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Physiology of the Skin: A New Look at Vitamin A

By Peter T. Pugliese, MD
Posted: April 23, 2008, from the May 2008 issue of Skin Inc. magazine.

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     Vitamin A intake. Most of the vitamin A in the body is from food, and is mainly from beta-carotenes, which are converted to vitamin A in the intestine and liver, although a portion is absorbed as beta-carotene from the intestines into the lymphatics, passing from there into the circulatory system. The beta-carotene is split into two molecules of retinol, which is then enzymatically changed into two other compounds.
     First, retinol is oxidized to form retinal, which is used to make rhodopsin for the eyes. Then retinal is oxidized to generate retinoic, which binds to certain proteins in the cytoplasm of the cells—a step necessary to allow it to enter the nucleus and bind with DNA. It is the action of retinoic acid on the DNA that accounts for all the biological effects on the skin. Figure 4 outlines this pathway in a simple form.
     Isomerization of the retinoids produces two major chemical formsb. One type, known as 11-cis-retinal, is the chromophore that is part of the visual pigment in the eye. The other one makes up the hormonal retinoids, which are known as all-trans and 9-cis retinoic acid. It is this form of retinoic acid that regulates the expression of cellular genes via the activation of the two classes of nuclear retinoid receptorsc. These receptors are known as retinoic acid receptors (RARs) and the other is called the retinoid X receptors (RXRs). Ultimately, these forms of retinoids carry out many physiological processes, such as reproduction, embryonic development, postnatal growth, differentiation and maintenance of various epithelia, certain functions of the immune response, and, of course, vision. At this time, little is known about what regulates the uptake of retinoids by cells.

Vitamin A and the skin
     Do retinoids actually get into the skin, and, if so, how much? The answer: yes, they get into the skin—although not much—and they enter through several routes. This is yet another mystery because the mechanism of transcutaneous absorption of topical retinoids is not well understood, just as the cellular uptake is not fully explained. Retinoic acid will be the model examined because it is the most studied of the retinoids.
     When applied to the skin, all-trans retinoic acid first undergoes isomerization, but this happens to only part of the applied amount. It goes from 9-cis to 13-cis. See Figure 3. Only about 20% will penetrate the skin, with 80% remaining on the surface. How much additional retinoid goes into the skin depends on a number of factors; mainly, how the product is formulated and the amount of hairy surface to which it is applied.1 Less than 5% of a cream-based retinoic acid will penetrate the skin in 30 minutes. This is odd because when retinoids are tested in an in vitro model on excised skin, penetration is fairly rapid.
     It is known that after a retinoid—such as retinol—is in the skin, it binds first to retinol-binding protein, then to specific cellular-binding proteins within the cell, known as CRBP-I and -II. Retinol binds to CRABP-I and retinoic acid binds to CRABP-II, respectively. These proteins act as both storage and as shuttle proteins within the cytoplasm, and, at the same time, serve to regulate the concentration of the retinoids within the cell. They both bind and release retinoids according the needs of the cells. Keep in mind that the ultimate goal of retinoids is to react with the nuclear DNA and program it for a specific action.2 One note: 13-cis retinoic acid is not bound by CRABP-I/-II or any other binding proteins in the cytoplasm. As a result, it is free to enter the nucleus once it is in the cell. This may explain why this form of retinoic acid is so irritating and teratogenic if taken orally or even applied topicallyd.3

     Retinol and retinol esters. Ask yourself, “Why am I using vitamin A? Does the skin need this vitamin—does it have enough or too much vitamin A. What am I trying to do with this ingredient?” These are fundamental questions that all too few skin care professionals ever raise, even if they are conscientious about treating their clients. Understand that vitamin A is an essential vitamin—people do not and cannot make it—yet the body needs it. The amount the body requires is tightly regulated, so when it is applied, how much is getting into the skin?
     Penetration is dependant on many things, including how the product is formulated. You buy vitamin preparations by the percent of vitamin they contain, but the body uses it in terms of international units, or IU, which are measured in terms of biological activity. One IU of vitamin A is equal to 0.3 micrograms of vitamin A. So, 1 gram of vitamin A would equal 1 million micrograms/0.3 = 3.33 million units of vitamin A. Just for fun, let’s see how many IU are in a 1% vitamin A preparation. A 1% solution contains 1 gram of a substance, consisting of 1 million micrograms. Our 1% vitamin A product, assuming it is retinol, contains 3.3 million units of vitamin A. This is an enormous amount. The major biological activities of retinol are the control of cellular morphogenesis, epithelial cell proliferation and differentiation, immune modulation, stimulation of the creation of new blood vessels, and production of collagen. Some other functions include inhibition of carcinogenesis; absorption of UV light; antioxidant functions; pigment control; and, because retinoids contain several conjugated double bonds, they can trap free radicals; and while absorbing UV radiations from the sun, they protect DNA, lipid membranes and proteins from UV-induced oxidative stress. However, vitamin A in all forms is destroyed by UV light—both in the UVB (290–320 nm) spectra and UVA (320–400) spectra.
     Applying various concentrations of retinol on skin produces a dose-response effect; that is, the higher the dose applied to the skin, the greater the effect on the skin. In Figures 5, 6 and 7, you can see the effects. Figure 5 is the control, or normal, untreated skin. Figure 6 is the effect of 0.1% retinol applied daily for seven days. Notice that the epidermis is thicker and the stratum corneum is less prominent. In Figure 7, you see the effect of 0.5% retinol, again applied daily for five days. There is a great deal of cellular activity with a marked increased in the size of the epidermis. This is called epidermal hyperplasia. Notice that the stratum corneum is also completely gone, due to exfoliation. Sometimes the stratum corneum will be compacted and appear thin. These histological examples illustrate the need to know not only the effect of retinol, but also to appreciate the importance of being familiar with the dosage you are applying.
     There is a feedback relationship between the epidermis and the dermis. As the epidermis grows, the dermis must increase the support elements of collagen and elastin—most likely, this is direct action on the fibroblast by retinol and/or retinoic acid. Fibroblasts seem to control the rate of proliferation in the epidermis. The final answer remains to be discovered, but what is known is that certain retinoids will impede collagen synthesis, while others will stimulate collagen formation. It remains a very complex question.
Even less is understood about the effect of retinoids on the production of melanin pigment. It is known that hydrocortisone steroids plus retinoic acid and hydroquinone will reduce pigmented spots after 3–6 months of treatment. Retinoids inhibit the growth, but enhance the differentiation of melanoma cells in tissue culture. Yet, they inhibit pharmacologically, as well as hormonally induced melanogenesis in these cells. This data was developed 14 years ago, but no definitive data is available to explain the effect of retinoic acid on normal human melanocytes. It appears that retinoic acid has little effect on normal melanogenesis when studied in normal human melanocytes in tissue culture in vitro. One study suggested that the changes in the shape of the melanocytes may indicate that retinoic acid targets the cytoskeleton proteins.4

