Paolo Giacomoni, PhD, Insight Analysis Consulting04.24.23
Tretinoin (all-trans retinoic acid) was developed by Albert Kligman and James Fulton as a treatment for acne under the brand name Retin-A in 1969. For more than 50 years, the skin care industry has been interested in “retinoids” as a “Holy Grail” to fight skin aging and unwanted skin conditions. As a result, consumers are familiar with the name, and are convinced that “retinoids” work.
Retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. In plain English, this means that retinoids are molecules having structural and/or functional similarities to vitamin A, in its different forms called retinol, retinal, retinoic acid etc. This is a very broad definition. Unfortunately, there are consequences to using broad definitions.
If we say that “truckoids” are objects with structural and/or functional similarities to trucks (i.e. things that have a shape similar to the one of trucks and/or that can be used to do what one does with a truck) then the family of “truckoids” would contain things as diverse as pickups, SUVs, children’s toys, bicycles, horse carriages, sailing boats, tankers, airplanes, missiles and, since sometimes one can sleep or listen to music in a truck, beds and motels and concert halls could also be considered to be “truckoids.” And this does not put any limitation on the number of “truckoid-like” things.
Read More: DSM Personal Care Announces new Grade of Retinol for Clean Beauty
The name “vitamin” was coined by Casimir Funk, the discoverer of thiamine. He called it “vitamin” to indicate that it was an amino-containing molecule essential to life (vita, in Latin). Thiamine was eventually called vitamin B1. Vitamins are essential nutrients that are not produced by the human body. They have been discovered because of the diseases caused by their deficiency.
Not all vitamins contain amino groups and vitamin A does not. Vitamin A is a fat-soluble molecule found in milk. Cows and rodents that are fed with diets lacking vitamin A do not grow well. Vitamin A was identified in 1913 by Elmer McCollum and Marguerite Davis; its structure was elucidated in 1931 by Paul Karrer; its first synthesis was performed in 1946 by Arens and van Dorp. In the 1950s, George Wald pointed out that vitamin A is a component of rods and cones in the retina and is essential for vision. Following this observation, the various chemical forms of vitamin A were called retin-something (retin-ol: the alcohol form; retin-al: the aldeheide form; retinoic acid: the acid form, etc.) and the concept of retinoid was born.
In the following years, the biochemical characteristics of vitamin A were thoroughly studied. In addition to the effects on vision, retinoic acid binds to specific receptors called RAR (retinoic acid receptors) and dictates cellular differentiation by acting on the expression of several hundred genes. Other Retinoids bind to RXR (retinoid X receptors) to perform similar actions. Intestine and lung epithelial differentiation are controlled by RARs and RXRs, and retinoic acid induces epidermal trans-differentiation (whatever it means) in chicken and rodent skin.
The effects of retinoic acid on differentiation are dose-dependent and this is possibly one of the reasons why orally administered retinoic acid to pregnant women can lead to malformations of the fetus. It might also be of interest to know that the conversion of retinol to retinoic acid is performed by the same dehydrogenases that metabolize ethanol. Ethanol is therefore a competitive inhibitor for the synthesis of retinoic acid and this explains why alcohol-addicted individuals are affected by vitamin-A-hypovitaminosis.
One might ask what retinoid we do think we need and what do we hope to obtain from it, besides the advantage of using a magic word in our advertising. As a matter of fact, in the 50 years since Kligman and Fulton’s work, the only successful molecule found in this search for the Holy Grail is, perhaps, adapalene. It is a drug used to treat moderate acne. It binds to RARs to form “super-complexes” with RXR so to induce specific gene transcription and the modulation of epidermal differentiation. Is it a retinoid? Is it “retinoid-like”? It is said to be a third-generation retinoid, whatever that means, and one should compare the structures of adapalene and of retinol to find the answer.
How do we look for a new retinoid? The reasonable approach would be to look for a molecule that is safe and able to provoke on the skin one or several of the biochemical reactions involving vitamin A that are beneficial to other organs of the human body. We could look for a molecule able to bind to a retinoid receptor and to trigger biochemical pathways that might achieve something positive for one’s skin; such as improve elasticity, reduce sebum, stimulate the synthesis of several collagens, enhance epidermal differentiation or reduce uneven skin tone. The immediate question is, of course, do the known forms of vitamin A perform such things on human skin? It is fair to say that retinoic acid is not safe and has to be administered under medical control, and this makes it unsuitable for skin care products. Retinol is moderately irritating and highly unstable. It must be formulated under specific conditions of yellow light and, even when stabilized1 it does not offer the miracles that are promised by the advertiser. The same can be said of retinal and of other structural analogs of vitamin A.
