J. Appl. Cosmetol.

25, 145-159 (October/December 2007)

FLAVONOIDS: A REVIEW FOR COSMETIC

APPLICATION. PART TWO
Mrs.ir. Elzbieta E.Brand-Garnys ',Dr. Horst Denzer ', Dr. Hamke Meijer', Dr.ir. Hans M.Brand '
' ELZBIETA COSMETICS B.V.. Nieuwerkerk a/d IJssel - The Netherlands
' KAO CHEMICALS GmbH, Emmerich - Germany

Received: March, 2007.

Key words: Bio-active substances; Biologica/ extracts; Enzyme manipulation; Enzyme

cofactor;

Summary
Flavonoids are now recognised as essential dietary components, although their functions are just on
the brilli< of understanding. Dietary requirements have been established. Their significance is proba-
bly egual to vitamins. Approximately 5000 flavonoids have been identified, and the list is quickJy
expanding. The functionality of flavonoids is frequently " multi-purpose", contrary to vitamins, enzy-
mes and (to a !esser extent) hormones .
Riassunto
I flavonoidi sono riconosciuti come componenti essenziali delle diete, anche se non sono state anco-
ra comprese appieno le loro funzioni. Comunque ne è stato riconosci uto il loro ruolo dietetico che
dovrebbe essere simile a quello delle vitamine.
Circa 5000 sono i flavonoidi già identificati ed il loro numero si incrementa di continuo. Al contra-
rio delle vitamine, degli enzimi e degli ormoni, l'attività di questi composti naturali è più complessa
e serve a molteplici scopi.

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 Flovonoids: o Review for Cosmetic Applicotion

BIOSYNTHESIS OF raspberries are excellent followers. In the range

of vegetables spinach, Brussels sprouts, alfalfa
FLAVONOIDS and broccoli score high. A recent study showed
that a high ORAC diet raised the antioxidant
Robinson (8) suggested that the C 15-skeleton of
capacity of the blood in the range of 10-25%.
flavonoids is composed of two parts: a phenolic
Table XI and XII give some ORAC data of par-
compound with six carbon atoms and an alkyl ticular flavonoids.
substituted phenolic compound with nine carbon
atoms. The tota! biosynthesis is not yet known,
but it has been shown, that the phenolic com- Table XI
pound with six carbon atoms is constructed from ORAC values expressed as
acetic acid using acetyl-coenzyme A. This was concentration. (in 11Mole)
concluded from feedi ng red cabbage plants with whereby 50% inhibition
14
C-labelled acetic ac id. Severa) authors also of lipid peroxidation occurs.
suggest that malonyl-coenzyme A is involved in
Baicalein 6,3
this process. Virtually ali reaction sequences in
the biosynthesis of flavonoids are enzyme con- Quercetin 8,5
trolled. Typical phenolics are catechol, quinol Myricetin 10,5
and resorcinol. Galangin 13,8
The alkyl substituted phenolic compound fol- Kaempferol 19,0
lows the shikimic acid (3,4,5-trihydroxycyclohe- Baicalin 20, 1
xene-1-carboxylic acid) pathway. This results in Fisetin 20,8
the formation of (substituted) cinnamic acid. Mo rin 23,0
This has been concluded from experiments using
14
Hyperoside 59,5
C-labelled shikimic acid, phenylalanine and 4-
Rutin 93,5
hydroxycinnamic acid, which ali showed to be
precursors for quercetin. It has become evident,
that especially phenylalanine plays a determi-
ning role in the biosynthesis of flavonoids. Also the antioxidant qualities of green tea flavo-
noids can clearly be demonstrated using the
THE FUNCTIONALITY OF ORAC values (9, 10).
FLAVONOIDS The ORAC values of antioxidants are not only
significant for food additives but also for perso-
Relative to the functionality of flavonoids most na! care and cosmetics. Skin ageing is usually
attention has probably been given to their ability related to lipid peroxidation and thus oxidation
to act as powerful anti-oxidants. The US of the bio-membranes present in the sub-cutane-
Department of Agriculture have done and dele- ous tissue. Also oxidative stress, oxidation of
gated a wide variety of studies relative to the squalene to squalene hydroperoxide instead of
anti-oxidant properties of flavonoids and has squalene-2,3-epoxide (which is the precursor for
defined the so-called Oxygen Radical steroid hormones) is a significant ageing factor.
Absorbance Capacity (ORAC). Among fruits The efficacy of flavonoids as anti-oxidants is
prunes are the absolute Jeaders when it comes to related to their ability to quench oxygen-based
ORAC value, while red grapes, blueberries and free radicals, such as singulet oxygen, Ho2 · and

