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Skin Pharmacol Physiol 2013;26:8–14
DOI: 10.1159/000343174
Caffeine’s Mechanisms of Action and Its
Cosmetic Use
A. Herman a A.P. Herman b
a Academy of Cosmetics and Health Care, Warsaw , and
b The Kielanowski Institute of Animal Physiology and
Nutrition, Polish Academy of Sciences, Jabłonna , Poland
Introduction
Caffeine is one of the alkaloids which can be found in
coffee, tea and some soft drinks. Caffeine is well known
as a mild stimulant of the central nervous system where
it is transported with blood after its absorption in the
stomach and small intestine. In the liver, caffeine is me-
tabolized by the cytochrome P450 oxidase system into 3
derivative dimethylxanthines: paraxanthine (speeds up
lipolysis), theobromine (expands blood vessels), and the-
ophylline (relaxes smooth muscles of the bronchi)
[1] .
These metabolites of caffeine after demethylation and ox-
idation pass to derivatives of xanthine and uric acid. Only
10% of the caffeine is excreted from the body by the kid-
neys in an unchanged form
[2] . In the brain, caffeine as a
ligand (instead of adenosine) blocks the adenosine A1
and A2 receptors
[3] . Both ligands, caffeine and adeno-
sine, show a high similarity of their chemical structures
[4] . They can affect the release of neurotransmitters such
as acetylcholine, dopamine, noradrenaline, gamma-ami-
nobutyric acid, and serotonin, which enhances mood
[5] ,
stimulates the organism, improves concentration and
eliminates physical fatigue
[6] . Caffeine also inhibits
phosphodiesterase (PDE) activity, an enzyme which is re-
Key Words
Caffeine ⴢ Penetration through the skin ⴢ Cellulite ⴢ
Microcirculation ⴢ Antioxidant
Abstract
Caffeine is being increasingly used in cosmetics due to its
high biological activity and ability to penetrate the skin bar-
rier. This alkaloid is frequently used as a hydrophilic model
substance in human and animal skin penetration as well as
different synthetic membrane using Franz diffusion cell ex-
periments. The commercially available topical formulations
of caffeine normally contain 3% caffeine. As for a cosmetic
purpose, caffeine is used as an active compound in anti-cel-
lulite products because it prevents excessive accumulation
of fat in cells. This alkaloid stimulates the degradation of fats
during lipolysis through inhibition of the phosphodiesterase
activity. Caffeine has potent antioxidant properties. It helps
protect cells against the UV radiation and slows down the
process of photoaging of the skin. Moreover, caffeine con-
tained in cosmetics increases the microcirculation of blood
in the skin and also stimulates the growth of hair through
inhibition of the 5- ␣ -reductase activity.
Copyr ight © 2012 S. Karger AG, Ba sel
Recei ved: April 3, 2012
Accepted a fter revision: August 29, 2012
Publish ed online: October 11, 2012
Ann a Herman, PhD
Academy of Cosmetics and He alth Care
Podwa le 13 street
PL–00-252 Warsaw (Poland)
E-Mail anna.herman @ wszkipz.pl
© 2012 S. Ka rger AG, Basel
1660–5527/13/0261–0008$38.00/0
Accessible online at:
www.karger.com/spp
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Caffeine’s Mechanisms of Action and Its
Cosmetic Use
Skin Pharmacol Physiol 2013;26:8–14
9
sponsible for the degradation of cyclic adenosine mono-
phosphate (cAMP) to the noncyclic form 5 ⴕ -A MP [3] . The
inhibition of PDE increases the cAMP concentration in
cells and also elevates blood pressure
[3] . Although the
impact of caffeine on the human organism is well under-
stood, the mechanism of the cosmetic action of caffeine
has not been fully explained. Given that coffee and caf-
feine are used increasingly for the production of many
cosmetics, it seems interesting to clarify whether it is re-
ally able to improve the skin’s appearance and the hair’s
condition. The ability of caffeine to penetrate the skin
barrier is essential when discussing the mechanism of its
action on skin and hair.
