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Retinoids cosmeceuticals

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Dermatologic Therapy, Vol. 19, 2006, 289 –296 Copyright © Blackwell Publishing, Inc., 2006
Printed in the United States · All rights reserved
DERMATOLOGIC THERAPY
ISSN 1396-0296

Retinoids in cosmeceuticals
Blackwell Publishing Inc

OLIVIER SORG, CHRISTOPHE ANTILLE, GÜRKAN KAYA, & JEAN-HILAIRE SAURAT

Geneva University Hospital, Geneva, Switzerland

ABSTRACT: Retinoids are natural and synthetic vitamin A derivatives. They are lipophilic molecules
and easily penetrate the epidermis. Their biologically active forms can modulate the expression of
genes involved in cellular differentiation and proliferation. Retinoic acid (tretinoin), its 13-cis isomer
isotretinoin, as well as various synthetic retinoids are used for therapeutic purposes, whereas reti-
naldehyde, retinol, and retinyl esters, because of their controlled conversion to retinoic acid or their
direct receptor-independent biologic action, can be used as cosmeceuticals. These natural retinoic
acid precursors are thus expected to be helpful in (i) renewing epidermal cells, (ii) acting as UV filters,
(iii) preventing oxidative stress, (iv) controlling cutaneous bacterial flora, and (v) improving skin
aging and photoaging. Retinol and retinyl esters are not irritant, whereas demonstrating only a
modest clinical efficiency. On the other hand, retinaldehyde, which is fairly well tolerated, seems to
be the most efficient cosmeceutical retinoid; it has significant efficiency toward oxidative stress, cuta-
neous bacterial flora, epidermis renewing, and photoaging.

KEYWORDS: cosmeceutical, photoaging, photoprotection, retinoids

Topical retinoids as “cosmeceuticals” ligand-receptor complexes modulate the expression

of genes involved in cellular differentiation and
proliferation (1–3). Retinol is produced in the
The scope of topical cosmeceutical retinoids
small intestine either by hydrolysis of retinyl
The rather ill-defined word cosmeceutical may esters, or by oxidation of various carotenoids (4 –6).
be understood as one applicable to a natural Retinol can be oxidized into retinaldehyde, and
compound, which is not a drug but still exerts then into retinoic acid, the biologically active form
demonstrable biologic activity without inducing of vitamin A (FIG. 1). On the other hand, retinol
side effects. In the field of topical retinoids, this can be esterified with fatty acids to form retinyl
would exclude retinoic acid because it is registered esters (2,7,8). In the blood and tissues, the two
as a drug, and all synthetic retinoids such as ada- predominant endogenous retinoids are retinol
palene, tazarotene, and bexarotene. The eligible and its esters. Retinoids are present in the skin:
candidates in the group of topical cosmeceutical retinol and retinyl esters account for more than
retinoids are: retinyl esters, retinol, retinaldehyde, 99% of total cutaneous retinoids, i.e., approxi-
and the group of oxoretinoids. mately 1 nmol/g, whereas retinaldehyde and
retinoic acid are under the limit of detection
(10 pmol/g) (9–11). Retinoic acid is catabolized
Endogenous cutaneous natural retinoids
either by phase I or phase II enzymes, giving rise
Retinoids define a class of substances comprising to retinoyl glucuronide or 4-oxoretinoic acid
vitamin A (retinol) and its natural and synthetic (12,13).
derivatives. As lipophilic molecules, they can
diffuse through cellular and other phospholipid
membranes. Inside the cells, they bind to nuclear Biologic evidence for the use of topical
receptors (RAR-α, -β, -γ, and RXR-α, -β, -γ) then the cosmeceutical retinoids
Address correspondence and reprint requests to: Olivier Sorg,
Ph.D, Clinique de Dermatologie, Hôpital Cantonal Universi- Although primarily an esthetic problem with sig-
taire, 24 rue Micheli-du-Crest, 1211 Genève 14 (Switzerland), or nificant psychologic effects, intrinsic and extrinsic
email: [email protected]. skin aging constitutes the background for the

289
Sorg et al.

FIG. 1. Structure of natural retinoids. The arrows show the enzyme-catalyzed conversions. The dotted-lined arrows are
probable conversions, although they have not been confirmed.

