The peoples of the Polar region had an unwritten law – never, under no circumstances eat the liver of a polar bear. They honestly warned the white aliens about it. But, as a rule, the latter did not listen to them, and, having killed a bear, first thing they did was to eat liver. The spirits punished them severely for that.

Those who broke the law were afflicted with a terrible disease: they were stricken with stomach cramps and vomiting, suffered from diarrhea, fell down with dizziness, and went crazy with headaches. To top it all off, their skin began to peel off. Witnesses said that the skin on the soles of those unfortunates literally fell off like plaster, and people could not move until they had new skin.

Unfortunate experience of Eskimos and successful experience of Egyptians were explained only in the XX century. The history of surprising discoveries began in 1909, when the German scientist Wilhelm Stepp isolated fat-soluble factor, necessary for embryo development, from egg yolk and then from milk. In 1920 the substance was named vitamin A.
In 1930, Swiss organic chemist Paul Carrer defined the structure of β-carotene and proved that it is a precursor of vitamin A, for which he was subsequently awarded the Nobel Prize. In the same year T. Moore synthesized retinol from carotenoids and began to study its effect on the body. It was not until 1943 that it was finally proven that retinol was the culprit for the misfortunes of the intrepid Arctic explorers and the last hope of the blind Egyptians.

Retinol deficiency is as dangerous as its excess. Insufficient intake of retinol in the body eventually leads to irreversible loss of vision, reduced resistance to infection, all kinds of skin problems and even death. Scientists have named the substances necessary for normal functioning and even for the very existence of the human body as vitamins (lat. vita – life) to emphasize their importance. Retinol was the first among them, receiving the honorary title of vitamin A.

We get vitamin A from food. Animal foods (liver, fish oil, egg yolks, milk, butter, etc.) contain retinol itself. But plants do not synthesize retinol, but they are a source of proretinol – the plant pigment β-carotene. In the cells of the intestinal mucosa, the enzyme dioxygenase splits β-carotene into two retinol molecules, which are then reduced to retinol. The amount of retinol synthesized is strictly regulated to prevent intoxication of the body. From the intestine, retinol goes to the liver, where it is deposited in the stellate cells mainly in the form of esters. From there, it is delivered to other organs, including the skin, as needed.

The biologically active form is not retinol itself, but its derivative, fully trans-retinoic acid (trans-RCA, better known to practitioners as tretinoin), which is formed in the cells themselves in two steps: first retinol is oxidized to retinal, which in turn is oxidized to trans-RCA.

Over time, scientists have found substances that have similar effects to vitamin A. Synthetic and natural compounds with a mechanism of action similar to retinoil became known as retinoids and were used to treat a variety of diseases, including skin diseases.

Cells are very sensitive to the concentration of retinol, and any, even a slight deviation from the norm, affects their life. The mechanism of cellular regulation of retinoid metabolism is a complex and well-adjusted system. It includes many enzymes and binding proteins which provide retinoid capture, metabolism, deposition and transport inside the cell.
Once inside the cell through the plasma membrane, retinoids are metabolized to active derivatives and bind to special proteins. In this form, they are delivered to the nucleus, where they are recognized by retinoid receptors. The activated receptor, in turn, binds to a short DNA sequence in close proximity to the promoter of the target gene and stabilizes the transcription factor. The role of the transcription factor is to ensure binding of RNA polymerase II enzyme to the promoter and trigger transcription.

The above scheme is greatly simplified, and in reality everything is much more complicated.

The presence of nuclear receptors and similarity in the molecular mechanisms of activation allows scientists to put retinol on a par with the steroid and thyroid hormones, since their action is also mediated through the nuclear receptors. Moreover, the nuclear receptors for retinoids, steroids, and thyroids are similar in structure and mechanism of action and can even influence each other’s activity. This explains, in particular, the fact that vitamin D (steroid precursor) acts synergistically with vitamin A, stimulating its uptake and metabolism in keratinocytes.

What explains the variety of clinical effects of retinol

The effects of retinol on the skin have been compared to an iceberg: we only see the tip – the clinical effects that result from changes in the cells deep within the skin. To understand the visible effects of retinol, it’s important to remember that retinol only affects living cells, and different cell types respond differently.

Retinoids and skin

Retinoids are small, lipophilic molecules that easily penetrate the stratum corneum. We can say that the stratum corneum is transparent for them. They just as easily penetrate into the greasy hair follicles. Retinoid concentration gradient is created in the skin decreasing towards the derma. In the epidermis retinoids control keratinization and pigmentation processes, and in the dermal layer they restore intercellular matrix gradually degraded in the process of aging or UV exposure. The transfollicular pathway makes it possible to obtain an increased concentration of retinoids directly in the follicles, which is especially valuable in the treatment of follicular pathologies, such as acne.

Keratinocytes and keratinization of the epidermis

Retinoids affect the proliferation and differentiation of basal keratinocytes, accelerating epidermal renewal.

