Review paper

Retinoids: active molecules influencing skin structure

formation in cosmetic and dermatological treatments

Malwina Zasada, Elżbieta Budzisz

Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy, Medical University of Lodz, Lodz, Poland
Adv Dermatol Allergol 2019; XXXVI (4): 392–397
DOI: https://doi.org/10.5114/ada.2019.87443

Abstract
Vitamin A is the first vitamin approved by the Food and Drug Administration as an anti-wrinkle agent that changes
appearance of the skin surface and has anti-aging effects. Vitamin A is in a group of fat-soluble substances and
belongs to the category of retinoids. Apart from retinol, that group includes structurally related substances with
the biological properties of retinol. Since the biological activity of the substances differs, for the purpose of stan-
dardization, it is given in retinol equivalents. Vitamin A and its derivatives are among the most effective substances
slowing the aging process. Retinoids regulate the cell apoptosis, differentiation and proliferation. Anti-wrinkle prop-
erties of retinoids promote keratinocytes proliferation, strengthen the protective function of the epidermis, restrain
transepidermal water loss, protect collagen against degradation and inhibit metalloproteinases activity. Retinoid
activity is related to high affinity for nuclear receptors: RAR – retinoid acid receptors and RXR – retinoid X receptors.
Key words: vitamin A, retinol, retinoids, skin aging, dermatology.

as well as synthetic analogues of retinol (Figures 1, 2).

Introduction Synthetic analogues have a benzene ring instead of cy-
According to the IUPAC (International Union of Pure clohexane (etretinate, acitretin, tazarotene). Based on
and Applied Chemistry) and IUBMB (International Union the molecular structure and properties, retinoids can be
of Biochemistry and Molecular Biology), retinoids are divided into three generations:
compounds containing four isoprene units with a head- – First generation – natural retinoids, monoaromatic
to-tail structure [1]. Retinol, retinoic aldehyde and retinoic compounds obtained by modifying polar groups at the
acid belong to retinoids with a non-aromatic fragment of end and side chain of the polyene vitamin that do not
β-ionone in their molecule. The term “retinoid” refers to act selectively – retinol (vitamin A) and its metabolites
the synthetic and natural analogues of vitamin A. Reti- – retinal, tretinoin, isotretinoin,
noids are a class of compounds derived from vitamin A – Second generation – monoaromatic retinoids, synthetic
or showing structural and/or functional similarities to vi- compounds in which the cyclohexene ring is replaced
tamin A. According to the latter definition, retinoids are by a benzene ring; synthetic analogues of vitamin A
molecules that can bind to and activate the appropriate (etretinate, acitretin),
nuclear receptors and to induce transcription of relevant – Third generation – polyaromatic retinoids formed as
genes either directly or after metabolic transformation a result of cyclization of polyene side chain and charac-
[2]. Retinoids are widely applied in cosmetics being a po- terized by selective activity towards receptor (arotinoid,
tent dermatological agent used in acne, psoriasis as well adapalene, tazarotene) [3].
as other skin diseases. Retinol, retinal and retinoic acid have the same bi-
The objective of this study is to introduce and com- ological features as vitamin A. Retinoids are involved
pare different types of retinoid uses in cosmetic and in the process of embryogenesis during development
dermatological treatments. Moreover, this paper should of the nervous system, liver, heart, kidneys, intestine,
address the issue of the cellular activity of retinoids. eyes and limbs. Retinoids are used in treatment of the
Retinoids are compounds of both natural, biologically so-called “night blindness” because they are responsi-
active forms of vitamin A (retinol, retinal and retinoic acid) ble for proper functioning of the organ of sight. They are

Address for correspondence: Malwina Zasada, Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy,
Medical University of Lodz, 1 Muszynskiego St, 90-151 Lodz, Poland, phone: +48 606 947 843, e-mail: [email protected]
Received: 24.03.2018, accepted: 9.04.2018.