development of precancerous and cancerous The intracrine-proligand concept as a basis for

skin lesions. Many clinical studies indicate that the genomic effects of cosmeceutical topical
certain structural changes induced by excessive retinoids
sun exposure can be reversed, to some extent, by
the use of topical retinoids (14). Retinoic acid is Instead of treating the skin with natural or syn-
widely used both for topical therapy of several thetic ligands of nuclear receptors (that are poten-
skin diseases and to improve the aspect of aging tially more toxic because they deliver preformed
skin. However, topical retinoic acid induces irrita- pharmacologic activity, thus their classification
tion of the skin, which precludes its use in some as drugs), delivery could be distinctly targeted
skin diseases that respond to systemic retinoids. with proligand, molecules that the target cell will
Irritation might be explained, at least in part, by transform in a controlled process into active
an overload of the retinoic acid-dependent path- ligands (15). This intracrine concept, in which the
ways with nonphysiologic amounts of exogenous active ligand is produced within the targets cells,
retinoic acid in the skin. It is still not established has been explored to deliver retinoid activity to
whether all the therapeutic activities of topical mouse and human skin topically with natural
retinoic acid are mediated by nuclear receptors, retinoids that do not bind to nuclear receptors
and whether irritation is necessary for obtaining (9,16–20). This might be one definition of cosme-
some of these activities. To overcome the prob- ceutical topical retinoids.
lems encountered by retinoic acid, one possibility
is that significant biologic activity may still be Experimental evidence
achieved with much lower concentrations of topical Validation of the concept implies that (i) epider-
retinoic acid; in this case, retinoic acid is delivered mal cells metabolize the precursors into retinoic
at a low rate from a large epidermal reservoir, i.e.,
the stratum corneum, to its intracellular targets. Table 1. Topical retinoids: effects relevant for
Topical cosmeceutical retinoids would reproduce anti-aging for activity
the different activities of retinoic acid, but through Epidermal cells renewal
different pathways, which would explain better Epidermal differentiation modulation
tolerability, albeit apparently lower biologic activity Extracellular matrix production
(Table 1). Inhibition of UV-induced extracellular matrix
Delivery of ligand for retinoic acid receptor degradation
(RAR) binding corresponds to the genomic effects Cytokine modulation – angiogenesis
of topical cosmeceutical retinoids, and many Melanocyte function modulation
other, either proved or putative biologic activities Oxidant/antioxidant
would account for other effects. This introduces Prevention of UV-induced vitamin A deficiency
Sunscreen effect
the notion of a specific profile of clinical potential
So-called surface effects
for each of the topical cosmeceutical retinoids.