Penetration of Caffeine through the Skin Barrier
The ability of active compounds from cosmetics or
pharmaceuticals to influence the metabolism of cells and
other processes occurring in the skin is largely dependent
on the capacity of these molecules to penetrate through
the skin barrier. Caffeine is frequently used as a hydro-
philic model substance in skin penetration experiments
[7–11] . Previous studies found out that caffeine penetra-
tion of the skin barrier was unchanged by occlusion
[12]
and skin thickness
[13 , 14] , but the application of 5% caf-
feine in a hydroxyethylcellulose gel for 7 days significant-
ly reduced transepidermal water loss in male skin com-
pared with female skin
[15] . The maximal absorption
rates of caffeine through the human skin were found to
be 2.24 8 1.43 g/cm 2 /h [13] , and the maximal absorp-
tion was reached at 100 min after local application in vivo
[16] . Touitou et al. [17] using quantitative skin autoradi-
ography found out that after 24 h, the greatest concentra-
tion of caffeine (280 g/tissue) was localized in the epi-
dermis, while the lowest amount of this alkaloid (50 g/
tissue) was detected in the dermis.
The penetration of caffeine was also compared in
Franz-type diffusion cell experiments with different
coated membranes, e.g. skin of humans
[8, 18, 19] and
animals
[9, 10] or synthetic materials [20, 21] . The perme-
ation of different concentrations of caffeine (3% and 1, 3,
and 5%) through human skin and synthetic membranes
(cellulose acetate impregnated with isopropyl myristate,
silicone rubber soaked in isopropyl myristate and poly-
sulfate) using Franz
diffusion cells were compared by
Dias et al.
[20] and Mustapha et al. [21] , respectively. Both
research groups did not find a correlation between caf-
feine transfers through the synthetic membranes and
those observed through the human skin. Moreover, Mu-
stapha et al.
[21] show ed t ha t the d if fusion flux of caf feine
permeation does not depend on the concentration but
rather on the quantity of formulation applied. Also Sha-
keel and Ramadan [10] confirmed that the type of emul-
sion affects the transdermal delivery of caffeine. A sig-
nificant increase in the permeability of caffeine in Franz
diffusion cells using rat skin as permeation membrane
was observed in water-in-oil nanoemulsion formulations
as compared to aqueous solutions of caffeine
[10] .
Other studies concerned the permeation of caffeine
from microspheres applied in aqueous suspension (diam-
eter of the microspheres: 2.8 m, caffeine loading: 2.3
mg/g of particles) and from solution through in vitro dif-
fusion measurements with Franz-type diffusion cells
over 24 or 72 h
[22] . After 24 h, the total amount of caf-
feine from microspheres carried out on full-thickness
skin without hypodermis was twice as high as that from
aqueous solution (22.6 vs. 9.99%). The results suggested
that microspheres could easily penetrate through the skin
and accumulate in the receptor compartment, ensuring
continuous caffeine release. After 72 h of exposure, the
receptor fluid contained 15.3% free caffeine and 27.8%
encapsulated fractions. For the cosmetic use of caffeine,
its penetration through the skin is the key.
Anti-Cellulite Properties of Caffeine
Cellulite (gynoid lipodystrophy), commonly called
‘orange peel effect’, is a typical women’s problem, which
mainly appears on the thighs and buttocks. Cellulite is
a complex disorder involving the microcirculatory and
lymphatic systems, the extracellular matrix and the pres-
ence of excess subcutaneous fat that bulges into the der-
mis
[23] . Lipolysis is the degradation process of triglycer-
ides from adipocytes by lipoprotein lipases, leading to
the formation of fatty acids and glycerol. Lipases located
on the fat cell membrane can be activated or inhibited
by catecholamines (noradrenaline and adrenaline) and
hormones (insulin, glucagon, and adrenocorticotropin).
Adrenaline, noradrenaline, glucagon, and adrenocorti-
cotropin activate the lipases, while insulin inhibits the
activity of these enzymes. Depending on the hormones
and type of adrenergic receptor ( ␣ or  ) in adipocytes, the
lipolysis process can be activated or inhibited. Insulin
binding to the ␣ adrenergic receptor stimulates the col-
lection of fat in adipocytes, while the second receptor ( 
adrenergic) binds to adrenaline, noradrenaline, gluca-
gon, or adrenocorticotropin and stimulates the degrada-
tion of fats during the lipolysis process. The biological
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Skin Pharmacol Physiol 2013;26:8–14
10
compounds activating the lipolysis pathway induce the
conformational change in the structure of the G protein-
coupled receptor and stimulate the adenylate cyclase to
synthesize the cytosolic cAMP. An increasing level of
cAMP stimulates protein kinase A to activate hormone-
sensitive lipase (HSL) by phosphorylation. Phosphorylat-
ed HSL hydrolyzes triglycerides into diglycerides, mono-
glycerides, free fatt y acids, and glycerol. The lipolysis pro-
cess can be inhibited by a decreasing level of cAMP. PDE
activity is responsible for the degradation of cAMP into
its noncyclic form 5 ⴕ -AMP [24, 25] .