146
 E. E.Brand-Garnys, H. Denzer. H. Meijer. H. M.Brand

HO' , but also NOx'. Free radicals are often produced by xanthine oxidase/hypoxanthine.
brought into connection with the occurrence of Determi nation of the level of 4-hydroxyproline
skin defects and premature skin age ing, particu- was monitored and it was shown that the colla-
larly in conjunction with over-ex posure to UV-A gen degradation could be completely inhi bited
and UV-B rad iation (photo-ageing; dermatohe- with these flavonoids .
liosis). In cosme tic practice it is common practi- Many flavonoids exhi bit anti-allergic properties
ce to compensate these effects using vitamin e and some are claimed fo r their anti-viral proper-
a nd/or vitamin E. Topica! application of flavo- ties ( 12) . Hesperidin, rutin, querceti n, quercitrin
no ids such as que rcetin and ru tin (the glycos ide and aurantiin were examined against vesicular
of quercetin with rutinose; rutinose is the disac- stromatitis virus (YSY) action on mouse fibro-
charide of glucose a nd mannose) has been plasts and hesperidin was also tested agai nst
shown to be at least 60 times more acti ve than influenza virus . Protection could be achieved for
ascorbic acid (vita min C) a nd 350 times more a period of 24 hours fora one-dose appl ication
tha n tocopherol (vitami n E) . In actual fac t, toco- of 200 µg/ml flavonoid . The results a re preven-
phe rol is only a weak anti-oxidant. tive rather than curati ve, but this application
Jt was also fou nd that many fl avonoids are able seems to be most suitable indeed for skin care
to protect human dermal fibroplasts signifi cantly products for the inhibition of topically active
better than vitam in C/E , irrespective the stabil ity viruses such as the herpes simplex virus . It goes
of especially vitam in C: ORAC values of ascor- without saying that cosmetic products, especial-
bic acid and d-a-tocophe rol are in the mMo le Iy facial care, are usuall y prophylactic rather
range. than reparative.
Jn add ition, flavonoids are also a ble to protect Also a large number of references have been
products vulnerable to oxidation, such as ascor- made to the anti-inflammatory, anti -thrombotic ,
bic acid and tocopherol, and it is the refore not d iuretic, fung icide and bactericide activity of fla-
surprising that e.g . the comb inati on { vitamin vonoids.
C+rutine} is much more effecti ve than the indi- Significant is also the sti mulat ing effect to pro-
vid uai ingredients . After ali , vita min C is a n tein synthesis . Many of these properties boil
important co-factor for various enzy mes; skin down to the ability of flavo no ids to interact with
lightning is a beautifu l exponent thereof. ali kinds of e nzymes.
The protective effec t of flavonoids obtained A number of flavono ids have been demonstrated
from bilberries and grapes has been de monstra- to be co-factors for enzy mes. In th is te rmino logy
ted by Monboisse et.al (11) . Calf skin ac id-solu- they could be considered compara ble to vita-
ble co llagen was exposed to free oxygen rad icals mins.

Table XII
ORAC va/11es of some green tea flavonoids

(-)-(2R,3R-Epicatecin Gallate 10,0

(-)-(2R,3R-Epigallocateci n Gallate 11 ,0
(-)-(2R,3R-Epigallocatecin 16,0
(-)-(2R,3R-Epicatecin 30,0

147
 Ftovonoids: o Review tor Cosmetic Applicotion

Although in many cases onl y a limited selectivi- the blood of diabetes type II patie nts. It certain-
ty of flavonoids fo r particul ar enzymes is obser- ly is a functional remedy to treat type II diabetes
ved , an increasing number of publications appe- patients, but this prope rty also could be applied
ar in the scientific literature reporting about an for slimming products. The acti ve substances
unexpectedly high degree of selectivity for par- have been dete rm ined as flavonoids: catechin ,
tic ular enzymes. prunin (naringenin-7-0-glucoside) and hesperi-
It has been shown that many flavonoids are able din-5-0-glucoside. Also myriceline and dihy-
to strengthen the fragile capillary blood vessels, dromyriceline have been proposed for that appli-
and thus are an excellent tool to fight couperosis. cation.
Frequently the d amaged blood vessels, particu- In addition to the anti-oxidant activity the phy-
larly around the nose and on the cheeks will siological effects of ma ny flavonoids can be
negati vely influence the fac ial appreciation. explained as a disti nct influencing of the enzyme
Ginkgo biloba is a we ll- known source for fla- system of the organism. Application can be do ne
vonoids, and this extract is a very potent product orally or topically. Given the fact that many fla-
to treat couperosis. This effect has also been vonoids are water-soluble, transdermal applica-
observed using rutin when mice were exposed to tion is certainly a valid mechanism , and proba-
excessive X-raying, whi ch results in destruction bl y better controll able than ora! or intravenous
of the arteries (Bruckne r). The rate of survi val appl ication . However, ma ny fla vonoids are
inc reased from 31 % to 56%. For that reason poorly soluble and will precipitate/crystall ise at
rutin is used for treating radiation sickness in room temperature. In that case excellent results
men, e.g. the victi ms of radiation accidents in have been obtained by incorporation of flavo-
nuclear installations and it is also clinically noids such as quercetin an/or rutin in the liqu id
applied for patients that suffer from erythraemia crystalline matri x of suitable emulsifiers. The
due to y- irradiation. flavonoids are mono-molecularly soluble in the
A greatly less examined source of fla vonoids for liquid crystall ine matrix and the bio-availability
use in persona! care and cosmetics are extracts of is therefore s ignificantly higher compared to a
d ifferent nuts such as bitte r almond (Prunus system that does not util ise a liquid crystalline
a mygdalus), plums (Pru nus domestica, contai- matrix. lt has also been demonstrated that the
ning the flavonoid pruneto)) and black cherry acti vity of poorly soluble flavonoids can be
(Prunus serotina). These extracts are very potent improved when applied in unsaturated phospha-
inhibitors for a number of enzymes. It is also tidyl choline organogels.
inte resting to note that the fatty acid composition Rutin (and to a !esser extent esculetin) are well-
of black cherry oil (also named wi ld cherry oil) known inhibitors for the enzy mes aldose red uc-
a nd prune oil is fully in line with the chemical tase, lipoxygenase and phosphodiesterase. It dra-
properties of the flavonoids as they occur in the matically stre ngthens the capillaries, has bacteri-
frui t flesh. cide and antiviral properties, and a variety of
T he extract of peach (Prunus persica) and apri- properties that are pharmaceutical by nature.
cot (Prunus armeniaca) contain the fla vonoid Rutin is also highly appreciated for its ability to
prunasin that inhibits the conversion of dopa- avoid erythraemia. This is beneficially applied in
c hrome to melanin, and for obvious reasons sun care products, hav ing said that rutin is not
these extracts have been proposed and patented class ified as a UV fi lter.
fo r skin whitening. The 3-rhamnoside of the flavonoid quercetin is
Flowering peach (Prunus davidiana) is already named quercitrin . Quercetin a nd quercitri n occur
known for 3000 years to lower glucose levels in in apples, ali kinds of berries, onions (in The