290
 Retinoids in cosmeceuticals

acid or another biologically active retinoid, (ii) matrix metalloproteinases (32). The integration
topical application of the precursor results in bio- of the retinoid-induced CD44, hyaluronate, and
logic effects, and (iii) tolerability of the precursor is HB-EGF modulation in the biologic effects of
better than that of the active metabolite (9,21–25). topical retinoids now requires further studies.
The ranking order of retinoid-like activity follow-
ing topical application is as follows: retinoic acid > Clinical evidence and implications
retinaldehyde > retinol > > retinyl esters; in other There are now many evidence-based clinical
words, this corresponds to the metabolic pathway observations establishing the effects of topical
(the closer to retinoic acid, the higher retinoid- cosmeceutical retinoids in this context (33).
like activity they have): retinyl esters are hydro- The first study on the effect of tretinoin on the
lyzed to retinol, which is oxidized to retinal, which wrinkles of the face was published in 1983 (34). In
is in turn oxidized to retinoic acid. On the other this small, vehicle-controlled study, tretinoin,
hand, probably for the same reason, the tolerance used at a concentration range of 0.001–0.05%, has
ranking order is the opposite: retinyl esters > been shown to produce a mild to moderate
retinol = retinaldehyde > > retinoic acid. improvement in wrinkles at 6 months and in
The genomic effects of topical retinoids most actinic lentigines at 4 months. In an open study,
probably account for inducing many of the bio- tretinoin 0.05% cream was used for 3–10 months
logic effects involved in reversing and preventing on photoaged skin of the face and forearm and
extrinsic and intrinsic skin aging such as the pre- a clinical improvement was observed (35). In a
vention of matrix metalloproteinase activation 4-month randomized vehicle-controlled trial, it
(26,27) and oxidative stress and the regeneration was shown that 0.1% tretinoin cream used once
of extracellular matrix (28) (Table 1). daily could significantly improve the fine facial
In particular, retinoids are known to inhibit wrinkling as a result of chronic sun exposure
keratinocyte differentiation and to stimulate epi- (36).
dermal hyperplasia. Heparin binding-epidermal Although there is extensive literature on the use
growth factor (HB-EGF) activation of keratinocyte of topical tretinoin for the treatment of photoaged
ErbB receptors via a RAR-dependent paracrine skin, few studies have been reported for other ret-
loop has been proposed to mediate retinoid- inoids. In a 36-week study of once-daily isotretin-
induced epidermal hyperplasia (29). It has been oin 0.1% cream, it was shown that isotretinoin
shown that CD44v3, a heparan sulfate-bearing was effective in the treatment of coarse and fine
variant of CD44 which is a multifunctional poly- wrinkles and actinic lentigines (37). When com-
morphic proteoglycan and principal cell surface pared to tretinoin, isotretinoin appears to be less
receptor of hyaluronate, recruits proteolytically irritating and maybe less effective. In two other
active matrix metalloproteinase 7, the precursor studies, a clinical improvement has been shown
of HB-EGF (pro-HB-EGF) and one of its receptors, in fine wrinkles after 36 weeks of treatment with
ErbB4, to form a complex on the surface of isotretinoin 0.05% and 0.1% cream (38,39). The
murine epithelial cells (30). The present authors efficacy of retinaldehyde 0.05% cream for treat-
have previously shown that topical application of ment of photoaging has been compared with
retinaldehyde increases the expression of CD44 in 0.05% tretinoin and vehicle creams during 18
mouse skin. The increased expression of CD44 weeks (40). Retinaldehyde produces significant
accompanying epidermal hyperplasia induced by clinical improvement in fine and deep wrinkles,
topically applied retinaldehyde is associated with which was maintained during 44 weeks. The posi-
an increase in epidermal and dermal hyaluronate tive effect of retinaldehyde on wrinkles has been
and with increased expression of hyaluronate- confirmed by a second study (41). Retinaldehyde
polymerizing enzymes, hyaluronate synthases 1, 2, seems to be significantly less irritant than tretin-
and 3 (31). The observations of the present authors oin. In a randomized, controlled trial it was
indicate that the hyaluronate system might be reported that a retinol-containing formulation
associated with the heparin-binding epidermal resulted in significant improvement in fine wrin-
growth factor (HB-EGF) paracrine loop, with the kles after 12 weeks of treatment (42). Retinol 0.4%
transcriptional up-regulation of CD44 and hyalur- has been shown to induce a similar epidermal
onate synthases. The present authors have also hyperplasia in human skin as tretinoin 0.1% but
shown that retinaldehyde-induced in vitro and in with significantly less irritancy (16) (Kaya et al.,
vivo proliferative response of keratinocytes is a CD44- unpublished data). In contrast, topical retinyl
dependent phenomenon requiring the presence propionate cream (0.15%) is not effective in the
of HB-EGF, another HB-EGF receptor, ErbB1, and treatment of photoaged skin (43).

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Sorg et al.