Caffeine can affect the above-mentioned intracellular
signaling pathways in several ways. It may affect the se-
cretion of catecholamine, which activates  adrenergic
receptors, increases the concentration of cAMP in cells
and activates HSL in the lipolysis process
[26] . This alka-
loid also blocks ␣ adrenergic receptors, preventing an
excessive accumulation of fats, and speeds up the lipoly-
sis process
[27, 28] . Caffeine also stimulates lipolysis via
the inhibition of PDE activity and by increasing the
cAMP levels in adipocytes
[29] . Then caffeine activates
HSL, which leads to the degradation of triglycerides in
G␥
Gs␣
GDP
GDP GTP
GTP AC
ATP
cAMP
AMP
5’-AMP
PDE
PKA
inactive
4 x cAMP
4 x cAMP
PKA
active
Adipocyte triglyceride
lipid droplet
Receptor
Caffeine
Adipocyte cell membrane
Cytoplasm
HSL
HSL-P
TG
DG
MG
FFA
Glycerol
Glycerol FFA
reduction of adipocyte
lipid droplet size
REDUCTION OF ADIPOCYTE SIZE
Lipolysis (hydrolysis of
stored triglycerides)
GGs␣
Fig. 1. Caffeine’s mechanism of action
during lipolysis in adipocyte. GDP = Gua-
nosine diphosphate; GTP = guanosine tri-
phosphate; AC = adenylate cyclase; ATP =
adenosine triphosphate; PKA = protein
kinase A; HSL-P = phosphorylated hor-
mone-sensitive lipase; TG = triglyceride;
DG = diglyceride; MG = monoglyceride;
FFA = free fatty acid.
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the lipolysis process, and takes part in the reduction of
cellulite ( fig.1 ). Caffeine also stimulates the draining
lymph systems in fatty tissue by removing accumulated
fat, toxin and unnecessary substances arising during the
lipolysis process, which all together may impede the mi-
crocirculation in blood vessels and foster the emergence
of cellulite.
Pires-de-Campos et al. [30] explored the effect of gel
application on swine hypodermis (dorsal area): gel with
ultrasound treatment (3 MHz, intensity: 0.2 W/cm
2 , rate:
1 min/cm
2 ), gel with caffeine (5%, water-in-water), and
gel with caffeine and ultrasound, daily for 15 days. A pre-
specified (fifth) area received no topical application and
was used as control. Among all the experimental groups,
only caffeine treatment associated with ultrasound ther-
apy was effective. The results showed a significant reduc-
tion in the thickness of the subcutaneous adipose tissue,
as well as damage of the adipocytes, consequently de-
creasing the number of cells. Velasco et al.
[31] also exam-
ined the effect of emulsion with caffeine, caffeine and so-
dium benzoate, and siloxanetriol alginate caffeine (SAC)
on the diameter and number of fatty cells with a light mi-
croscope. Emulsion with caffeine and its derivatives was
applied topically for 21 days on Wistar female mice.
Emulsion with caffeine and SAC provoked a reduction of
the diameter of fatty cells compared with controls of 17
and 16%, respectively, while the emulsion with caffeine
and sodium benzoate did not cause alterations of the cell
diameter; moreover, sodium benzoate inhibited the effi-
ciency of caffeine. Caffeine also had a significant anti-
cellulite effect versus baseline, shown by its superiority
versus placebo in the skin’s macrorelief (it decreased the
‘orange peel’ effect), and increased the cutaneous micro-
circulation
[32] .
Caffeine’s Effect on Microcirculation of Blood
Vessels
Caffeine can improve the microcirculation of blood
vessels. Some research carried out using computed to-
mography showed that a dose of 250 mg caffeine given
orally increased the circulation of blood in the human
brain by 30%
[33] and a dose of 100 mg caffeine given
orally increased the microcirculation of blood in the hu-
man ocular fundus
[34] . The study performed by Lupi et
al.
[35] showed that a 7% caffeine solution affected the
reduction of cellulite and improved the microcircula-
tory blood flow in all women taking part in the experi-
ment. For observing the changes in the blood microcir-
culation, a noninvasive method was used – orthogonal
polarization spectral imaging, which determined capil-
lary density (number of flowing capillaries per unit area
of the skin) and centimetrical measurements of thighs
and hips. In the same study, the inf luence of tobacco,
alcohol and physical activity on the effectiveness of the
cellulite treatment was also examined. A significant re-
duction of thigh circumferences in more than 80% of the
cases and a reduction of hip circumference in 67.7% were
observed after 1 month of treatment. The capillary den-
sity after 1 month of caffeine administration was slight-
ly increased, but the changes were not statistically sig-
nificant. The results of Lupi et al.’s study
[35] showed
that smoking, alcohol consumption and regular physi-
cal activity do not affect the reduction of hip circuit in
women.
