20 SKIN CARE
biological effect on tissues but becomes active after transformation into more active metabolites, the most important one being the retinoic acid, characterised by its multilateral action. Retinoic acid, occurs in the form of two isomers: the fully-trans form and the 9-cis form that affects proliferation and differentiation of cells by regulating the respective genes. Retinoids are involved in diverse biological activities including cellular growth, cellular cohesion, immunomodulatory effects, and anti-tumour functions. Vitamin A and its derivatives, particularly
retinol, are substances slowing the ageing process most effectively. Fat-soluble retinol penetrates the stratum corneum and it slightly penetrates into the dermis. When retinol reaches a keratinocyte, it enters its interior and binds to an appropriate receptor. There are four groups of receptors with high affinity towards retinol (CRBP).5,6 Retinol stimulates the cellular activity
of keratinocytes, fibroblasts, melanocytes and Langerhans cells. By interacting with receptors inside keratinocytes, it promotes their proliferation, strengthens the epidermal protective function, reduces trans epidermal water loss, protects collagen against degradation and inhibits the activity of metalloproteinases which are responsible for degradation of the extracellular matrix. Moreover, it enhances remodelling of reticular fibres and stimulates angiogenesis in the papillary layer of the dermis. Irritant properties of vitamin A and its derivatives as well as their instability are factors that limit their application in cosmetic and pharmaceutical products.7
Retinoids: a mode of action Retinoids, as compounds that are sparingly soluble in body fluids (lipophilic compounds), need specialised proteins to transport them (complex with Transthyretin – (prealbumin) is a retinol binding protein (vitamin A). A study by Hyung et al. proved new applications of RBP and retinoids as stabilisers of transthyretin.8 These are proteins such as RBP and CRBP. Cytosolic retinol binding protein (CRBP), which is present in cytoplasm, shows affinity for retinol, while cytosolic retinoic acid binding protein (CRABP) has affinity for retinoid acid. There are two sub-types of both groups
of receptors: CRBP I and II and CRABP I and II. Intracellular concentration of retinoids depends on their binding to cellular CRABP I and II. Studies show that CRABP II (the main form present in the epidermis) is much more abundant in the skin than CRABP I (whichmodulates the level of retinoic acid in different tissues).9 These proteins activate appropriate
nuclear receptors, thanks to which retinoids exert their biological effect on particular tissues, organs and cells. Retinoid nuclear receptors (RNRs, which represent a steroid thyroid hormone receptor) include: ■ Retinoic acid receptors (RARs), whose natural ligand is retinoic acid (RA), and ■ Retinoid X Receptors (RXR) whose natural ligand is 9-cis-retinoic acid.
PERSONAL CARE October 2021
β-lonone ring
Unsaturated isoprenoid side chain (all-trans)
H3 C CH3 CH3
Attaching group
Figure 1: Chemical structure of retinol (vitamin A1) Within these receptors, there are three
types of isotypes: α, β and γ (RARα, RARβ, RARγ). They may be further divided into isoforms. The human skin mainly contains RXRγ and RARα. Retinoids activate receptors in the form of dimers which in turn bind to the appropriate RARE element, i.e. the domain of the DNA response. They are located near the gene promoter sequences regulated by retinoids. Receptor expression is not regular and is described in only some tissues and organs, including the epidermis, dermis, sebaceous glands and hair follicles, or in cells of the immune system. Vitamin A and its derivatives are involved
in embryogenesis. Retinoids take part in the development of the nervous system, liver, heart, kidneys, intestine, eyes and limbs. Two-step oxidation occurring in the target organ cells results in conversion of retinol to its active form – retinoic acid. After entering the cell, retinol dehydrogenase (RDH) or alcohol dehydrogenase (ADH) catalyse the oxidation of retinol to retinal. This reaction may be reversed by the same enzyme because oxidation of retinol to retinoic aldehyde is a reversible process. Moreover, many enzymes can catalyse the reverse reaction, i.e. the conversion from retinamide to retinol. It indicates the presence of an additional mechanism which regulates the local retinol concentration in the tissues.5 Subsequently, retinol is oxidised to retinoid
acid by retinaldehyde dehydrogenase (RALDH) or some enzymes of the CYP family (belonging to the cytochrome P450 family). This reaction is irreversible; the product formed is a natural ligand of nuclear receptors and it reflects the activity of vitamin A. Further oxidation of the retinoic acid by CYP26 enzyme results in obtaining inactive vitamin A metabolites. Vitamin A and its derivatives, particularly
retinol, are among the most effective substances delaying the process of ageing. Fat-soluble retinol penetrates into the stratum
corneum and, to a small extent, into the dermis. It is important to increase penetration of retinol, thus increasing its spectrum of activity, to control a potential action in laboratory tests, and then to enhance the procedure effectiveness. Retinol, after reaching keratinocyte, penetrates into its interior and binds to an appropriate receptor. Cytosolic retinol binding protein receptors show high affinity for retinol.6,7 In the epidermis, retinoids may
influence secretion of transcription and growth factors. They are responsible for proliferation of the living layer, strengthening of the protective function and reduction in excessive trans-epidermal water loss (TEWL). Moreover, retinoids protect against degradation of collagen, and inhibit activity of metalloproteinases (MMPs) and enhances the angiogenesis in the papillary layer of the dermis.10
The irritant effect of vitamin
A and its derivatives and their instability are factors limiting their use in cosmetic and pharmaceutical products. Intracellular penetration is the main way of transport during which molecules move through the intercellular cement structure composed of ceramides, sterols, phospholipids and fatty acids. Intercellular cement has a lamellar structure, the lipid layer and hydrophilic layer are arranged alternately.9,12 Further studies on retinol activity in various
cosmetic formulas are required in order to select the one that is best tolerated by the skin and to determine whether the concentration significantly influences the effect it exerts on the skin. Natural retinoids have a positive effect on the skin parameters. They are characterised by good absorbability (they are fat-soluble), which improves the skin function. Retinoids boost production of epidermal proteins and accelerate the process of keratinisation, forming a layer of keratin which is more developed. Retinol penetrates into the basal layer of the epidermis (composed
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