Nongenomic effects of topical cosmeceutical toward alcohols and amines; retinaldehyde may
retinoids thus exert a direct activity by reacting nonenzy-
matically with many biologic molecules on skin
Retinoids might exert a biologic activity indepen- surface, as well as on bacterial flora, independent
dently of their binding to nuclear receptors. These of its conversion to retinoic acid and subsequent
effects are probably differently exerted by retinyl activation of nuclear receptors (55–59).
esters, retinol, retinaldehyde, and retinoic acid,
which introduce a further level of choice for the Clinical evidence and implication: Although vita-
clinician amongst cosmeceutical topical retinoids. min A was recognized as a putative anti-infective
Some of these effects have been well demon- agent as early as in the 1920s (60), its mechanism
strated experimentally, and some evidence of of action still remains elusive. Retinoic acid has
their clinical application already obtained. been shown to protect dendritic cells in mice (61)
and topical retinaldehyde, owing to its better tol-
The paradoxical UV filter properties erance profile than retinoic acid, was successfully
Experimental evidence: Besides their biologic applied for a long period of time to patients with
action mediated by nuclear receptors, because of inflammatory dermatoses (23). More recent stud-
their side chain containing conjugated double ies demonstrated a higher antibacterial profile of
bonds, retinoids strongly absorb ultraviolet (UV) retinaldehyde and nonretinoid aldehydes than
light, and thus appear as potential UV filters. retinoic acid on several bacterial strains in vitro,
To assess the relevance of this concept, the present as well as a good antibacterial action of topical
authors first developed an in vitro model in which retinaldehyde 0.05% in vivo (Propionibacterium
liposomes, the membranes of which are enriched acnes and Staphylococcus spp.) (58,59).
in a lipophilic putative UV filter, are encapsulated
with a fluorescent probe; this model appears Topical cosmeceutical retinoids as antioxidants
suitable to easily analyze the filtering capacities Oxidative stress has been shown to be the corner-
of new molecules within a simulated biologic stone of the biochemical pathways leading to
environment. photoaging (3,62–65). Although the skin, like the
In a series of experiment in mice, the present other organs, possesses an efficient antioxidant
authors demonstrated that natural retinoids system, the latter is able to counteract the delete-
(retinoic acid, retinaldehyde, retinol, and retinyl rious effects of occasional oxidative stress of
palmitate) were efficient in preventing UVB-induced moderate magnitude, but in the case of chronic or
apoptosis and DNA photodamage (44). The similar severe oxidative stress, it reaches its limit and irre-
potencies of these retinoids indicate a physical mediable tissue damage is unavoidable (66–70).
action mediated by their spectral properties On the other hand, the endogenous antioxidant
rather than a biologic action mediated by the systems become less efficient in the elderly (71–74).
binding to nuclear receptors. There is thus a need for topical antioxidants to
In a human study, the photoprotective action scavenge the remaining reactive oxygen species
of topical retinyl palmitate 2% was shown to be as and free radicals when endogenous antioxidants
efficient as that of a sunscreen with a sun protec- are saturated.
tion factor of 20 in preventing UVB-induced
erythema and DNA photodamage (45). Experimental evidence: Retinoids have been
shown to exert a free radical scavenging activity in
Clinical evidence and implication: Although the vitro (75–79). In hairless mice, topical menadione
risk incurred when exposing the skin to the sun (vitamin K3) induced the peroxidation of epidermal
following topical retinoids is still a matter of lipids in hairless mice; this effect was completely
debate, it is important to underline that human prevented by pretreatment with either 0.25%
studies showed prevention or no effect of topical topical α-tocopherol (vitamin E, a known efficient
retinoids on nonmelanoma skin cancers (46–50). endogenous cutaneous antioxidant) or topical
The studies reporting a potentiation by retinoids retinaldehyde 0.05% (78).
of UV-induced skin diseases are based on studies
performed in vitro or in animal models (51–54). Clinical evidence and implication: Although peo-
ple with a low serum retinol are at higher risk to
The antibacterial activity of retinaldehyde develop various forms of cancers (80,81), there is
Experimental evidence: Aldehydes represent a a lack of clinical evidence regarding the efficiency
class of highly reactive compounds, especially of topical natural retinoids as antioxidants.