148
 E. E.Brand-Garnys, H. Denzer, H. Meijer, H. M.Brand

Netherlands 54% of the ora! flavo noid intake botanica! extract is req uired, to such an extent
comes from onions, and 28% from apples), but that also side effects of undesired products may
also in nuts, flowers and the bark of many trees become apparent.
to which it gives a typical yellow colour.
Quercetin also occurs in significant amounts in BOTANICAL EXTRACTS RICH
botanica! extracts such as Gi nkgo biloba (gin- IN FLAVONOIDS
kgo), Hypericum perforatum (St.John 's wort),
Sambucus canadensis and Sambucus nigra
Botankal extracts are often rich in flavonoids,
(elder). Quercetin and quercitrin are potent anti-
and the diversity can be massive. In many publi-
oxidants and have a strong interaction with cations first priority is given to the antioxidant
enzymes. Quercetin inhibits xanthine oxidase properties of these flavonoids, but it has become
and in vitro experiments have shown that it also clear that flavonoids have a far more significant
inhibits lipid peroxidation. This is most signifi- role in topically applied products. Many flavo-
cant indeed as peroxidation of the unsaturated noids act as co-factors forali k.inds of enzymes.
fatty acids in the subcutaneous membranes As an example 3-galloyl-3' ,4 ' ,5,5 ' ,7-pentahy-
res ults in premature ageing.
droxyflavanone (EGCG), a flavonoid that occurs
Anti-inflammatory properties of quercetin and in camellia sinensis (green tea), has been demon-
quercitrin appears to be due to its anti-oxidant strated to inhibit the enzyme squalene monooxy-
and inhibitory effects on inflammation inducing genase . This reaction is important for the con-
enzy mes such as cyclo-oxygenase and lipoxyge- version of squalene to lanosterol/cholestero.I
nase, and the subsequent inhibited formation of (1 3) .
leukotrienes and prostaglandins. There is also
Enzyme manipulation via flavonoids is probably
evidence that quercetin and quercitrin inhibit
a generai working mechanism in the human
elastase, collagenase, hyaluronidase and tyrosi- body by adjustment of the dietary habits, but
nase. Ali these enzymes are most significant to also on the surface of the body via persona! care
the cosmetic chemist as they enable to contro! and cosmetic products . The tota) amount of fla-
and manipulate the quality of the skin. No data vono ids acqu ired via the daily food intake has
on ad verse effects of excessive dosage of flavo- been shown to be insufficie nt because of impro-
noids have been reported. The effective concen-
per dietary habits. Consequently the amount of
tration of flavonoids such as quercetin, querci-
fla vonoids topically present is in generai insuffi-
trin and rutin in cosmetic preparations is low cient to allow the topica) enzyme system to per-
(0,05-0 ,15%), although also at this low concen- form smoothl y. A similar discussion continuou-
tration the solubility of these flavonoids may be sly takes place on vitamins (also important, indi-
a limiting factor in formulation development. spensable, cofactors for enzymes).
Noteworthy is the normalising effect of flavo-
noids on the enzyme system. Many processes Chamomile (Chamomilla recufita)
that result in skin disorders boil down to a distur-
bed enzyme balance on the skin and in the sub-
Three well-known species of chamomile are in
cutaneous tissue . Flavonoids are a fabulous and
use: German or wild chamomile (Chamomilla
safe tool to alleviate these disorders. Although
recutita), Roman chamomile (Anthemis nobilis)
many botanica! extracts are also a significant
and golden chamomile (Anthemis tinctoria) .
source for flavonoids, their concentration is
Roman chamomile is commerciall y cultivated .
usually significantly lower and to reach a similar
Chamomile is an extremely rich source of flavo-
leve! of bio-activity a high concentration of