Caffeine can effectively reduce swelling of the tissue
around the eyes. Amnuaikit et al.
[18] compared the im-
pact of both a 3% caffeine gel and a gel base on the de-
crease of puffy eyes among Thai volunteers (18 women
and 16 men, aged 19–24 years). An insignificant differ-
ence between the efficacy of caffeine gel and gel base to
reduce puffy eyes was found as only 23.5% of the volun-
teers responded to the caffeine activity.
Antioxidant Properties of Caffeine
It is well known that UV rays accelerate photoaging of
the skin, reduce the synthesis of procollagen, affect the
fiber of collagen, reduce skin elasticity, cause expansion
and cracking of skin blood vessels, stimulate the forma-
tion of wrinkles, spots and discoloration, and in extreme
cases they can lead to cancer of the skin, e.g. melanoma
[36] . UV radiation also increases the production of free
radicals, leading in consequence to cell damage. Adding
caffeine to the formula of sunscreen cosmetics raises its
protective effect against UV radiation, reduces the for-
mation of free radicals in skin cells and could be useful
in preventing UV-induced skin cancers
[37, 38] . Leon-
Carmona and Galano
[39] revealed that caffeine is an ef-
fective scavenger of hydroxyl radicals ( ⴢ OH) and alkoxyl
radicals ( ⴢ OCH 3 ), a poor scavenger of HOO( ⴢ ) radicals,
inefficient for directly scavenging O
2 ( ⴢ –) and ( ⴢ )OOCH 3
radicals and most likely other alkyl peroxyl radicals.
There are also reports concerning the impact of caffeine
on the protection of skin cells from cancer caused by UV
radiation.
Caffeine affects the UV-damaged cells of human
skin causing cellular divisions and apoptosis before they
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Skin Pharmacol Physiol 2013;26:8–14
12
begin to transform into cancer cells. Kerzendorfer and
O’Driscoll
[36] demonstrated that caffeine administered
orally or topically accelerated apoptosis of mice keratino-
cytes damaged by UVB radiation. The study performed
by Abel et al. [40] also demonstrated that daily intake of
coffee ( 1 6 cups) caused a 30% reduction in the prevalence
of nonmelanoma skin cancer in Caucasian women. Oth-
ers found that caffeine has the ability to selectively induce
apoptosis in vitro in UV-damaged keratinocytes
[41] .
Studies were carried out on p53-mutated keratinocytes,
isolated from the human skin. This cell line contains
about 4% mutated keratinocytes from all isolated kerati-
nocytes of the human skin. In comparison with the other
keratinocytes isolated from the skin, p53-mutated kerati-
nocytes are more resistant to UV-induced apoptosis.
Sunlight also acts as a tumor promoter by favoring the
clonal expansion of p53-mutated cells over the other ke-
ratinocytes of the skin. Caffeine induced apoptosis in
p53-defective cells. Lu et al.
[42] demonstrated that topi-
cal application of caffeine to mice enhanced the elimina-
tion of p53-mutated keratinocytes from the skin. Immu-
nohistochemical analyses showed that topical applica-
tions of caffeine increased apoptosis in nonmalignant
skin tumors and in squamous cell carcinomas, but there
was no effect on apoptosis in tumor-free areas of the epi-
dermis. Also Kramata et al.
[43] reported that mice oral-
ly treated with caffeine or green tea during chronic UVB
irradiation showed changes in the mutation profile of the
p53 gene in early mutant p53-positive epidermal patches.
Topical applications of caffeine after discontinuing the
chronic UVB irradiation specifically eliminated patches
harboring homozygous p53 mutations. Studies carried
out by Heffernan et al.
[44] explained the caffeine’s mech-
anism of action for these important observations. Caf-
feine at a concentration of 2 m
M inhibits cAMP PDE, in-
creases the intracellular levels of cAMP and promotes
apoptosis in UV-damaged primary human keratinocytes
[44] . Also Conney et al. [45] showed that the oral admin-
istration of green tea or caffeine to hairless SKH-1 mice
for 2 weeks stimulated apoptosis in UV-induced sun-
burnt cells in the epidermis. A similar effect was observed
when caffeine was applied topically immediately after
UV exposure. In mice pretreated with UV radiation for
22 weeks (high-risk mice without tumors), topical appli-
cations of caffeine 5 days a week for 18 weeks with no
further UV treatment inhibited carcinogenesis and stim-
ulated apoptosis in the tumors. In another next experi-
ment, Conney et al.
