular, the monographs
on Ginkgo and hawthorn extensively review the cardiovascular effects of flavonoids, an area not
emphasised in this chapter.
Toxicology
Flavonoid aglycones, but not their glycosides, are mutagenic in various assay systems.
Quercetin is probably the most mutagenic (and most widespread) flavonoid. When glycosides are
incubated with beta-glucosidase or bacteria possessing this enzyme, they acquire mutagenic properties.
However, the presence of methoxy groups markedly decreases the mutagenicity of the flavonoid.
Concerns about the mutagenicity and carcinogenicity of quercetin first arose among Japanese
researchers who were searching for the carcinogenic compounds in bracken fern. However, those
compounds were later identified to be ptaquilosides. Dietary quercetin also enhanced pretumorous
lesions in a model of rat pancreatic carcinogenesis, indicating possible promoting and progressing
effect, but lacked tumour-promoting effects in a different model.
On the other hand flavonoids, including quercetin, have shown antimutagenic effects and are
widely considered to be antimutagens. With the initial discovery of the mutagenicity of quercetin and
concerns about the carcinogenicity of bracken fern, tests were conducted to determine if quercetin was
carcinogenic. While two studies were positive in rats, many other studies in rats, mice and golden
hamsters failed to demonstrate carcinogenic activity. This is reassuring since quercetin is the most
common flavonoid in the human diet. Proposed reasons for the lack of carcinogenicity included poor
absorption and rapid microbial degradation, as already discussed. However, the lack of carcinogenicity
of a massive exposure to quercetin at 10% of diet suggests that more active mechanisms might be at
work. This was confirmed in a study that demonstrated the rapid metabolic inactivation of quercetin by
catechol-O-methyltransferase to form non-mutagenic methoxy groups on the flavonoid.243 This could
be a major reason for the lack of carcinogenicity of other flavonoids in vivo. A more recent critical
review of the data related to the safety of quercetin noted a lack of in vivo toxicity (including a lack of
carcinogenic properties) and concluded that the weight of the available evidence supports the safety of
this flavonoid.
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