Clinical applications of retinoids
     Vitamin A can be used to treat several clinical conditions, including acne, aging skin and hyperpigmentation. Each of the forms of vitamin A—retinol, retinyl acetate and retinyl palmitate—has specific reasons why it would be selected for a particular treatment.

      Acne vulgaris. This is a disorder of the sebaceous follicles that is the scourge of teenagers and young adults, both female and male. Most skin care professionals understand that the major pathogenic include hyperkeratinization, which blocks sebum excretion and normal exfoliation due to infundibular obstruction; androgenic stimulation of sebaceous gland secretion; Propionibacterium acnes in the hair follicle, which produce fatty acids and cause inflammation; and a genetic component. Although the full story about how acne is transmitted is not known, a family history of acne is associated with an early onset of acne, more severe acne and often treatment-resistant acne.5
      One of the problems associated with hyperkeratosis is the increase in desmosomes and tonofilaments seen in keratinocytes in comedones. Recently, substance P, a neuropeptide, was found to stimulate sebaceous gland cells, increasing the size of these cells. As you may know, substance P can be elicited with stress and, perhaps this could explain “the giant date pimple.” The social problems of the acne patient only serve to add to the severity of the condition.

      Treatment. Although no one has demonstrated the conversion rate of vitamin A to retinoic acid, I believe it is about one-tenth the strength of retinoic acid, based on my observations of comparative studies of retinol and retinoic acid on mouse skin using the degree of proliferation of the epidermis as an endpoint. The final goal of any acne treatment program should be to heal the acne and restore normal skin, prevent scarring and attempt to reduce the psychological stress associated with acne. Obviously, a good treatment program that clears the acne lesion can reduce social stress a great deal.
     Skin care professionals should feel comfortable and competent when treating acne that consists of comedones and pustules without cysts. A cyst, which can produce scars, is most often a sign of trouble and should be referred to a physician. See Guidelines for Treating Acne for recommendations on how to treat the issue.
     I prefer retinyl acetate for the vitamin A form in acne as it penetrates faster and is less irritating than retinol; however, they all work well. Recently, retinaldehyde has become available and will probably be the retinoid of choice for treating acne since it has all the other actions of retinol, but it is an effective germicide, as well. This is most likely due to the carbonyl group (the aldehyde group) at the end of the molecule.

     Aging skin. Unfortunately, there are many treatments for aging. Without question, the greatest boon to aging treatment methods was the introduction of retinoic acid by Albert M. Kligman, MD, PhD, in 1986. Since then, the world of vitamin A has exploded and many, many new compounds have been developed to treat a host of skin diseases. Aging skin still ranks as the No. 1 problem for most women.
No one really knows the whole story about aging. It is known that some genetic components are at work, as well as many environmental factors, some internal factors, such as wear and tear, and a lot of metabolic and dietary factors. It is interesting that individuals are not programmed to die at a specific set point, even though maximum life span is now thought to be 122–125 years. Quite a bit is being learned, however, because people are living longer and are healthier than ever. What is considered middle age has jumped 15–20 years during the past 50 years, and will continue to rise. One reason that vitamin A is so important as a factor in aging is the critical role it plays in skin health, but vitamin A is rapidly depleted by UV light—both UVA and UVB—so most who are exposed to UV light even indoors, such as fluorescent lighting, will have quite a lot of the vitamin A in their skin destroyed daily. For some reason, this factor in aging is not mentioned very often by aging experts.
     When examining all these factors, no one ingredient is going to solve all the aging skin problems. A composite approach is needed and should include several ingredients in a comprehensive treatment program. Vitamin A is needed, but it requires other active ingredients, as well.