[46] s ho wed t ha t c af fe in e a nd ca ff ei ne
and sodium benzoate may be useful as novel inhibitors of
sunlight-induced skin cancer. They found out that the ap-
plication of caffeine and sodium benzoate was more ac-
tive as sunscreen than caffeine alone. Also caffeine and
sodium benzoate stimulated apoptosis of UVB-induced
carcinogenesis more than caffeine and they were also
highly active in inhibiting carcinogenesis in UVB-pre-
treated high-risk mice.
Caffeine’s Effects on the Growth of Hair
5- ␣ -r edu ct as e is a n enz ym e t hat conv er ts te stosterone
into the more active dihydrotestosterone (DHT), which
is responsible for baldness. Particularly sensitive to the
action of DHT are hair follicles. Its application results in
a shortened anagen phase of the hair growth cycle, most
of the hair goes into the telogen phase with fallowing hair
follicle miniaturization and reduction of hair roots. The
newly growing hair is thinner and shorter, and after sev-
eral cycles of hair growth, the hair ceases to grow. Caf-
feine inhibits the activity of the 5- ␣ -reductase enzyme
and allows a renewed growth phase of the hair
[47] . Caf-
feine in concentrations of 0.001 and 0.005% led to a sig-
nificant stimulation of human hair follicle growth in vi-
tro
[47] . The stimulating effects of caffeine on the growth
of the hair can also be explained by its ability to inhibit
PDE enzymes. Inhibiting PDE activity increases the in-
tracellular concentration of cAMP, stimulating cellular
metabolism in a multitude of new cells
[47] . Caffeine re-
duces smooth muscle tension near the hair follicle caus-
ing an easier delivery of nutrients through the blood ves-
sels of the papillae of the hair
[47] . Caffeine also arouses
capillary vessel microcirculation in the skin of the head,
thereby contributing to nurture hair bulbs. It strength-
ens and stimulates rapid growth by regularly providing
nutrients with blood to the hair
[46] . Teichmann et al.
[48] and Lademann et al. [49] demonstrated that a 2-min
contact of a shampoo with caffeine was sufficient for the
formulation to penetrate deeply into the hair follicles and
remain there for up to 48 h, even after washing of the
hair. Otberg et al.
[50] showed that there is a quantitative
distinction between follicular penetration and interfol-
licular diffusion of a formulation containing 2.5% caf-
feine applied to the chest of male Caucasian volunteers
aged 26–39 with normal body mass indices. Caffeine
(3.75 ng/ml) was detected in blood samples 5 min after
topical application, when the follicles remained open.
When the follicles were blocked, caffeine was detectable
after 20 min (2.45 ng/ml). The highest values (11.75 ng
caffeine/ml) were found 1 h after application, when the
follicles were open. The ability of caffeine to penetrate
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13
the hair follicles and to stimulate the human hair growth
in vitro may have an important clinical impact on the
management of androgenetic alopecia, a common prob-
lem in men of all ages.
S u m m a r y
Extracts from coffee have a wide spectrum of actions;
therefore, they are used in many kinds of cosmetics. Caf-
feine stimulates the metabolism, contributes to the re-
moval of deposits of toxins from the organism, reduces
puffy eyes, accelerates the drainage of the lymph system
from fatty tissue, improves the microcirculation of the
blood in the capillary vessels, exhibits anti-cellulite prop-
erties, activates lipolysis, and releases the excess of fat
from adipocyte cells by reducing their size. Polyphenol
compounds contained in coffee have antioxidant proper-
ties (protecting against the UVB radiation), neutralize
free radicals, and therefore are used as sunscreen in anti-
wrinkle and anti-aging cosmetics. Caffeine is also used
in hair-care products because it reduces and slows down
the process of baldness and also stimulates hair growth.
All these properties make caffeine an important biologi-
cally active compound which can be used in different cos-
metic products. New findings concerning the biological
proper ties of t his alkaloid wi ll make that the spec tru m of
caffeine applications in the field of cosmetology and der-
matology in the future may be even wider. For this pur-
pose, more research is necessary to determine the appro-
priate doses and delivery systems for caffeine penetration
through the skin. There is little scientific data based on
clinical trials and none about the side effects of the cos-
metic use of caffeine. More research is needed to confirm
or deny the cosmetic application of caffeine.