292
 Retinoids in cosmeceuticals

Topical cosmeceutical retinoids and pigmentation (myeloperoxidase activity), and (iii) depigmentation
Topical retinoic acid has been used for many years, of the tail (Sorg and collaborators, manuscript in
alone or in combination with hydroquinone, for preparation). In this model, topical 4-oxoretinol
the depigmentation of human skin (82,83). 0.05% demonstrated a lower biologic activity. Par-
allel to the action of 4-oxoretinoids, no retinoic
Experimental evidence: The present authors used acid could be detected in the skin, indicating that
the model of mouse tail to compare the efficiency of 4-oxoretinoids exerted a direct biologic activity,
topical retinaldehyde 0.05% and 4-oxoretinaldehyde which was not the result of the conversion of 4-
0.05% (see succeeding discussions) to decrease oxoretinoids to their non-oxo counterparts. These
epidermal pigmentation. Following a 3-week results thus confirm in vitro studies demonstrating
treatment of daily application, topical retinalde- that 4-oxoretinol and 4-oxoretinaldehyde are capable
hyde and 4-oxoretinaldehyde decreased epidermal of binding to and transactivating RARs (87,89).
melanin by 80% and 54%, respectively (Sorg and
collaborators, manuscript in preparation). Clinical evidence and implication: No clinical trial
using topical 4-oxoretinoids has been reported so
Clinical evidence and implication: According to far. However, the mentioned data on the biologic
the previously mentioned discussion on the activity of 4-oxoretinaldehyde, and to a lesser
biologic actions of retinol, a much higher concen- extent 4-oxoretinol, let us imagine potential bene-
tration would be required to replace topical fits of these new natural vitamin A derivatives.
tretinoin by retinol to produce similar results. In Future trials are needed to determine whether it is
the formula of Kligman and Willis, tretinoin 0.1% possible to use these retinoids at high concentra-
accelerates the loss of epidermal melanin, hydro- tions with better response than tretinoin and with
quinone 5% suppresses its production, whereas acceptable side effects.
dexamethasone 0.1% prevents the irritant derma-
titis induced by tretinoin (82). A clinical trial in
which retinol 10% and lactic acid 7% replaced The specific profile of clinical potential
tretinoin 0.1% and dexamethasone 0.1% in the
formula of Kligman and Willis was successfully
for each of the topical cosmeceutical
applied to patients with hyperpigmented lesions retinoids
on the face (84). This new formula was shown to
be comparable to that of Kligman and Willis, with Retinaldehyde
the advantage of preventing the steroid-induced
skin atrophy (84). Retinaldehyde, the precursor of retinoic acid (FIG. 1),
is much less irritant than retinoic acid. Retinaldehyde
Oxoretinoids has been shown to be well tolerated and effective
As mentioned previously, the biologic effects of in treating photoaging: in particular, retinaldehyde
retinoids are believed to be mediated by their produced significant improvement in fine and
interaction with the nuclear receptors RARs and deep wrinkles, whereas side effects of topical retinoic
retinoid X receptors (RXRs). The known endoge- acid affected compliance of the patients (23,41).
nous ligand for RARs is retinoic acid, whereas its Retinaldehyde does not bind to nuclear retinoid
9-cis isomer (9-cis-RA) activates both RARs and receptors and selectively delivers low concentra-
RXRs (85,86). 4-Oxoretinoic acid (FIG. 1), the product tions of retinoic acid (22,93); this prevents an
of the action of CYP26, a phase I enzyme, on retinoic excess of retinoic acid in the skin, a condition that
acid, was considered an inactive catabolite of contributes to cutaneous irritation (9,15) and confers
retinoic acid. However, two other 4-oxoretinoids, to retinaldehyde the required properties for the
i.e., 4-oxoretinol and 4-oxoretinaldehyde (FIG. 1), intracrine concept (15). This concept has been
have been shown to exert direct retinoid-like expanded in a recent study on ex vivo human skin
activity in vitro, which suggests a potential benefit by combining retinaldehyde and a vitamin E
for their use as cosmeceuticals (87–92). precursor (tocopheryl glucose): this improved the
protection against the generation of free radicals –
Experimental evidence: In a mouse model, topi- a condition leading to aging – as well as the skin
cal 4-oxoretinaldehyde 0.05% induced a moderate elasticity (94).
retinoid-like activity compared to topical retinoic Because of its aldehyde functional group, reti-
acid 0.05%, as assessed by (i) epidermal hyperpla- naldehyde exerts direct receptor-independent
sia and metaplasia, (ii) cutaneous inflammation biologic actions not shared by other retinoids. This

293
Sorg et al.

explains the usefulness of topical retinaldehyde tolerance profile among topical retinoids, whereas
0.05% against P. acnes and Staphylococcus spp. (58,59). being the weaker retinoic acid precursors (17).
As mentioned above, retinoids strongly absorb This concept has been illustrated in the mentioned
in the UV range and thus appear as putative filters study on UV-induced apoptosis and DNA damage
when applied to the skin. Retinaldehyde absorbs (44), as well as in another study reporting a com-
in the UVA-visible range (λmax = 385 nm) and may parable photoprotective action of topical retinyl
decrease the fluence received in this window sig- palmitate 2% and a commercial sunscreen with
nificantly. This concept has been illustrated in the a sun protection factor of 20 on UVB-induced
present authors’ recent study reporting a similar erythema and DNA damage (45).
filter effect of the various topical natural retinoids
0.05% (retinyl palmitate, retinol, retinaldehyde
and retinoic acid) on UV-induced apoptosis and References
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