392 Advances in Dermatology and Allergology 4, August / 2019

 Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments

associated with formation of rhodopsin. They are used b-Ionone ring Unsaturated isoprenoid side
in pharmacotherapy of diseases such as acne and rosa- chain (all-trans)
cea, psoriasis, cancer, inflammation of hair follicles with
bacterial aetiology, pyoderma, lupus erythematosus and
CH3 CH3
ichthyosis. Retinol does not exert a significant biological H3C CH3
effect on tissues but becomes active after transformation CH2OH
into more active metabolites, the most important one
being the retinoic acid characterized by its multilateral CH3
action. Retinoic acid (RA), occurs in the form of two iso- Attaching
mers: the fully-trans form and the 9-cis form that affects group
proliferation and differentiation of cells by regulating the
respective genes. Retinoids are involved in diverse biolog- Figure 1. Chemical structure of retinol (vitamin A1)
ical activities including cellular growth, cellular cohesion,
immunomodulatory effects, and anti-tumour functions. A CH3 CH3
Vitamin A and its derivatives, particularly retinol, are H3C CH3
CH2OH
substances slowing the aging process most effectively.
Fat soluble retinol penetrates the stratum corneum and
it slightly penetrates into the dermis. When retinol reach- CH3
es a keratinocyte, it enters its interior and binds to an
appropriate receptor. There are four groups of receptors
with high affinity towards retinol (CRBP) [4, 5]. Retinol
stimulates the cellular activity of keratinocytes, fibro- B CH3 CH3 H
blasts, melanocytes and Langerhans cells. Retinol, by in- H3C CH3
C O
teracting with receptors inside keratinocytes, promotes
their proliferation, strengthens the epidermal protective
function, reduces transepidermal water loss, protects CH3
collagen against degradation and inhibits the activity of
metalloproteinases which are responsible for degrada- C
tion of the extracellular matrix. Moreover, it enhances re- CH3 CH3
H3C CH3
modelling of reticular fibres and stimulates angiogenesis CH2OH
in the papillary layer of the dermis. Irritant properties of
vitamin A and its derivatives as well as their instability
CH3
are factors that limit their application in cosmetic and
pharmaceutical products [6].
D CH3 CH3
Retinoids: a mode of action H3C CH3
CH2OH
Retinoids, as compounds that are sparingly soluble
in body fluids (lipophilic compounds), need specialized
CH3
proteins to transport them (complex with Transthyretin
– (prealbumin) is a retinol binding protein (vitamin A). Figure 2. Structural formulas of selected retinoids: retinol (A),
Results of the study by Hyung et al. proved new applica- retinal (B), 3-dehydroretiol (vitamin A2) (C), 13-cis-retinol (D)
tions of RBP and retinoids as stabilizers of transthyretin
[7]. These are proteins such as RBP and CRBP. Cytosolic Retinoid nuclear receptors (RNR, which represent a ster-
retinol binding protein (CRBP), which is present in cyto- oid thyroid hormone receptor) include:
plasm, shows affinity for retinol, while cytosolic retinoic – RA receptors (RAR), its natural ligand is retinoic acid
acid binding protein (CRABP) has affinity for retinoid acid. (RA), and
There are two subtypes of both groups of receptors: CRBP I – R etinoid X Receptors (RXR), its natural ligand is
and II and CRABP I and II. Intracellular concentration of 9-cis-retinoic acid.
retinoids depends on their binding to cellular CRABP I Within these receptors, there are three types of
and II. Studies show that CRABP II (it is the main form isotypes: α, β and g (RARα, RARβ, RARγ). They may be
present in the epidermis) is much more abundant in the further divided into isoforms. The human skin mainly
skin than CRABP I (modulates the level of retinoic acid in contains RXRg and RARα. Retinoids activate receptors in
different tissues) [8]. These proteins activate appropriate the form of dimers which in turn bind to the appropriate
nuclear receptors, thanks to which retinoids exert their RARE element, i.e. the domain of the DNA response. They
biological effect on particular tissues, organs and cells. are located near the gene promoter sequences regulated