So, what would be the point of having something “better than retinol” when we know that retinol does work poorly if at all? I would suggest forgetting about the hype and buzzwords and stick to analyze the molecules that have been studied according to rigorous protocols and that do perform in reality what some retinoids only perform in the dreams of the advertisers.
Let’s take for instance bakuchiol: phenol, 4-[(1E,3S)-3-ethe-nyl-3,7-dimethyl-1,6-octadienyl], a purified meroterpene from the Indian plant Psoralea corylifolia seeds that has been tested in vivo and in vitro and compared to Retinol.
Relevant Retinol Formulary: Overnight Renewing Oil
In a study with 44 volunteers, topically applied 0.5% bakuchiol was proven to be safe, insofar as it does not provoke scaling and does not elicit itching, stinging and burning, whereas 0.5% retinol does negatively impact skin.2 In the same study, bakuchiol and retinol had a moderate efficacy in reducing pigment intensity and surface of involvement, with bakuchiol showing efficacy in 2 out of 3 volunteers and retinol showing efficacy only in 2 out of 5 volunteers.
In another in vivo study, 3 0.5% bakuchiol was shown to be well tolerated by the volunteers, whereas 0.15% retinol was not, and 23% of the 53 volunteers dropped out because of erythema, dryness, itching or desquamation. In an in vitro wound healing model, 100mM bakuchiol stimulated epidermal regeneration after 40 hours, whereas 100mM retinol did not have any effect. Bakuchiol at 1, 2.5, 5 and 10mM inhibits the synthesis of PGE2 in human dermal fibroblast, three times better than equimolar retinol. In this study, though, bakuchiol and retinol did not have relevant efficacy in stimulating the synthesis of collagen 7 or collagen 1 in cultured human fibroblasts, and neither did 10 ng/ml of FGF.
From these studies it can be concluded that bakuchiol is safe and that it has anti-inflammatory properties, that it is able to stimulate epidermal growth and differentiation as well as to reduce the intensity and the extent of cutaneous hyperpigmentation, whereas retinol does not.
Why don’t we stop looking for alternatives to retinol and start looking for molecules that are better than bakuchiol? N
1. Nguyen, Boussoira, Prince, Giacomoni. Association of a Retinoid with a polyamine polymer. European Patent EP 0 608 433
2. Dhaliwal et al (2019) Prospective, randomized, double-blind assessment of topical bakuchiol and retinol for facial photoaging. British Journal of Dermatology 180, pp289–296
3. Bluemke et al (2022) Multidirectional activity of Bakuchiol against cellular mechanisms of facial ageing - Experimental evidence for a holistic treatment approach. Int J Cosmet Sci 44 : 377-393
Retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. In plain English, this means that retinoids are molecules having structural and/or functional similarities to vitamin A, in its different forms called retinol, retinal, retinoic acid etc. This is a very broad definition. Unfortunately, there are consequences to using broad definitions.
If we say that “truckoids” are objects with structural and/or functional similarities to trucks (i.e. things that have a shape similar to the one of trucks and/or that can be used to do what one does with a truck) then the family of “truckoids” would contain things as diverse as pickups, SUVs, children’s toys, bicycles, horse carriages, sailing boats, tankers, airplanes, missiles and, since sometimes one can sleep or listen to music in a truck, beds and motels and concert halls could also be considered to be “truckoids.” And this does not put any limitation on the number of “truckoid-like” things.
Read More: DSM Personal Care Announces new Grade of Retinol for Clean Beauty
Vitamins Background
The name “vitamin” was coined by Casimir Funk, the discoverer of thiamine. He called it “vitamin” to indicate that it was an amino-containing molecule essential to life (vita, in Latin). Thiamine was eventually called vitamin B1. Vitamins are essential nutrients that are not produced by the human body. They have been discovered because of the diseases caused by their deficiency.
Not all vitamins contain amino groups and vitamin A does not. Vitamin A is a fat-soluble molecule found in milk. Cows and rodents that are fed with diets lacking vitamin A do not grow well. Vitamin A was identified in 1913 by Elmer McCollum and Marguerite Davis; its structure was elucidated in 1931 by Paul Karrer; its first synthesis was performed in 1946 by Arens and van Dorp. In the 1950s, George Wald pointed out that vitamin A is a component of rods and cones in the retina and is essential for vision. Following this observation, the various chemical forms of vitamin A were called retin-something (retin-ol: the alcohol form; retin-al: the aldeheide form; retinoic acid: the acid form, etc.) and the concept of retinoid was born.
In the following years, the biochemical characteristics of vitamin A were thoroughly studied. In addition to the effects on vision, retinoic acid binds to specific receptors called RAR (retinoic acid receptors) and dictates cellular differentiation by acting on the expression of several hundred genes. Other Retinoids bind to RXR (retinoid X receptors) to perform similar actions. Intestine and lung epithelial differentiation are controlled by RARs and RXRs, and retinoic acid induces epidermal trans-differentiation (whatever it means) in chicken and rodent skin.
