The quest for a whiter shade of pale in skin care
Eric Dupont, PhD. Immanence, Quebec, Canada
Claude Léveillé, MD. Plastic Surgeon, Quebec, Canada
Juan Gomez Immanence, Québec, Canada
Estelle Loing, PhD. Unipex Innovations, Quebec, Canada
Diane Bilodeau, PhD. Consultant, Quebec, Canada
Introduction
The quest for a whiter shade of pale dates back to ancient civilizations, when a pale complexion was
associated with aristocratic lineage. During the Tang dynasty (618-907), Chinese women used
ground pearl powder as a whitening make-up. In ancient Persia, field workers bleached their skin
with pure natural hydroquinone to keep it from darkening under the sun. In Europe, during the
Renaissance, lead and mercury compounds applied to the face, neck, and chest, became popular as
peel-off skin lighteners. Unknown at the time, many of the earlier lightening ingredients were in
fact toxic and this led to their ban for cosmetic use.
However, even nowadays, skin lightening remains a popular goal in skin care. A fair skin tone is
increasingly associated with a healthy skin and youthful appearance. The field of potential
applications for lightening products has grown accordingly to include more specific pigmentation
concerns, such as lentigines (dark spots appearing, with older age, on sun-exposed skin), freckles
(irregular grouping of pigment-containing cells or melanocytes), melasma (hormonal
hyperpigmentation), inflammation-related hyperpigmentation, and even hypopigmentation. Skin
lighteners are now perceived as multi-usage cosmetic products although with some geographical and
cultural differences. Westerners seek them essentially for their anti-aging benefits, while Asians
people rather use them for general lightening of their skin.
With the advancement of science over recent decades, our knowledge of the physiology of skin
pigmentation has improved drastically. As we better understand the complex regulation of this
physiological process, it is becoming clear that the future of lightening skin care lies in the
combination of several actives addressing simultaneously and complementarily the various facets of
skin pigmentation. In fact, the trend worldwide is now to offer skin cares that combine multiple
modulators of pigmentation with anti-aging actives. This makes sense. After all, factors
contributing to skin aging such as UV exposure, hormones, oxidation, and inflammatory reactions
also affect skin pigmentation, and irregular skin pigmentation is seen increasingly with age.
2
This article will review our current knowledge of the mechanisms involved in skin pigmentation,
highlight effective ways of modulating these mechanisms with a combination of selected
commercially available actives (see Table I), and comment the efficacy and safety of a serum
(aImage Blanc™) integrating this knowledge. The serum described here additionally contains a core
anti-aging technology (aREGEN 16™) which has already been described elsewhere1.
Insert table I here
The cellular and molecular physiology of skin pigmentation
The life of melanin, the main pigment responsible for skin pigmentation, is a fascinating journey.
Starting within melanocyte cells with the amino acid tyrosine as the raw material, melanin pigments
are assembled in specialized incubators called melanosomes, conveyed to finger-like structures at
the tip of melanocytes and then gently transferred to neighboring keratinocyte cells that
rearrange them as protective umbrellas around their DNA. As these pigmented keratinocytes
mature, they progress to the edge of the stratum corneum from which they eventually shed
through desquamation, leading to pigment loss. Each step of the melanin journey mobilizes various
enzymes and signaling factors that may turn out to be interesting targets for the modulation of
skin pigmentation.
• Melanosome maturation The production and maturation of melanosomes are under the responsibility of melanocytes at the
basal layer of the epidermis. Within melanocytes, melanosomes start as spherical vesicles. Their
maturation takes place in several steps2. In UV-induced tanning, binding of α-melanocyte
stimulating hormone (α-MSH) to its receptor (MC1R) at the surface of melanocytes is an early
event in melanosome formation. Activation of the receptor triggers a cascade of events within
melanocytes that culminates in the induction of the microphthalmia transcription factor (MITF).
Signals emerging from non UV-induced pigmentation (intrinsic, hormonal and inflammatory) also
converge at MITF level making it a key master of skin pigmentation3. Among other things, MITF
commands the expression of melanogenic proteins, including that of PMEL-1 whose task is to form a
fibrous scaffold on which the biosynthesis and deposition of melanin will eventually take place4.