Advances in Dermatology and Allergology 4, August / 2019 393

Malwina Zasada, Elżbieta Budzisz

by retinoids. Receptor expression is not regular and is the effect it exerts on the skin. Natural retinoids have
described in only some tissues and organs, including the a positive effect on the skin parameters. They are char-
epidermis, dermis, sebaceous glands and hair follicles, or acterized by good absorbability (they are fat-soluble)
in cells of the immune system. which improves the skin function. Retinoids boost pro-
Vitamin A and its derivatives are involved in em- duction of epidermal proteins and accelerate the process
bryogenesis. Retinoids take part in development of the of keratinization, forming a layer of keratin which is more
nervous system, liver, heart, kidneys, intestine, eyes and developed. Retinol penetrates into the basal layer of the
limbs. Two-step oxidation occurring in the target organ epidermis (composed of living (nucleated) cells that are
cells results in conversion of retinol to its active form constantly producing new cells) as well as to a small ex-
– retinoic acid. After entering the cell, retinol dehydro- tent, into the dermis and marginally to the subcutaneous
genase (RDH) or alcohol dehydrogenase (ADH) catalyse tissue. In the case of retinol applied topically, there is an
the oxidation of retinol to retinal. This reaction may be interaction with specific nuclear receptors. Retinol makes
reversed by the same enzyme because oxidation of reti- the connections between epidermal cells more loose and
nol to retinoic aldehyde is a reversible process. Moreover, facilitates keratosis. What is more, it enhances epidermis
many enzymes can catalyse the reverse reaction, i.e. the turn-over and accelerates proliferation of the basal layer
conversion from retinamide to retinol. It indicates the of epidermal cells and the stratum corneum. In keratino-
presence of an additional mechanism which regulates cytes, proliferation AP-1 transcription factor, exposed to
the local retinol concentration in the tissues [4]. Subse- various stimulants, growth factors and cytokines, plays
quently, retinol is oxidized to retinoid acid by retinalde- a major role. In retinol-treated aged human skin, AP-1
hyde dehydrogenase (RALDH) or some enzymes of the complex is comprised of c-Jun/c-fos and c-Jun transcrip-
CYP family (belonging to the cytochrome P450 family). tion factor was increased [12]. Due to the fact that reti-
This reaction is irreversible; the product formed is a nat- noids exert anticomedogenic effects, they regulate the
ural ligand of nuclear receptors and it reflects the activi- process of shedding within sebaceous glands ducts. What
ty of vitamin A. Further oxidation of the retinoic acid by is most important, retinoids decrease activity of enzymes
CYP26 enzyme results in obtaining inactive vitamin A participating in lipogenesis and block differentiation
metabolites. and cellular divisions of sebocytes [12]. Moreover, they
Vitamin A and its derivatives, particularly retinol, are reduce discoloration of the skin, reduce its pigmentation
among the most effective substances delaying the pro- by about 60% and contribute to a proper distribution of
cess of aging. Fat-soluble retinol penetrates into the stra- melanin in the skin. Topically applied retinoids also in-
tum corneum and, to a small extent, into the dermis. It is fluence the function of melanocytes, providing regular
important to increase penetration of retinol, thus increas- arrangement of melanin in the epidermis. They also block
ing its spectrum of activity, and to control a potential ac- transport of melanin to epidermal cells and diminish the
tion in laboratory tests, and then to enhance the proce- activity of stimulated melanocytes. An increase in synthe-
dure effectiveness. Retinol, after reaching keratinocyte, sis and activity of tyrosinase, disturbances in subsequent
penetrates into its interior and binds to an appropriate steps of melanogenesis or a decrease in the amount of
receptor. Cytosolic retinol binding protein receptors show melanocytes is related to inhibition of melanogenesis.
high affinity for retinol [5, 6]. In epidermis, retinoids may Retinoids are also commonly known as biologically ac-
influence secretion of transcription and growth factors. tive anti-aging molecules. Retinol stimulates fibroblasts
They are responsible for proliferation of the living layer of to synthesize collagen fibres (stimulates the activity of
the epidermis, strengthening of the protective function fibroblasts and increases their number), improves skin
of epidermis and reduction in excessive transepidermal elasticity (removes degenerated elastin fibers) and pro-
water loss (TEWL). Moreover, retinoids protect against motes angiogenesis [13]. Some studies indicate that
degradation of collagen and inhibit activity of metallo- retinol also enhances production of elastin fibres [14].
proteinases, enhances angiogenesis in the papillary layer Moreover, retinol inhibits matrix metalloproteinases
of the dermis [9, 10]. The irritant effect of vitamin A and (MMPs) and enhances synthesis of tissue inhibitors of
its derivatives and their instability are factors limiting metalloproteinases (TIMPs) [15]. Changes within colla-
their use in cosmetic and pharmaceutical products. Intra- gen and elastin fibres are associated with photoaging.
cellular penetration is the main way of transport during It leads to occurrence of wrinkles and loss of the skin
which molecules move through the intercellular cement firmness and elasticity. Collagen fibres atrophy is caused
structure composed of ceramides, sterols, phospholipids by an increased expression of collagenases (MMP-1),
and fatty acids. Intercellular cement has a lamellar struc- gelatinases (MMP-2) and stromelysin-1 [16] as well as
ture, the lipid layer and hydrophilic layer are arranged enhanced expression of elastase and MMP-9 associated
alternately [8, 11]. Further studies on retinol activity in with degradation of elastin fibres. Retinol counteracts
various cosmetic formulas are required in order to select development of precancerous conditions as a result of
the one that is best tolerated by the skin and to deter- hampering the activity of atypical cells, which has been
mine whether the concentration significantly influences proved by the results of studies [17]. ECM-producing cells