149
 Flavonoids: a Review far Cosmetic Application

noids: apigenin , Juteolin , quercetin , apiin , isor- ski n. The following substances are listed in the
hamnetin, patuletin , and a wide variety of glyco- literature as actives of the plant: amaranthin ,
sides such as apigetrin-7-acetylglucoside, luteo- rutin (quercetin-3-rutinose) and two other yet
lin-7-glucoside, luteolin-4'-glucoside, luteolin- unidentified complex glycosides deri ved from
7-ruti -noside, 6-hydroxy-luteolin-7 -glucoside, quercetin . Amaranthin is not a flavonoid but an
quercimetrin , patulitrin , rutin, hyperoside, isor- indole-based betaine with two sugar moieties
hamne tin-7-glucoside and c hrysoeriol-7-gluco- linked to it (one is a hexuronic acid).
side. Also a number of coumarins are present,
specifically to be menti oned coumarin , umbelli- Khella (Visnaga vera)
fero ne, methylumbelliferone and herniarin.
Luteolin , as it occurs in chamom ile, is a high ly Khel la grows in the Mediterranean countri es, but
useful substance; re ported activities: aldose- has also been brought to the Middle East and
reductase inhibitor, antiang iogenic, anticarcino- South America. Khella is commercially culti va-
genic, antioestrogenic, a ntimutagenic , antitu- ted in the United States. It is used in locai medi-
mour (powerful), no-synthase inhibitor, metallo- cine for the treatment of bronchitis, coug hs, hi gh
proteinase inhibitor, succinoxidase inhibitor, blood pressure, proble ms with the li ver and gal-
xanthine oxidase inhibitor, topoisomerase inhi- lbladder, but most of a li fo r coronary di seases . It
bitor. fortifies the arteries and is known to act on irre-
C hamom ile extract has anti-inflammatory, anti- gular heartbeat. In the treatment of kidney stones
itching, anti septic, bactericidal and disinfectant it ass ists to relaxing the ducts to the bladder,
properties. The beneficiai properties of c hamo- al lowing the stones to pass.
mile extract are well docume nted, and many pro- The principal active ingredient in khe lla extract
perties of the chamomile extract that product is khelline (v isamine), present in 0 ,3-0,4% .
development chemists use boil down to e nzyme Khelline has outspoken vasodilatory and vaso-
manipulation using flavonoids present in the ex- protective properti es, a nd therefore khella
tract. extract is most suitab le for the treatment of cou-
pe rosis.
Amaranth Next to khelline a wide variety of other fla vo-
(Amaranthus caudafus) noids are present, more specifically myricetin-3-
glucoside, myricetin-3-rhamnoglucoside, rutin ,
In foods, amaranth is used similarly to wheat as isoque rcetin , kaempferol-3-rutinoside and astra-
a cerea! grai n. It was one of the staple foodstuffs galin .
of the lncas, and it is known as kiwicha in the Also flavonoids structural ly related to khelline
Andes today. It was also used by the ancient (which has a psoralen structure) are present, to
Aztecs, who called it huautli . Amaranth species be mentioned visnad in , samidin , dihydrosami-
are culti vated and consumed as a leaf vegetable din , visnagin , visammidin , visnagenin and
in many parts of the world. In Indonesia , visnagidin.
Malays ia and China it goes by the name Khella e xtract is not subject to restrictions for
"bayam". use in persona! care and cosmetic products,
Orally, amaranth is used for the treatment of which is surpri sing given its potential.
ulcers , diarrhea, and infla mmation of the mouth Khella extract shall not be used in daytime
and throat. It is also used orally to treat hyper- cosme tics , but preferably in night care cosmetics
cholesterolemia and for the treatment of impure or in products such as masks.

150
 E. E.Brand-Garnys, H. Denzer, H. Meijer, H. M.Brand

hamnoside, kaempferol coumaroyl glucorham-

noside, luteolin glucoside and leuco-anthocya-
nins .

