How vitamin A was found to be a Vitamin

Vitamins are organic compounds that are essential to human metabolism, but that humans are unable to synthesize so they must be acquired through food. During evolution, we “simply” lost some enzymes required for their synthesis. Observations made before 1900: Nutritional deprivation caused corneal ulcers, blindness, and high mortality. Also, an unknown substance present in milk and egg yolk is essential for nutrition.

In the early 20th century it was found that this unknown substance was fat soluble. The growth-supporting “accessory factor” in milk and egg yolk became known as ‘fat-soluble A’ in 1918 and then ‘vitamin A’ in 1920. Further research, and huge advances in chemistry and biochemistry in the 20th century, elucidated the chemical structure of the molecule and eventually lead to its chemical synthesis in the laboratory.

One of the very important roles of vitamin A is maintaining epidermal integrity. Vitamin A appears to maintain normal skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells.

Vitamin A activity step by step (it is complicated)

After retinoic acid enters the cell, it binds to specific nuclear receptors. These “activated” nuclear receptors in turn bind to specific regulatory sequences (called retinoic acid response elements) in the DNA inside the nucleus and directly change gene expression of specific genes. Such changes in gene expression translate into changes in the production of proteins, and are responsible for the biological and therapeutic effects of retinoids.
Acne and retinoids

In the 1970s, retinoic acid was used topically to control acne, and the effect was thought to be through reduction of sebum secretion. In 1979 a synthetic derivative of vitamin A, 13-cis-retinoic acid (isotretinoin), was found to help with severe nodulocystic acne by reducing the size and secretion of the sebaceous glands. Although it is known that a certain fraction of isotretinoin breaks down to retinoic acid, the mechanism of action of the drug (original brand name Accutane) remains unknown and is a matter of some controversy. Isotretinoin also reduces bacteria in both the ducts and skin surface. This is thought to be a result of the reduction in sebum, a nutrient source for the bacteria.

The chemistry of vitamin A

The vitamin A found in animal sources, retinyl ester, is fat soluble. This is also the form of vitamin A we use in our Skin Actives products, and what is used in commercial vitamins. Retinol (the alcohol) and retinal (the aldehyde) are very unstable.

Plants can be a source of pro-vitamin A because, if they contain alpha carotene, beta carotene, and other carotenes (as long as they contain the beta-ionone ring), the animals (including humans) that possess the enzymes required can transform these carotenoids into retinal.

Why the use of some retinoids must be medically supervised

Retinoids have significant effects on normal embryonic development. Retinoic acid has recently been characterized as a vertebrate morphogen, i.e. a signaling molecule that controls the spatial pattern of differentiation and the shape of the developing embryo. The potent teratogenic effects (malformations of the embryo) of retinoids are well established and are a consequence of their central role in morphogenesis. Isotretinoin is also a teratogen with a number of potential side-effects, so its use requires medical supervision and it is strictly controlled by law.

Retinoids are not interchangeable

Retinol and its esters (retinyl acetate and retinyl palmitate) are converted into retinoic acid and bind to receptors on the nuclear membrane, and through these receptors they exert their effects.

Some effects of vitamin A deficiency are reversed by retinoic acid, but some organs (i.e. the retina and testes) require retinal or retinol, depending on the metabolism of the organ. Skin requires retinoic acid. In short, not all of the effects of vitamin A in every organ require the same chemical form of vitamin A.

Hundreds of different chemicals share some of the activities of vitamin A, but their different structures also mean that side effects will be different. When it comes to synthetic derivatives, like isotretinoin, part of the effects may be due to its partial conversion in the body into retinoic acid. However, there is more to the mechanism of action, and this part of the story is still a matter of investigation (in other words, caveat emptor, because we have no idea how it works).

Too much can be too much

In general, retinoids tend to normalize cellular proliferation and differentiation. In human epidermis, low concentrations of retinoids generally increase keratinocyte proliferation, but high concentrations can be inhibitory. This effect is used in the treatment of psoriasis.

How vitamin A was found to have effect on aging skin

The benefits of topical tretinoin on human photodamaged skin were first observed in middle-aged women treated for persistent acne. These women described smoother, less wrinkled skin in addition to the clearing of acne. Improvements were noted in skin texture, wrinkling, pigmentation, and sallowness. Although these effects were first studied using tretinoin, retinyl acetate (vitamin A) has similar effects BUT without the irritation caused by tretinoin (and without the need for medical supervision required for the synthetic retinoid).

Many people can’t use topical tretinoin because of its side effects, which include skin irritation. We know that this is not a problem with retinyl esters, like retinyl acetate, because they work just as well or better, because they don’t have serious side effects and don’t require medical supervision. The take home lesson is that it is simply not worthwhile to suffer the side effects of tretinoin and other synthetic forms of vitamin A. We have two ready made products, Vitamin A Cream and Vitamin A Serum to deliver the benefits of retinyl acetate safely.

-Dr. Hannah Sivak

Reference: J.J.J. Fu, G.G. Hillebrand, P. Raleigh, J. Li, M.J. Marmor, V. Bertucci,_P.E. Grimes, S.H. Mandy, M.I. Perez, S.H. Weinkle and J.R. Kaczvinsky (2010). A randomized, controlled comparative study of the wrinkle reduction benefits of a cosmetic niacinamide⁄peptide⁄retinyl propionate product regimen vs. a prescription 0.02% tretinoin product regimen. British J. Dermatology, 162: 647–654