394 Advances in Dermatology and Allergology 4, August / 2019

 Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments

in the skin are activated by retinol and cause its produc- or cream applied topically. Retinoic acid may have differ-
tion in the aged skin. Activation of fibroblast production ent formulas: gel (0.01%, 0.25%), cream (0.025%, 0.05%,
is stimulated through TGF-b/CTGF pathway. Connective 0.1%), new technology microspheres (0.04%, 0.1%), solu-
tissue growth factor (CTGF) including immunostaining tion (0.05%), and emollient (0.05%) [21, 22].
of TGF-b1, which is the regulator of ECM homeostasis, Retinol is most frequently used in cosmeceutical
is increased by retinol [18]. By reducing the amount of treatment. It is very stable in product formulations and
sebum secreted by the skin, retinoids reduce the tenden- well tolerated. It provides better effects than retinoic
cy to form blackheads [19]. Excessive degradation of the acid applied in equivalent doses. Retinoic acid proves
stratum corneum and keratosis of hair follicles is asso- to be approximately 20 times more powerful than reti-
ciated with vitamin A deficiency. Regulation of secretion nol. Firstly, retinol is converted to retinoic acid through
within sebaceous gland ducts make retinoids produce an a two-step oxidation process. Retinol has an ability to
anticomedogenic effect. Retinoids decrease the activity bind to the retinoic acid receptors. The process begins
of enzymes participating in lipogenesis. Moreover, they when free retinol is combined with a specific cytoplas-
block cellular division of sebocytes and differentiation mic protein that binds retinol. The resultant complex is
[20]. They are widely used externally in the treatment of a substrate for retinol dehydrogenase, an enzyme that
acne, psoriasis, excessive dryness, skin keratosis and hair catalyses the conversion of retinol to retinaldehyde. Ret-
and nail disorders [13, 20]. inaldehyde is oxidized to retinoic acid by retinaldehyde
oxidase [23]. Retinol is known to be a molecule which
improves the skin texture, dyspigmentation, dryness, and
Application in cosmetology and dermatology
fine lines. The optimal concentration to balance the skin
(Table 1)
irritation against effectiveness has not been determined.
Tretinoin (all trans-retinoic acid) is the most bioac- Retinol concentration in the cosmetic product is between
tive form among retinoids applied topically to the skin. 0.0015% and 0.3% [24].
Tretinoin increases the epidermal cellular turnover, it Retinal is the aldehyde formulation of vitamin A, i.e.
also causes dispersion of melanin granules. Tretinoin’s the oxidized form of retinol. Retinal is used in cosme-
inhibition of MMPs results from blocking AP-1, not upreg- ceuticals, however, its efficacy in the skin treatment is
ulating the tissue inhibitor of MMPs (TIMP1). The most limited. Similarly to retinyl esters, it is a stable derivative
commonly used tretinoin concentration in anti-acne ther- of vitamin A but it only mildly improves wrinkles and the
apy varies from 0.01% to 0.4%. It comes in the form of gel skin texture. As compared to retinoic acid, it is less irri-