Melanosome maturation can be prevented early, using antagonists of α-MSH such as Lepidium sativum (cress) sprout extract or the small molecule undecylenoyl phenylalanine5. Acting a step
further, α-bisabolol extracted from chamomile is able to interrupt the cAMP signaling cascade
normally turned on by α-MSH6. α-Bisabolol additionally reduces MITF expression6, as also do
thioctic acid7 (α-lipoic acid), and oligopeptide-68, the latter being a peptide derived from TGF-
beta8,9. Working at a more distal point, a Pisum sativum (pea) extract has been shown to act
directly on PMEL-1, the scaffolding protein, to inhibit melanosome maturation.
• Pigment production In the later steps of melanosome maturation, three important proteins for melanogenesis, namely
tyrosinase (TYR), tyrosinase-related protein-1 (TRP1), and dopachrome oxidase (DCT), are
processed and transported into the organelle10. The three enzymes work in concert to produce two
distinct types of pigments. One is a red/yellow pigment (pheomelanin) while the second is a
3
black/brown pigment (eumelanin). The balance between these two pigments determines the color of
a person skin and hair11. The MC1R receptor, at the surface of melanocytes, partly controls the
switch between eumelanin and pheomelanin12. Eumelanin is the preferred pigment as it confers
better sun protection. As just mentioned above, activation of MC1R leads to induction of MITF
which, besides being involved in melanosome maturation, also controls the expression of TYR, TRP1,
and DCT, thus pigment production13.
As a key enzyme in melanin production, tyrosinase has traditionally been a major target for skin
whitening products. Inhibitors of tyrosinase activity include Glycyrrhiza glabra (licorice) root
extract14, phenylethyl resorcinol, Rumex occidentalis (willow) extract, the arbutin-containing Urva-Ursi (bearberry) leaves extract 15, and magnesium ascorbyl phosphate16. It is also possible to
stabilize tyrosinase in its inactive conformation using diacetyl boldine, an active derived from the
bark of a Chilean tree. Other inhibitors of melanine production act through down-regulation of TYR,
TRP-1, or DCT gene and protein expression. Ingredients from this category include Humulus lupulus
(hop) strobile, oligopeptide-688,9, and octadecenedioic acid17. Not surprisingly, ingredients acting
upstream of tyrosinase, will also inhibit melanin formation. These include the previously discussed
Lepidium sativum (cress) sprout extract, undecylenoyl phenylalanine, α-bisabolol, thioctic acid (α-
lipoic acid), oligopeptide-68, and Pisum sativum (pea) extract. Vitamin E, for its part, has been
shown to favor production of the lighter pheomelanin pigment, leading to lighter skin pigmentation18.
• Melanocyte dendricity As melanosomes are maturing, filling up with dark pigments, they also develop finger-like (dendrite)
projections in preparation for pigment transfer4. This is a remarkable ability requiring a
considerable reorganization of the cell cytoskeleton. Very few cell types in the body have such
potential. Melanocyte dendrite formation is regulated through multiple signaling pathways in
response to UV rays, hormonal stimulation, and other incentives, including pro-inflammatory stimuli
such as prostaglandin E2 (PGE2)19,20. All these signals converge at the level of MITF who
contributes largely to melanosome dendricity21. The formation of dendrites opens highways on
which fully matured melanosomes can now be transported.
Actives with the potential to inhibit dendrite formation include α-bisabolol6, thioctic acid7 (α-lipoic
acid), and oligopeptide-688,9, for their action on MITF, and dipotassium glycyrrhizate, through
inhibition of PGE222.
• Melanosome transport Upon melanogenic stimulation, melanosome, otherwise packed in the center of melanocytes, are
mobilized toward the tip of the dentrites. The process involves special structures (microtubules)
acting as rails for the cargo of melanosomes, the driving force being assured by motor proteins10,23.
Pretty much as sushi trains, melanosomes move up and down dendrites until they are picked up at
the tip of a dendrite and hold in place by a complex of proteins, in the wait for their transfer to
keratinocyte cells. Again, MITF plays a role in melanosome transport by controling the expression
of proteins essential for the capture of melanosomes at the tip of the dentrites24.
Useful actives in inhibiting melanosome transport include those acting on MITF, like α-bisabolol6,
thioctic acid7 (α-lipoic acid), and oligopeptide-688,9.