OH

HO
O=t1 o-eI ...'OH
OH

H3C - 'cH-CH2CH3
tH3
A CATECHIN
VISNADIN

A number of catechins is present such as cate-

Ginkgo (Ginkgo bilobo) chin , epicatech in, gallocatechin and epigalloca-
techin.
Ginkgo biloba, also named maidenhair tree, is Catechins aJso belong to the group offlavonoids,
the last me mber of the Ginkgoaceae which had but lack (compared to flavanones) the carbonyl
their first appearance on Mother Earth some group on the 4-position (catechins can be consi-
200-250 mi llion years ago. Darw in named it a dered as " hydroge nated anthocyanidi ns") .
li ving fossi!. Ginkgo contains some unusual che- Because of the saturation of the ~2 -3 double
mical substances that are found nowhere else in bond a chiral cente r is prese nt on the 3-position.
nature : bilo balide (a sesquiterpene), gi nkgo lides Both enantiomers do occur naturally.
(diterpenes with 20 carbon atoms) and aromatic Traditionally the gi nkgo extract is used to com-
prod ucts suc h as ginkgo), bilobdol and ginkgolic bat disorders of the bronchi al tubes. For persona!
acid. Little is known about the phys iological care and cosmetic products enzyme inhibition is
effects of these substances, although gi nkgo the keyword.
extracts are used in traditional medicine for 4000 The extract of G inkgo biloba is probably the
years for the treatment of a variety of di sorders strongest botanica! enzyme inhibitor known; a
and complaints. Ginkgo biloba extract is also a wide variety of publications on this topic have
valuable source for shikimic acid , a building appeared in the scientific literature. The extract
block for the synthesis of flavono ids, in a com- inhibits various elastases, the seven hyaluronida-
parable fashion as phe nylalanine . ses known and a wide variety of phosphatases.
Ginkgo extract is also a very rich source for fla- These enzymes exhibit an increasing activity
vonoids. The extract contains quercetin, isoquer- with increasing age , and result in visi ble signs of
cetin , isorhamnetin, kaempferol, myricetin, bilo- ageing. Consistent use of the ginkgo extract will
betin (only one source known , and this is also notably reduce these effects, and can therefore
val id for ginkgetin and isoginkgetin), sciadopy- be considered as a superior anti-ageing product.
tisin. Other cosmetically significant properties of the
Also a variety of glycosides is present such as
ginkgo extract are vasodilatation and the stimu-
quercetin-3-rhamnoglucoside, kaempferol-3- lating effects. There is sufficient reason to belie-
rhamnoglucoside, quercetin coumaroyl gl ucor- ve that these properties boil down to enzyme

151
 Flovonoids: o Review tor Cosmetic Appficotion

inhibition by flavonoids. Also the anti-oxidant One of the major functionalities from licorice
properties (the ability to quench free radicals) of extract is the inhibition of two enzymes: tyrosi-
the ginkgo extract are important, and an impor- nase and superoxide dismutase. This inhibition
tant tool to avoid peroxidation of membrane results in a scenario whereby skin lighteni ng can
lipids as well as oxidative stress. be ach ieved while reducing simultaneous ly
reducing oxidative stress. This goes hand-in-
Calendula (Calendula Officinalis) hand with the stimulation of the enzyme squale-
ne monooxygenase to promote the topica! pro-
Calendula extract, or calendula oil , is probably duction of cholesterol . Licorice has also bacte-
the most spirited advocate of homeopathy. This riostatic properties that originate from the flavo-
is largely attributed to a wide range of terpenoids noid fonnonometin (7-hydroxy-4'-methoxyiso-
present, but also to flavonoids that occur both in flavone).
calendula extract and calendula oil. These have
anti-inflammatory properties, are appreciated Me
irritation quenchers, and have antiseptic, astrin-
Me
gent, fung icide, soothing, wound healing and
tonifying properties. Quercetin is the most
important flavonoid present, next to a wide range
of glycosides of quercetin and isorhamnetin.
Kalvatchev (14) showed that organic extracts of
dried calendula flowers inhibit HIV-l reverse
transcriptase, while aqueous extracts did not
OH
show this property. For this reason the fl avo-
noids present in this extract are examined on the GLABRA DINE
potential application for the treatment of HIV
infections, although their mode of action is not Glabradine has been identified as the most acti-
understood. ve flavonoid . It is, in chemical terminology, a
Quercetin is without doubt the most widespread catechin. The heterocyclic 6-membered ring on
fla vonoid that is known . lt indeed is a powerful the 7 ,8-position is composed of an isoprene unit
anti-oxidant, but it is also a powerful enzyme that originates from reaction with dimethylallyl
inhibitor, in particular for phosphodiesterases pyrophosphate (DMAPP). Two additional flavo-
and lipases . noids are present that are structurally related to
glabradin (glabrol, formonometin) that are also
Licorice (Glycyrrhiza glabra) physiologically active.

Licorice extract is a powerful extract, and the Horse Chestnut

basis for that is the presence of qui te a number of (Aescu/us Hippocastanum)
flavonoids: glabradine , liquiritine, isoliquiritine,
liquiritigenin , isoliquiriti-genine, isoliquiritosi- Horse chestnut is a powerful source for flavo-
de, diglucoliquiritoside, and some coumarins noids . The flavonoid composition is dependant
(umbelliferone and hemiarin). Licorice extract is on the part of the tree that is considered. The
also used in food industry to make children's bark contains 3% aescu lin (camarin g lycoside),
sweets aesculetin, aescin, fraxin, scopolin , fraxetin , sco-