References
1 Kerrigan S, Lindsey T: Fatal caffeine over-
dose: two case reports. Forensic S ci Int 2005;
153: 67–69.
2 Burlando B, Verotta L, Cornara L, Bottini-
Massa E: Herbal Principles in Cosmetics.
Properties and Mechanism of Action. Lon-
don, CRC Press, 2010, pp 178–179.
3 Fisone G, Borgkvist A, Usiello A: Caffeine as
a psychomotor stimulant: mechanism of ac-
tion. Cell Mol Life Sci 2004;
61: 857–872.
4 Hua ng ZL, Qu WM, Eguchi N, Chen JF,
Schwarzschild MA, Fredholm BB, Urade Y,
Hayaishi O: Adenosine A2A, but not A1, re-
ceptors med iate the arousa l effect of ca ffeine.
Nat Neurosci 2005;
8: 858–859.
5 Zhang WY: A benefit-risk assessment of caf-
feine as a n analgesic adjuv ant. Drug Sa f 2001;
24: 1127–114 2.
6 Smith A: Effects of caffeine on human be-
havior. Food Chem Toxicol 2002;
40: 1243–
1255.
7 Kim C, Shim J, Han S, Chang I: The skin-
permeation-enhancing effect of phosphati-
dylcholine: caffeine as a model active ingre-
dient. J Cosmet Sci 2002;
53: 363–374.
8 Trauer S, Patzelt A, Otberg N, Knorr F, Ro-
zycki C, Balizs G, Büttemeyer R, Linscheid
M, Liebsch M, Lademann J: Permeation of
topically applied caffeine through human
skin – a comparison of in vivo and in vitro
data. Br J Clin Pharmacol 2009;
68: 181–186.
9 Johnson S, Moss G, Thomas CP: In vitro
transdermal delivery of caffeine, theobro-
mine, theophylline and catechin from ex-
tract of Guarana, Paullinia Cupana. Int J
Pharm 2006;
317: 26–31.
10 Shakeel F, Ramadan W: Transdermal deliv-
ery of anticancer drug caffeine from water-
in -oi l na noem uls ions . Co lloi ds S urf B Bio in-
terfaces 2010;
75: 356–362.
11 Trauer S, Lademann J, Knorr F, Richter H,
Liebsch M, Rozycki C, Balizs G, Buttemeyer
R, Linscheid M, Patzelt A: Development of
an in vitro modified skin absorption test for
the invest igation of the foll icular pene tration
pathway of caffeine. Skin Pharmacol Physiol
2010;
23: 320–327.
12 Treffel P, Muret P, Muret-D’Aniello P,
Coumes-Marquet S, Agache P: Effect of oc-
clusion on in vitro percutaneous absorption
of two compounds with dif ferent physico-
chemica l properties. Sk in Pharmacol 1992;
5:
108–113.
13 van de Sandt JJ, van Burgsteden JA, Cage S,
Ca rm ich ae l PL , Di ck I , Ke nyo n S, Kor int h G ,
Larese F, Limasset JC, Maas WJ, Montomoli
L, Nielsen JB, Payan JP, Robinson E, Sar-
torelli P, Schaller KH, Wilkinson SC, Wil-
liams FM: In vitro predictions of skin ab-
sorption of caffeine, testosterone, and ben-
zoic acid: a multi-centre comparison study.
Regul Toxicol Pharmacol 2002;
39: 271–281.
14 Wil kinson SC, M aas WJ, Nielsen JB , Greaves
LC, van de Sandt JJ, Williams FM: Interac-
tions of skin thickness and physicochemical
properties of test compounds in percutane-
ous penetration studies. Int Arch Occup En-
viron Health 2006;
79: 405–413.
15 Brandner JM, Behne MJ, Huesing B, Moll I:
Caffeine improves barrier function in male
skin. Int J Cosmet Sci 2006;
28: 343–347.
16 Zesch A, Schaefer H, Stuttgen G: The quan-
titative distribution of percutaneously ap-
plied caffeine in the human skin. Arch Der-
matol Res 1979;
266: 277–283.
17 Touitou E, Lev i-Schaffer F, Dayan N, Alha-
ique F, Riccieri F: Modulation of caffeine
skin delivery by carrier design: liposomes
versus permeation enhancers. Int J Pharm
1994;
103: 131–136.
18 Amnuaik it T, Maneenuan D, Boonme P:
Eva luat ion of caf feine gels on phy sico chem i-
cal characteristics and in vivo efficacy in re-
ducing puf fy eyes. J Appl Pharmac Sci 2011;
1: 56–59.