4
• Melanosome transfer & uptake How exactly melanosomes are transferred from the dendrites of melanocytes to keratinocytes is
still a matter of debate. So far, four mechanisms have been proposed: cytophagocytosis,
exocytosis, membrane fusion, and vesicles trafficking25,4. Cytophagocytosis implies that the tip of a
melanocytic dendrite is pinched off and engulfed by a neighboring keratinocyte. According to
exocytosis, melanosomes and melanocytes fuse through their membranes to release melanin
pigments in the extracellular space, where they are taken up by keratinocytes through phagocytosis.
In the membrane fusion model, a melanocytic dendrite fuses with a keratinocyte creating a channel
for melanosomes transfer. The vesicles trafficking model implies that melanin containing vesicles
are shed in the extracellular space before being absorbed by keratinocytes. Chances are that more
than one process is used at any given time.
Actives that inhibit dendrite formation on melanocytes will also inhibit the transfer of melanosomes
to surrounding keratinocytes. As discussed above, α-bisabolol, thioctic acid (α-lipoic acid),
oligopeptide-68, and dipotassium glycyrrhizate fall in this category. To more directly inhibit
melanosome phagocytosis by keratinocytes, it is possible to use Artocarpus heterophyllus (Jack
fruit) seed extract. A plausible explanation for this activity is that Jack fruit extract contains a
lectin and lectins have the potential to inhibit close interactions between melanocytes and
keratinocytes as required for pigment exchange25. Another way to interfere with pigment transfer
is to modulate calcium flow regulation in melanocytes26 and diacetyl boldine has been shown to do
that. Retinol also inhibits pigment transfer, but the precise mechanism remains to be fully
elucidated27.
• Keratinocyte maturation and skin desquamation Following their uptake by keratinocytes, melanosomes fuse with lysosomal structures and are
transported close to the cell nucleus. There, melanin pigments rearrange themselves forming a cap
that protects the nuclear keratinocyte DNA from the deleterious effects of UV radiation28. As
part of their maturation process, pigmented keratinocytes move upward to the statum corneum
from which they eventually shed. Any intervention that increases epidermal renewal and
desquamation will thus help getting rid of acquired pigmentation18.
Adenosine monophosphate can be used to stimulate epidermal turnover. Adenosine is the building
block of adenosine 5'-triphosphate (ATP), the main intracellular source of energy. Since energy is
essential for cell proliferation and maturation, supporting ATP levels with topical adenosine safely
accelerates epidermal turnover29. Topical adenosine also proved to be effective for treating
hyperpigmentary disorders, such as melasma30. To favour proper epidermal desquamation,
treatment with a mixture of Centella asiatica (gotu kola) extract, Carica papaya (papaya) extract,
and Iris florentina (iris) extract has been reported to be helpful. Other actives such as retinol18,
Salix nigra (willow) bark extract, and Vibrio exopolysaccharide extract are also effective for
desquamation and additionally stimulate keratinocyte renewal.
Oxidative and inflammatory incentives for skin pigmentation
5
Oxidative stress and inflammation can result from both normal and pathological reactions.
Whatever the cause, both processes have a big influence on skin pigmentation and on skin aging as a
matter of fact. Recognizing that has provided new tools to address pigmentation concerns.
• Oxidation Skin pigmentation is greatly influenced by ultraviolet (UV) radiation from sun exposure. UV rays
trigger the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that
may dangerously alter the DNA of skin cells. Since melanin pigments can act as ROS scavengers31,
the skin response to UV exposure and ROS challenge naturally involves the proliferation of
melanocytes and the release of hormones and factors that stimulate melanogenesis. Given their low
level of natural antioxidant (catalase) expression32, melanocytes themselves are especially sensitive
to ROS and prolonged excessive exposure quite often results in irregular pigmentation and may even
cause the apparition of white patches (vitiligo)33.
Numerous cosmetic ingredients have proven to be useful in supporting natural skin antioxidant
defenses for better control of skin pigmentation34. Following is a short list of interesting actives,
on that aspect. For instance, dipalmitoyl hydroxyproline, Glycyrrhiza glabra (licorice) root extract,
Lepidium sativum (cress) sprout extract, phenylethyl resorcinol, retinol, sqalane, thioctic acid (a-
lipoic acid), vitamin E, ubiquinone, and a mixture of Helianthus annuus (sunflower) seed oil, ethyl
ferulate, Rosmarinus officinalis (rosemary) leaf extract, and disodium uridine phosphate have
documented ROS scavenging abilities35. Dimethylmethoxy chromanol can neutralize RNS oxidative
molecules. Most interestingly, a small salen-manganese complex (EUK-134™) can be used to mimic
the antioxidant activity of two important endogenous antioxidant enzymes (SOD and catalase)36.