152
 E. E.Brand-Garnys, H. Oenzer, H. Meijer, H. M.Brand

poletin, quercitrin, quercetin and leukoanthocya- blems in terms of bio-availability. This problem
nes. The flowers contain kaempferol-3-glucosi- can be bypassed to molecularly dissolving quer-
de, kaempferol-3-arabinoside , kaempfero l-3- cetin in a Iiquid crystalline matrix composed of
rhamnoglycoside, rutin , and isoquercetin. The particular amphiphilic products (emulsifiers).
seed contains only a minor amount of flavo- Quercetin is a powerful anti-oxidant suitab le for
noids, but the leaves are rich in fraxin and sco- appl ication in food products. The anti-oxidant
polin. properties of flavonoids are easily understood
A major property of horse chestnut extract is to because of the presence of a large number of
activate those enzymes that are responsible for phenolic hydroxy groups, enabling free radicals
stimulation of the hair follicle. Consequently the leapfrogging over the aromatic system. As an
extract is frequently used for hair growth prepa- example, the anti-oxidant properties of quercetin
rations. Another significant property of the fla- enable a much better uti lization of ascorbic acid
vonoids present in horse chestnut is the abi lity to (vitamin C), having said that ascorbic acid is an
eli minate bui ld-up of body liquids. The applica- antioxidant by itself.
tion of a gel containing 5-10% horse chestnut Quercetin is 20 times more potent than ascorbic
extract to the legs after an interconti-nental flight acid, and 50 times more potent than tocopherol
wi ll resolve the edema in 10-15 mi nutes. (vitamin E) . It has also been demonstrated that
querceti n is able to avoid oxidation of membra-
THE MOST SIGNIFICANT ne lipids (usually with a high degree of unsatura-
FLAVONOIDS tion) and to reduce oxidative stress.
In a number of publications synergistic mixtures
It has been demonstrated that flavonoids are have been suggested of quercetin with either
indispensable products that shall be prut of the ascorbic acid or ~-glucans, or a combination of
daily d iet, but they ate high ly fu nctional ingre- these three ingredients, taking advantage of the
dients for persona! care and cosmetic products. re-enforcement of the auto-immune system by
~-gl ucans . Contrary to statements in earlier
A healthy skin will cover a healthy organism.
For this reason it is useful to discuss the major publications it is probably not possible to use
flavonoids separately. quercetin to guarantee the oxidative stability of
ascorbic acid in cosmetic emulsions.
Quercetin: 3,3',4',5,7-penfahy- In a way flavonoids, and quercetin in particular,
can be compared to vitamins. Quercetin has been
droxyflavone
identified as a positive or negative cofactor fora
Quercetin (synonyms: meletin, sophoretin , quer- number of enzymes. For both vitamins and fla-
vonoids is valid that the human body is not able
ceto!, xanthaurine, CI 75670, Natural Yellow 10)
is a high melting, yellow solid (3 16-3 17° C). lt to produce them (with the exception of vitamin
D3 and D4) and is dependant on them via the
is poorly soluble in water (both cold and warm),
intake offood. The average daily intake offlavo-
but soluble in warm ethanol and acetone.
Quercetin is also soluble in acetic acid , organic noids (in mg) is given in table XlII.
Given the oral intake of relatively large amounts
amines and in alkali . Solutions of quercetin in
alkali are intense yellow. However, because of of flavonoids accumulative and toxicological
the limited solubility in commonly used solvents effects ha ve been studied in detail. Schneider
(15) showed that Eubacterium ramulus (which
applied in cosmetic products complete dissolu-
tion may occasionally cause form ulation pro- occurs in human faeces) degrades quercetin (and