Table 1. Retinoid uses in cosmetic and dermatological skin care treatments

Retinoids Functions/mechanism of action Application in cosmetic and dermatological
treatment
Retinol (all-trans retinol) Inhibits collagenase and MMP expression; Anti-wrinkle treatments, improvement of texture,
stimulates collagen type 1 and GAGs synthesis dyspigmentation, dryness, and fine lines
Retinoic acid (all-trans Stimulates the process of epidermal cell Acne, psoriasis, chronic inflammation of hair
retinoic acid, tretinoin) proliferation, accelerates the elimination of follicles and sebaceous glands
sebum remaining in ducts, therefore reducing
inflammation in sebaceous glands; loosens
connections among cells in stratum corneum and
inhibits keratosis
Retinyl esters (retinyl First converts to retinol by cleavage of the ester Antioxidant, wrinkles, stabilising properties
acetate and palmitate) bond, and then converts into retinoic acid,
stimulates the epidermal cell proliferation,
regulates the sebum
Retinaldehyde First oxidizes to retinoic acid by retinaldehyde Stabilising properties, wrinkles, texture
dehydrogenases (e.g., RALDH2) or some enzymes of
the CYP family and then stimulates the epidermal
cell proliferation
Adapalene Changes gene expression and mRNA synthesis; it is Acne, inflammation, excessive keratosis
(naphthalenecarboxylic a strong modulator of keratinization of hair follicle
acid) cells, modifies keratinocyte metabolism, increases
their proliferation, and thus has a keratolytic effect
Tazarotene Receptor-specific retinoid regulates down markers Acne vulgaris, psoriasis, chronically photodamaged
of keratinocyte differentiation, keratinocyte skin, photoprotection from sunlight
proliferation and inflammation

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Malwina Zasada, Elżbieta Budzisz

tating and well tolerated. It is used to improve signs of Conclusions

photoaging [25].
Retinol and their active metabolites such as retinal,
Retinyl esters, such as retinyl acetate and palmitate,
tretinoin, isotretinoin and alitretinoin belong to a group
are commonly used in cosmeceuticals. They are very
of first-generation retinoids. Retinol has the ability to
stable but first they need to be converted to retinol by
effectively penetrate the stratum corneum (lipophilic
cleavage of the ester bond, and in the subsequent stage
nature of retinoids). Age, cellular metabolism, cardio-
into retinoic acid. It results in decreased effectiveness of
vascular function, stratum corneum thickness, level of
anti-wrinkle properties (smaller increase in the epidermal
hydration and analysed area of the face are important
thickness) as compared to retinol and retinoic acid [26].
factors in mature skin therapies. The number of scientific
Adapalene is a naphthalenecarboxylic acid derivative
reports on the activity of retinoids was the reason for
with a retinoid-like activity. As a result of intracellular as-
this study.
sociation with nuclear receptors of retinoic acid, it chang-
es gene expression and mRNA synthesis. It is a strong
modulator of keratinization of hair follicle cells, moreover, Acknolwedgments
it modifies keratinocyte metabolism, increases prolifera-
The financial support from the Medical University of
tion, and thus exerts a keratolytic effect [20].
Lodz (grant No. 502-03/3-066-02/502-34-094) is grate-
Tazarotene, approved by the US Food and Drug Ad-
fully acknowledged.
ministration, is a synthetic retinoid (prodrug). It is applied
in topical treatment of plaque psoriasis and acne vulgaris
(AV). Tazarotene is also used in adjunctive treatment of Conflict of interest
specific clinical manifestations of chronically photodam- The authors declare no conflict of interest.
aged skin (hyperpigmentation and hypopigmentation as
well as facial fine wrinkling and benign facial lentigines).
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