19 Mustapha RB, Lafforgue C, Fenina N: Effect
of concentration on skin permeation of caf-
feine from gel for mulations. Journ al of Phar-
macy & Bioresources 2010;
7: 43–54.
20 Dias M, Farinha A, Faustino E, Hadgraft J,
Pa i s J , To sc an o C : To pi ca l de li ve ry of ca f fe in e
from some commercial formulations. Int J
Pharm 1999;
182: 41–47.
21 Mustapha RB, Lafforgue C , Fenina N, Mart y
J: Inf luence of drug conce ntration on the di f-
fusion parameters of caf feine. Indian J Pha r-
macol 2011;
43: 157–162.
22 Bourgeois S, Bolzinger MA, Pelletier J,
Valour JP, Briançon S: Caffeine micro-
spheres – an attractive carrier for optimum
skin penetration. Int J Cosmet Sci 2010;
32:
318–321.
23 Rawlings AV: Cellulite and its treatment. Int
J Cosmet Sci 2006;
28: 175–19 0.
24 Cawthorn WP, Sethi JK: TNF- ␣ and adipo-
cyte biology. FEBS Lett 2008;
582: 117–131.
Downloaded by:
89.75.75.202 - 4/20/2016 10:47:40 PM
Herman /Herman
Skin Pharmacol Physiol 2013;26:8–14
14
25 Conti M: Phosphodiesterases and cyclic nu-
cleotide signaling in endocrine cells. Mol
Endocrinol 2000;
14: 1317–1327.
26 Diepvens K, We stert erp KR , Weste rterp-
Plantenga MS: Obesity and thermogenesis
related to the consumption of caffeine,
ephedrine, capsaicin, and green tea. Am J
Physiol Regu l Integr Comp Physiol 20 07;
292:
77–85.
27 Dodd SL, Herb R A, Powers SK: Caffeine and
exercise performance. An update. Sports
Med 1993;
15: 14–23.
28 Panchal SK, Poudyal H, Waanders J, Brown
L: Coffee extract attenuates changes in car-
diovascular and hepatic structure and func-
tion without decreasing obesity in high-car-
bohydrate, high-fat diet-fed male rats. J Nutr
2012;
142: 690–697.
2 9 Vog elg es an g B, Bo nn et I , G od ard N, Soh m B ,
Perrier E: In v itro and in vivo efficacy of
sulfo-carrabiose, a sugar-based cosmetic in-
gredient with anti-cellulite properties. Int J
Cosmet Sci 2011;
33: 120–125.
30 Pires-de-Campos MS, Leonardi GR, Choril-
li M, Spadari-Bratfisch RC, Polacow ML,
Grassi-Kassisse DM: The effect of topical
caffeine on the morphology of swine hypo-
dermis as measured by ultrasound. J Cosmet
Dermatol 2008;
7: 232–237.
31 Velasco MV, Tano CT, Machado-Santelli
GM, Consiglieri VO, Kaneko TM, Baby AR:
Effects of caffeine and siloxanetriol alginate
caffeine, as anticellulite agents, on fatty tis-
sue: histological evaluation. J Cosmet Der-
matol 2008;
7: 23–29.
3 2 Be rt in C, Zu ni no H , P it tet JC , B eau P, Pi ne au
P, Massonneau M, Robert C, Hopkins J: A
double-blind evaluation of the activity of an
anti-cellulite product containing retinol,
caffeine, and ruscogenine by a combination
of several non-invasive methods. J Cosmet
Sci 2001;
52: 199 –210.
33 Came ron OG, Modell JG, Ha riharan M : Caf-
feine and human cerebral blood flow: a posi-
tron emission tomography study. Life Sci
1990 ;
47: 1141–1146 .
34 Okuno T, Sugiyama T, Tominaga M, Kojima
S, I keda T: Effec ts of ca ffeine on microci rcu-
lation of the human ocular fundus. Jpn J
Ophthalmol 2002;
46: 170–176.
35 Lupi O, Semenovitch IJ, Treu C, Bottino D,
Bouskela E: Evaluation of the effects of caf-
feine in the microcirculation and edema on
thighs and buttocks using the orthogonal
polarization spectral imaging and clinica l
parameters. J Cosmet Dermatol 2007;
6: 102–
107.
36 Kerzendor fer C, O’Driscoll M : UVB and caf-
feine: inhibiting the DNA damage response
to protect aga inst the advers e effects of UV B.
J Invest Dermatol 2009;
129: 1611–1613.