EUK-134™ has the unusual ability of regenerating its antioxidant potential which makes it a long
lasting molecule37.
• Inflammation Pigmentary changes are also common features of post-inflammatory events, including sunburns of
course, but also mechanical injuries or cutaneous disorders such as eczema or acne for example.
These changes involve the release of cytokines, growth factors, and pro-inflammatory lipids such as
leukotrienes and PGE238. These mediators can increase melanin production by melanocytes and/or
stimulate melanin transfer to keratinocytes. This leads to hyperpigmentation, a problem more
common in people with darker skin. In older individuals, chronic inflammation associated with aging
favors the formation of age-spots (lentigines)39. This cosmetic concern affects more than 90% of
white people older than 50 years40 and even appears at a much younger age in Asian skin41.
Many actives have anti-inflammatory activity that may help reduce such pigmentations problems.
For instance, α-bisabolol is a good inhibitor of leukotrienes synthesis42 and glycyrrhizate inhibits
the production of PGE2. Cynara scolymus (artichoke) leaf extract and thioctic acid (α-lipoic acid)
both interfere with the activation of NF-kB, a major intracellular signaling molecule involved in
inflammation reactions43. Palmitoyl tripeptide-8 reduces the production of an inflammatory
cytokine (IL-8). Humulus lupulus (hop) strobile inhibits the release, by keratinocytes, of an
inflammatory factor (GM-CSF) involved in lentigo formation38. Other actives also have non-specific
anti-inflammatory actions, such as sesame seed oil & wheat germ oil, Glycyrrhiza glabra (licorice)
root extract, Salix nigra (willow) bark extract, a mixture of hesperidin methyl chalcone &
6
dipeptide-2 & palmitoyl tetrapeptide-7, and also a mixture composed of ethyl ferulate, Rosmarinus officinalis (rosemary) leaf extract, and disodium uridine phosphate.
Globally, the diversity and complementarities of the ingredients discussed above should altogether
be addressing all know major mechanisms involved in skin pigmentation. To verify this hypothesis,
these ingredients were formulated in a serum and tested under dermatological control for clinical
efficacy in the modulation of skin pigmentation.
Clinical Efficacy
This integrated approach to skin pigmentation was tested in a case study conducted in Canada,
under the supervision of a medical doctor. This clinical study was aimed at evaluating the potential
of the serum described above to reduce the appearance of hyperpigmentation (age spots and
melasma) of the face and hands of volunteers. For this purpose, 10 Caucasian women aged between
38 and 82 applied the serum locally, twice daily for up to 10 weeks, on hyperpigmented spots
present on their face and hands. The effect of the serum was documented through before-and-
after photographs and doctor evaluation.
Figure 1, Figure 2, and Figure 3 are representative of results obtained with the serum, when applied
to the face. As can readily be seen on photographs, a noticeable improvement in the appearance of
dark spots is observed within 1 to 2 months of twice daily local application. According to doctor
evaluation, global improvement in skin pigmentation was estimated to reach between 20% and 80%,
depending on the volunteer. The serum was very effective in improving the appearance of melasma
on younger skin (Figure 1). A noticeable improvement in the appearance of age spots was also seen
with older skin (Figure 2 and 3). No adverse effects were reported in the course of the study.
Insert Figure 1 here
Insert Figure 2 here
Insert Figure 3 here
The study just described is preliminary and was designed to gain a first impression of the potential
of this approach. The benefits reported here serve as a proof of concept and warrant a more
extensive clinical study including rigorous controls.
Safety Testing
• HRIPT Human repeat insult patch testing (HRIPT) was conducted to document the cutaneous irritating and
sensitizing potentials of the serum, following repeated applications on the skin, under occlusive
patch, in 50 healthy adult volunteers. The non diluted serum was repetitively applied during an
induction period of 3 weeks, followed by a rest period, and a challenge period. Under the conditions
of the test, no evidence of dermal irritation or sensitization was observed for the tested serum
(data not shown).