The effects of retinoic acid on differentiation are dose-dependent and this is possibly one of the reasons why orally administered retinoic acid to pregnant women can lead to malformations of the fetus. It might also be of interest to know that the conversion of retinol to retinoic acid is performed by the same dehydrogenases that metabolize ethanol. Ethanol is therefore a competitive inhibitor for the synthesis of retinoic acid and this explains why alcohol-addicted individuals are affected by vitamin-A-hypovitaminosis.
Retinol Alternatives
One might ask what retinoid we do think we need and what do we hope to obtain from it, besides the advantage of using a magic word in our advertising. As a matter of fact, in the 50 years since Kligman and Fulton’s work, the only successful molecule found in this search for the Holy Grail is, perhaps, adapalene. It is a drug used to treat moderate acne. It binds to RARs to form “super-complexes” with RXR so to induce specific gene transcription and the modulation of epidermal differentiation. Is it a retinoid? Is it “retinoid-like”? It is said to be a third-generation retinoid, whatever that means, and one should compare the structures of adapalene and of retinol to find the answer.
How do we look for a new retinoid? The reasonable approach would be to look for a molecule that is safe and able to provoke on the skin one or several of the biochemical reactions involving vitamin A that are beneficial to other organs of the human body. We could look for a molecule able to bind to a retinoid receptor and to trigger biochemical pathways that might achieve something positive for one’s skin; such as improve elasticity, reduce sebum, stimulate the synthesis of several collagens, enhance epidermal differentiation or reduce uneven skin tone. The immediate question is, of course, do the known forms of vitamin A perform such things on human skin? It is fair to say that retinoic acid is not safe and has to be administered under medical control, and this makes it unsuitable for skin care products. Retinol is moderately irritating and highly unstable. It must be formulated under specific conditions of yellow light and, even when stabilized1 it does not offer the miracles that are promised by the advertiser. The same can be said of retinal and of other structural analogs of vitamin A.
So, what would be the point of having something “better than retinol” when we know that retinol does work poorly if at all? I would suggest forgetting about the hype and buzzwords and stick to analyze the molecules that have been studied according to rigorous protocols and that do perform in reality what some retinoids only perform in the dreams of the advertisers.
Let’s take for instance bakuchiol: phenol, 4-[(1E,3S)-3-ethe-nyl-3,7-dimethyl-1,6-octadienyl], a purified meroterpene from the Indian plant Psoralea corylifolia seeds that has been tested in vivo and in vitro and compared to Retinol.
Relevant Retinol Formulary: Overnight Renewing Oil
Research Results
In a study with 44 volunteers, topically applied 0.5% bakuchiol was proven to be safe, insofar as it does not provoke scaling and does not elicit itching, stinging and burning, whereas 0.5% retinol does negatively impact skin.2 In the same study, bakuchiol and retinol had a moderate efficacy in reducing pigment intensity and surface of involvement, with bakuchiol showing efficacy in 2 out of 3 volunteers and retinol showing efficacy only in 2 out of 5 volunteers.
In another in vivo study, 3 0.5% bakuchiol was shown to be well tolerated by the volunteers, whereas 0.15% retinol was not, and 23% of the 53 volunteers dropped out because of erythema, dryness, itching or desquamation. In an in vitro wound healing model, 100mM bakuchiol stimulated epidermal regeneration after 40 hours, whereas 100mM retinol did not have any effect. Bakuchiol at 1, 2.5, 5 and 10mM inhibits the synthesis of PGE2 in human dermal fibroblast, three times better than equimolar retinol. In this study, though, bakuchiol and retinol did not have relevant efficacy in stimulating the synthesis of collagen 7 or collagen 1 in cultured human fibroblasts, and neither did 10 ng/ml of FGF.
From these studies it can be concluded that bakuchiol is safe and that it has anti-inflammatory properties, that it is able to stimulate epidermal growth and differentiation as well as to reduce the intensity and the extent of cutaneous hyperpigmentation, whereas retinol does not.
Why don’t we stop looking for alternatives to retinol and start looking for molecules that are better than bakuchiol? N
References
1. Nguyen, Boussoira, Prince, Giacomoni. Association of a Retinoid with a polyamine polymer. European Patent EP 0 608 433
2. Dhaliwal et al (2019) Prospective, randomized, double-blind assessment of topical bakuchiol and retinol for facial photoaging. British Journal of Dermatology 180, pp289–296
3. Bluemke et al (2022) Multidirectional activity of Bakuchiol against cellular mechanisms of facial ageing - Experimental evidence for a holistic treatment approach. Int J Cosmet Sci 44 : 377-393