37 Koo SW, Hirakawa S, Fujii S, Kawasumi M,
Ngh iem P: Prote ctio n from photo dama ge by
topical application of caffeine after ultravio-
let irradiation. Br J Dermatol 2007;
156: 957–
964.
38 Kawasumi M, Lemos B, Bradner JE,
Thibodeau R, Kim Y, Schmidt M, Higgins E,
Koo SW, Angle-Zahn A, Chen A, Levine D,
Nguyen L, Heffernan TP, Longo I, Mandi-
nova A, Lud YP, Conney AH , Nghiem P: Pro-
tection from UV-induced skin carcinogene-
sis by genetic i nhibition of the ata xia telang i-
ectasia and Rad3-related (ATR) kinase. Proc
Nat Acad Sci USA 2011, DOI: 10.1073/
pna s.11113 78108.
39 Leon-Carmona JR, Galano A: Is caffeine a
good scavenger of oxygenated free radicals?
J Phys Chem B 2011;
115: 4538–4454.
40 Abel EL, Hendrix SO, McNeeley SG, John-
son KC, Rosenberg CA, Mossavar-Rahmani
Y, Vitolins M, Kruger M: Daily coffee con-
sumption and prevalence of nonmelanoma
skin c ancer in Caucasia n women. Eur J Can-
cer Prev 2007;
16: 446–452.
41 Jonason AS, Kunala S, Price GJ, Restifo RJ,
Spinelli HM, Persing JA, Leffell DJ, Tarone
RE, Br ash DE: Frequent clones of p53-mutat-
ed keratinocytes in normal human skin.
Proc Natl Acad Sci USA 1996;
93: 140 25–
140 29.
42 Lu YP, Lou YR, Xie JG, Pen g QY, Liao J, Yang
CS, Huang MT, Conney AH: Topical appli-
cations of caffeine or ( ␣ )-epigallocatechin
gallate (EGCG) inhibit carcinogenesis and
selectively increase apoptosis in UVB-in-
duced skin tumors in mice. Proc Natl Acad
Sci USA 2002;
99: 12455–12460.
43 Kramata P, Lu YP, Lou YR, Cohen JL, Olcha
M, Liu S, Conney AH: Effect of administra-
tion of caf feine or green tea on the mutation
profile in the p53 gene in early mutant p53-
positive patches of epidermal cells induced
by chronic U VB-irrad iation of hairles s SKH-
1 mice. Carcinogenesis 2005;
26: 1965–1974.
44 Heffernan TP, Kawasumi M, Blasina A, An-
deres K, Conney AH, Nghiem P: ATR–Ch k1
pathway inhibition promotes apoptosis after
UV treat ment in primar y human keratino-
cytes: potential basis for the UV protective
effects of caffeine. J Invest Dermatol 2009;
129: 180 5–1815.
45 Conney AH, Lu YP, Lou YR, Huang MT: In-
hibitory effects of tea and caffeine on UV-
induced carcinogenesis: relationship to en-
hanced apoptosis and decreased tissue fat.
Eur J Cancer Prev 2002;
11: 28–36.
46 Conney AH, Kramata P, Lou YR, Lu YP: Ef-
fect of caffeine on UVB-induced carcinogen-
esis, apoptosis, and the elimination of UVB-
induced patches of p53 mutant epidermal
cells in SKH-1 mice. Photochem Photobiol
2008;
84: 330–338.
47 Fischer TW, Hipler UC, Elsner P: Effect of
caffeine and testosterone on the prolifera-
tion of human hair follicles in vitro. Int J
Dermatol 2007;
46: 27–35.
48 Teichman n A, Richter H, Knorr F, Antoniou
C, Sterr y W, Lademann J: Invest igation of the
penetration and storage of a shampoo for-
mulation containing caffeine into the hair
follicles by in vivo laser scanning microsco-
py. Laser Phys Let t 2007;
4: 464–468.
49 Ladem ann J, Richter H, Sc hanzer S, K lenk A,
Sterry W, Patzelt A: Analysis of the penetra-
tion of a caffeine containing shampoo into
the hai r follicles by in v ivo laser sca nning mi-
croscopy. Laser Phys 2010;
20: 551–556.
50 Otberg N, Patze lt A, Rasu lev U, Hagemeister
T, Linscheid M, Sinkgraven R, Sterry W,
Lademann J: The role of hair follicles in the
percutaneous absorption of caffeine. Br J
Clin Pharmacol 2008;
65: 488–492.
Downloaded by:
89.75.75.202 - 4/20/2016 10:47:40 PM