153
 Flovonoids: o Review tor Cosmetic Applicotion

also rutin, kaempferol, luteolin, luteolin-7-glu- present in ginkgo extract stimulates proliferation
coside, eriodictyol , naringenin , tax ifolin and of human skin fibroplasts and increase the pro-
phloretin) to phenolic acids, in the case of quer- duction of collagen and extracellular fibronectin .
cetin to 2,4,6-trihydroxybenzoic acid. Quercetin is heavily involved in this process,
The FDA has nominated quercetin for toxicity next to ginkgolide, bilobalide, kaempferol and
and carcinogenicity studies in the rat as querce- sciadopitysin , and that both observations bo il
tin is subject to a considerable dietary intake. down to enzyme inhibition.
The study was done via a two year feeding study Quercetin showed to be potent in the cytotoxici-
on male and fornaie F344/N rats. The results ty against tumor cell lines. Scambia et. al. (19)
indicate that there is no evidence of toxic and/or demonstrated that quercetin inhibits the growth
carcinogenic activity in fornaie rats, and that of severa! cancer line cells and that the anti-pro-
there was onJy minor and insignificant evidence liferative activ ity is rnediated by a so-caUed type
on male rats, receiving 1.000, 10.000 and 40.000 II estrogen binding site . Many other flavonoids
ppm (max.4%) . also have estrogen properties, but quercetin is
Quercetin is a powerfu l enzyme manipulator. believed to be one of the more potent products,
Thome et.al. (16) demonstrated that q uercetin comparable to genistein .
selectively inhibits the activity of JE5-lipoxyge- It was remarkable that quercetin showed itself to
nase and other enzymes known to be involved in be a strong synergist for cis-platinum relative to
the metabolism of arachidonic acid in cells. the anti-proliforative effects of the ovarian can-
Quercetin exhibits both allergie mediator release cer celi line OVCA-433. The effects observed
activity and selective inhibition of the biosynthe- were demonstrated to originate from enzyme
sis of pro-inflammatory arachidonic acid meta- inhibition.
bolites, and is a prototype for the development of
new anti -allergic and anti-inflammatory com- Quercetin Glycosides
pounds. These properties make quercetin to a
highJy desired product for cosmetic products. Next to quercetin, an aglycon, also a wide varie-
Castelli (17) showed that a combination of gin- ty of glycosides are known, many of them being
kgo extract and carboxy-methy l- 1 ,3-~-glucan physiologically active products .The hydroxy
applied to the skin for two weeks significantly group on the 3-position of quercetin may be
reduced dermatitis fora number of allergens fo r occupied by a rutinose unit (6 - (~-1 -1-rhamnosi­
a large group of woman in a double blind study. do)-d-glucose) and is named rutin (quercetin-3-
Analysis by GC/MS showed that quercetin and, rutinose) .
to a !esser extent, kaempforol were responsible Rutin may be extracted from D imorphandra
for the observations . mollis and Ruta graveolens (Rue).
In addition, Kim ( 18) showed that the flavonoids

Table XIII
Average human daily intake offlavonoids.

Quercetin 8,5 Kaempferol 5,0

Rutin 1,5 Myricetin 0,6
Fisetin 0,4 Luteolin 0,3
Eriodictyol 0,3 Myricitrin 0,01

154
 E. E.Brand-Garnys, H. Denzer, H. Meijer, H. M. Brand

Historically rue has been used by thousands of rose hips.

women in Latin America as a contraceptive to According to a JOmt Canadian/United States
prevent pregnancy. It is known that rutin research program quercitrin has been claimed to
responds positively to the calcium and magne- be promising for the treatment of various forms
sium metabolism, and has potential benefits for of cancer. This would include prostate cancer,
the treatment of osteoporosis. lu ng cancer, melanoma and breast cancer
Rutin has been reported to have anti-oxidant (results presented on the 219'h national meeting
properties and is vita! in its ability to improve of the American Chemical Society). Tangeretin,
capillary fragility (increasing the strength of nobiletin and quercitrin, flavo noids present in
capi llary blood vessels) and to regulate their per- tangerine juice, were the most effective inhibi-
meability. tors of human prostate cancer cells. These pro-
Rutin has synergistic acti vity with ascorbic acid ducts also inhibited the growth of melanoma
in keeping collagen in healthy condition and to cells and were effective against breast cancer
enable proper absorption and use of ascorbic cells, with comparable activity as tamoxifen
acid. Rutin inhibits the degradation of collagen (anti-breast cancer drug). Animai studies are to
by the enzyme xanthinoxidase to smaller pepti- date not completed yet.
des, and has been shown to reduce the activity of Quercitrin is useful in the treatment of high
lipoxygenase (tested on soybean lipoxygenase) . blood pressure due to their capillary-strengthe-
Quercitrin is characterised as the 3-rhamnoside ning and blood vesseldi lating properties. It is
of quercetin. Quercitrin may occur in either also useful in capillary fragility disorders such as
anhydrous form (MP=250°C) or monohydrate easy bruising, bleeding of the gums, and also in
(MP=l82°C). It is insoluble in cold water but circulatory disorders of the retina of the eye. It is
soluble in hot water. It is also soluble in glacial particularly useful in the treatment of vein and
acetic acid, ethanol and in alkaline solution. capi ll ary problems such as varicose veins,
Alkali ne solutions of quercitrin are very intense venous insufficiency (poor return of blood to the
yellow coloured, and may develop a precipitate heart from the ve ins of the legs), and eye pro-
in time due to hydrolysis of the glucoside. blems such as diabetic retinopathy and macular
Quercitrin is a powerful anti-oxidant. Quercitrin degeneration.
is well tolerated in the gastro-intestina! tract. Hyperoside (hyperin , quercetin-3-galactoside) is
Dong et. al. (20) showed that quercitrin is degra- found in Hyperic um perforatum (St.John 's
ded to either quercetin and rhamnose, but aJso wort). Hyperoside is a powerful anti-ageing pro-
further degradation (under anaerobic conditions) duct because of the inhibition of the enzyme ela-
occurred, resulting in the formation of 3 ,4-dihy- stase. Combined with chickweed the extract of
droxyphenylacetic acid and 4-hydroxybenzoic St.John 's wort is useful for the treatrnent of eczema.
acid. Both products were identified as the meta- Hawthorn (Crataegus pinnatifida) is a thorny
bolites. 3,4-Dihydroxyphenylacetic acid and 4- tree, widely distributed in the north temperate
hydroxylphenylacetic acid are potent in vitro regions. It is an important source of hyperoside,
anti-platelet aggregation activitors . next to protocatechuic and chlorogenic acid, epi-
Polygonum fagopyrum (B uckwheat) is an catechin , querceti n, isoquercetin and rutin. The
important source for quercitrin. The dried leaves psoralen leve! is low. Also loquat (Eriobotrya
contain 3-8% flavonoids, the majority being Japonica) is a valuable source of hyperoside.
quercitrin and rutin. Significant amounts of Hawthorn and loquat show efficacy on the sup-
quercitrin are also found in citrus fruits and in pression on the inhibitory effect on Cu 2+ media-