Through keratinocytes, retinoids also affect other skin cells. Here’s an example: retinol reduces the production and release of growth factors by normal keratinocytes of epithelial cells lining blood capillaries and thus prevents excessive development of the capillary network.

Sebocytes and the problem of acne

Vitamin A is one of the regulators of sebaceous glands and is necessary for their normal functioning.

A local deficiency of vitamin A can lead to the development of acne, which is characterized by impaired synthetic processes in the sebocytes and increased cell proliferation. This is confirmed by the effectiveness of topical application of trans-RC (tretinoin preparations) in mild to moderate acne, which compensates for retinoid deficiency.

Langerhans cells (skin macrophages), the only immune cells in the epidermis, are also sensitive to retinol.
Macrophages recognize a foreign agent (antigen), capture it, and then produce an antibody to it. Leaving the epidermis and penetrating into local lymph nodes, macrophages and antigen to T-lymphocytes, which at the next meeting with the antibody will be able to recognize it independently. As it turned out, retinol modulates the ability of macrophages to present the antigen.

Melanocytes and skin pigmentation

The use of retinoids is usually accompanied by a mild bleaching effect. This indicates that retinoids interfere with the skin pigmentation process.
Retinoic acid is able to affect the melanocytes themselves and through the receptor apparatus.

Fibroblasts and wrinkle smoothing

The gradual thinning of the dermal skin layer during aging (including photoaging) is associated with two parallel processes:

activation of metalloproteinases – intercellular enzymes destroying collagen and elastin fibers of derma;
slowdown of new collagen synthesis by fibroblasts.

As a result of degradation of derma intercellular substance, skin elasticity and firmness decrease, wrinkles form. Use of topical retinoids stimulates fibroblast proliferation, collagen synthesis, and decreases the activity of collagen-destroying metalloproteinases.
Retinoids enhance the synthesis of another important component of the matrix – glycosaminoglycans. Correction and normalization of derma intercellular matrix composition increases skin elasticity and smoothes fine wrinkles.

Dermatological and Cosmetological History of Vitamin A. The
retinoids were discovered in dermatology by Albert Kligman. In the 1960s, interested in the dermatological effects of trans-RC (tretinoin), he discovered its positive effect on acne-prone skin. The first company to market a topical product with retinoic acid was Ortho Parmaceutical, a subsidiary of Johnson & Johnson. It acquired a patent from Albert Kligman, and in 1971 the acne treatment Retin-A (0,1% Tretinoin) was presented to the public, quickly gaining popularity. 25 years later, in 1996 Ortho Parmaceutical released another remedy – Renova, designed for the prevention of aging skin changes and recovery from photodamage. Renova contains 0.05% tretinoin in a soft cream base and is used to fight fine lines and hyperpigmentation. Renova was the first photoaging drug to receive FDA approval.
Consumers highly evaluated the retinoval products and the successful example of Ortho Parmaceutical was followed (with great caution, though) by other pharmaceutical companies. Both Retin-A and Renova, as well as generics containing tretinoin, belong to medicines. Accordingly, they should have medical registration, be sold in pharmacies and be prescribed by doctors.
In the mid 1990s, cosmetics with vitamin A appeared, and the indications for its use were practically the same: skin care with increased sebosecretion and acne, photoaging. Today a wide range of retinol products is available, from face creams to nail care products. Here are the main categories of retinol cosmetics.

face and body skin care products:
– Aging prevention,
– Hyperkeratosis,
– Correction of photoaging signs,
– Skin with increased sebum secretion, seborrhea,
– Mild acne,
– Post-acne.
After-sun cosmetics (for prevention and correction of photo ageing).
Nail care products.
Peelings.

There are even sunscreens with retinol, though, frankly, it is not quite clear why they contain retinol – all its activity disappears straight away when you fall under direct sunlight. It makes more sense to use retinol in after-sun care products, and also in nourishing and regenerating creams at night, because vitamin A has a much more important restorative effect.

Cosmetics or medicine

A question that needs to be considered separately: how should topical retinoid-based products be classified? Why do some of them have medical registration with all the ensuing requirements for sales and prescriptions while the others are sold uncontrolled and are treated as cosmetics?
Let’s start with the fact that all synthetic retinoids are medical substances and are not approved for use in cosmetics.
As for natural retinoids (endogenous derivatives of vitamin A), it all depends on their form

– biologically active trans-RC or 13-cis-RC are medical substances

– inactive precursors (retinol, retinal, retinol esters) are cosmetic ingredients.

Let us remind you that cells store retinol and when necessary convert it into the active form, which binds with nuclear receptors. If the cell is “fed” trans-RK, it will no longer be able to self-regulate the amount of active molecules it needs, and the cellular response will be forced, fast and bright. If retinol or its esters get into the cell, they are deposited and then gradually activated, so the effect will be slow and not as pronounced. Cosmetic products are based on an intracrine concept of using retinoids, consisting in local application of precursors, which easily pass through the skin barrier and are metabolized in skin cells to their biologically active forms.
In this regard, it is more correct to say retinol cosmetics, but retinoid medication.

Retinol and the regulation of physiological skin renewal