• CHALLENGE TESTS
7
Challenge tests were conducted that involved the standard protocol of exposing the material to
specified types of bacteria and fungi to determine whether it is adequately preserved over its
intended shelf-life. Interpretation of the data was based on official protocols. Results from the
challenge tests showed that the serum met the Personal Care Products Council (PCPC) requirements
and guidelines for antimicrobial preservative effectiveness (data not shown).
Conclusion
Skin lightening products are gaining in popularity on the global market. Early generations of skin
whitening agents were effective but safety concerns led to their ban from the cosmetic market
forcing the industry to look at new innovative and safer ways to improve skin pigmentation. This has
been a big incentive to better understand the physiology of skin pigmentation and elucidate its
complexity.
One clear link that has emerged is the close relationship between aging and skin pigmentation
concerns. The recently developed microarray technology has pointed at up-regulation of genes
related to inflammation, fatty-acid metabolism, and melanin production, but down-regulation of
cornified envelope-related genes44. Accordingly, it seems that increase uneven pigmentation in
aging is associated with keratinization impairment, on a chronic inflammation background. Thus,
simply targeting tyrosinase activity to solve pigmentation problems does not seem adequate
anymore. Skin pigmentation needs to be addressed globally, as part of the aging process.
The trend is toward the integration of multiple actives covering all mechanistic aspects of skin
pigmentation, as well as addressing the skin aging process. The serum “Image Blanc™” described
here does it all and leads the way for better integrated skin cares.
8
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11
Table 1. Mechanisms of pigmentation modulation by selected actives
INCI Name MMa PPr Den PTp PUp Dsq Oxd Inf
Adenosine √
Artocarpus heterophyllus seed extract √
α-Bisabolol √ √ √ √ √ √
Sesame seed oil & wheat germ oil √
Diacetyl boldine √ √
Humulus lupulus strobile √ √
Cynara scolymus leaf extract √ Centella asiatica extract & Carica papaya extract & Iris florentina extract
√
Dimethylmethoxy chromanol √
Dipalmitoyl hydroxyproline √
Dipotassium glycyrrhizate √ √ √
Ethylbisiminomethylguaiacol manganese chloride √
Glycyrrhiza glabra root extract √ √ √ Helianthus annuus seed oil, ethyl ferulate, Rosmarinus officinalis leaf extract, disodium uridine phosphate
√ √
Hesperidin methyl chalcone & dipeptide-2 & palmitoyl
tetrapeptide-7 √
Lepidium sativum sprout extract √ √ √
Octadecenedioic acid √
Oligopeptide-68 √ √ √ √ √
Palmitoyl tripeptide-8 √
Phenylethyl resorcinol √ √
Pisum sativum extract √ √
Retinol √ √ √
Rumex occidentalis extract √
Salix nigra bark extract √ √
Sqalane √
Thioctic acid √ √ √ √ √ √ √
Tocopheryl acetate √ √
Ubiquinone √
Undecylenoyl phenylalanine √ √
Uva-Ursi leaf extract & magnesium ascorbyl phosphate √
Vibrio exopolysaccharide extract √ Legend:
MMa= Melanosome maturation PPr= Pigment production Den= Dendricity PTp= Pigment transport
PUp= Pigment uptake Dsq= Desquamation Oxd= Oxidation Inf= Inflammation
Figure 1. Effect of the serum on pigmented spots of the face:
Subject: Caucasian woman
Age: 38
Type of skin: normal, except for pigmented spots
Application: on pigmented spots
Frequency: 2 x/day
Duration: 35 days
Doctor evaluation:
Improvement = 60%
13
aImage Blanc™ and REGEN 16™ are products of Immanence Integral Dermo Correction
Figure 2. Effect of the serum on pigmented spots of the face:
Subject: Caucasian woman
Age: 62
Type of skin: normal, except for pigmented spots
Application: on pigmented spots
Frequency: 2 x/day
Duration: 70 days
Doctor evaluation:
Improvement = 50%
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aImage Blanc™ and REGEN 16™ are products of Immanence Integral Dermo Correction
Figure 3. Effect of the serum on pigmented spots of the face:
Subject: Caucasian woman
Age: 82
Type of skin: normal, except for pigmented spots
Application: on pigmented spots
Frequency: 2 x/day
Duration: 70 days
Doctor evaluation:
Improvement = 40%