155
 Flavonoids: a Review for Cosmetic Application

ted oxidation of human LDL and has a protecti- cal extracts is dedicated to fla vonoids.
ve effect on a-tocopherol in human LDL. Flavonoids are powerful antioxidants, and in vir-
Hyperos ide has bactericidal properties tually ali cases they outperform artificial anti-
(MIC=250-500 µg/ml) and has been reported as oxidants and poor antioxidants such as tocophe-
an anti-viral. It is used to treat fragility of the rol and ascorbic acid. They enable to contro) oxi-
capillaries (couperosis), dermatitis, has anti- dative stress and peroxidation of membrane
inflamrnatory properties and is cancer preventive. lipids.
Isoquercetin (quercetin-3-glucoside) is found in Flavonoids are powerful enzyme modulators; in
significant amounts in Equisetum arvense (hor- many cases it has been shown that they are posi-
setail). The hollow, jointed stems of this flower- tive or negative cofactors for various enzymes
less plant contain large amounts of water-soluble such as phosphodiesterases, hyaluronidases, ela-
(5-8%) with excellent bio-availability. stases, aldose reductases, lipoxydases and lipo-
Horsetail reduces the risk of excessive bleeding xygenases.
and contributes to the building of healthy blood The application of flavonoids in
cells. Topically applied it has positive impact on pharmacy/medical technology and food supple-
the bloodstream. lt has been shown that horsetail ments has been well developed. The appl ication
increases the number of phagocytes, germ-kil- of fla vonoids in persona! care and cosmetic pro-
ling enzymes, greatly improving the well-fun- ducts is Jess developed , although the use of bota-
ctioning of the entire immune system. nica) products is common practice. Maj or appli-
Isoquercetin is frequently outperfo rming ~-glu­ cations of fla vonoids are in anti-ageing, anti-cel-
cans on the protection of the auto-immune lulite, anti-couperosis and skin lightening pro-
system. ducts, and applications as soothing, astri ngency,
Horsetail contains a significant amount of iso- bactericide properties, and many others.
quercetin (up to 0,5%), next to two flavone gly- The use of purified fla vonoids has a significant
cosides characteristic for horsetail (galuteolin & potential in persona! care and cosmetics as the
equisetrin). The combination of these flavonoids application of botanica] extracts will never ena-
is responsible for the bactericidal properties. ble to reach a cosmeceutical leve] of acti vity.
Like most flavonoids, isoquercetin is a powerful This goes together with the fact that raising the
anti-oxidant. concentration of botanica! extracts in consumer
lsoquercetin is a well-known aldose-reductase products implicitly means also an increased
inhibitor. It has also antibiotic and diuretic pro- leve] of less desired products (e.g. al kaloids and
perties. Some sources for isoquerceti n are saponines) present in the fmal consumer product.
Filipendula ulmaria (meadowsweet), A number of flavonoids are commercially avai-
Foeniculum vulgare (fennel), psidium guajeva lable, such as quercetin, quercitrin, isoquercetin ,
(guava) and Viscum album (rnistletoe). apigenin , biochanin, geniste'ine, daidzein and
rutin.
CONCLUSION The beneficiai properties of the use of pure fla-
vonoids start to be recognised by the persona!
Flavonoids comprise a Jarge group of products care and cosmetics industry. The first consumer
that bave similar structural properties. Ali flavo- products have already arrived in the market
noids are from vegetable origin; many botanica) piace.
extracts contain significant amounts of flavo-
noids. In many cases the functionality of botani-

156
 E. E.Brand-Garnys. H. Denzer, H. Meijer, H. M.Brand

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ration and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr. Cancer
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3) Hirono I , Ueno I , Hosaka S, Takanashi H., et al (1981) . Carcinogenicity examination of quer-
cetin and rutin in ACI rats. Cancer Lett.,13: 15-21.

157
 Flavonoids: a Review tor Cosmetic Application

4) Aeschbacher HU, Meier H, Ruch E . (1982). Non-mutagenicity in vivo of the food fla-vonol
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23) Doan DD, Nguyen NH, Doan HK., et al (1994). Studies on the indi viduai and combined diure-
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Author Address:
Dr. lr. Hans M. Brand
Elzbieta Cosmetics B.V.
Bronsmos 41
2914 AD Nieuwerkerk a/d IJssel
The Netherlands
Fax +31-180-318164
E-mail: [email protected]

159