resorcinol derivatives - a big family of whitening agents.
Source | Jumei
Author | Xiaolizi
In the cosmetics industry, whitening ingredients have always been the direction of continuous attention of various brands and enterprises.
In the popular science article "A Brief Discussion on Whitening Cosmetics and Whitening Agents" by the National Medical Products Administration in December 2021, it was pointed out that the commonly used whitening agents in cosmetics in my country, Japan and South Korea include: arbutin, nicotinamide , photoglyceridine, phenethyl resorcinol , ascorbic acid (i.e. vitamin C), ascorbic acid glucoside, 3-o-ethyl ascorbic acid, magnesium ascorbic acid phosphate, coagulation acid, potassium methoxysalicylate, red mycolytic alcohol, etc.
Among these whitening agents, phenethyl resorcinol - the famous "377", is actually a type of resorcinol derivative, and resorcinol derivatives usually have different degrees of whitening effects.
In fact, in addition to 377, many companies have applied for patents on resorcinol derivative whitening agents. For example, the Rucinol patent ingredient launched by POLA in 1998 and is still in use today, Estee Lauder's unique Yamasugaran extract patent, and the powerful whitening agent "peptide Ammito" launched by Byersdorf in recent years are all resorcinol derivatives. The key to whitening of
: Make tyrosinase not working
Before explaining how resorcinol derivatives play a whitening role, let’s first understand how the skin turns dark.
First of all, the skin becomes darker or pigmentation problems such as chloasma and sun spots are caused by the production of melanin. The production of melanin is essentially to cope with external pressures such as ultraviolet radiation and oxidation to reduce damage. When spots appear, the production of melanin is excessive. The formation of melanin in
is a complex process as a whole, but scientists found that in the formation process of , there are three enzymes that play an important regulatory role and are considered to be the key enzymes for melanin production: tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein-2 (TRP-2), TRP-1 and TRP-2 are believed to mainly play a role in increasing TYR activity.
and TYR have both tyrosine hydroxylase activity (catalyzed tyrosine → dopa) and dopa oxidase activity (catalyzed dopa → dopa quinone). Under the action of TYR, the raw material tyrosine is catalyzed to form dopa quinone, which is an intermediate for melanin formation. [1]
Therefore, we can block melanin formation by inhibiting the activity of TYR. In addition to inhibiting TYR activity, inhibiting the transport of melanosomes to keratinocytes and promoting epidermal metabolism can also reduce pigment.
The main mechanism of action of resorcinol derivatives is to inhibit the activity of TYR or reduce the generation of TYR in different ways. It can be roughly divided into the following three types:
1, competitive inhibition of
, Simply put: a resorcinol derivative looks very similar to the tyrosine it wants to catalyze. TYR will mistake this molecule for tyrosine and bind it to the catalytic active center (tyrosine is catalyzed to dopa here).
However, after TYR binds to this molecule, it cannot be catalyzed into dopaquinone and further converted into melanin, so this molecule successfully blocks the formation of melanin.
2, non-competitive inhibition of
In this case, the resorcinol derivative does not directly bind to the active center of TYR, but binds to other parts of TYR. TYR can still bind to tyrosine after binding to this molecule; or TYR has already bound to tyrosine but can still bind to the molecule before catalysis is completed. In short, the binding of this molecule to tyrosine and enzyme does not interfere with each other and does not have "competitiveness".
But When these three (tyrosine, TYR, a resorcinol derivative molecule) are combined, TYR cannot continue to catalyze tyrosine, so the synthesis of melanin is interrupted.
3. Reduce the expression of tyrosinase
The above two methods are to directly inhibit the activity of TYR through the binding of molecules and enzymes. In addition, some resorcinol derivatives can downregulate the expression of related genes while inhibiting enzyme activity, in other words, directly reduce TYR synthesis from the source.
In summary, briefly said that some resorcinol derivatives have whitening effects is that this type of molecule can inhibit the activity of tyrosinase or reduce the production of tyrosinase through different ways, prevent tyrosinase from catalyzing tyrosine into an intermediate for melanin synthesis, thereby reducing the synthesis of melanin and playing a whitening role.
The same structure, different molecules
are currently clearly defined in cosmetics. There are 5 ingredients of resorcinol derivatives, namely: phenethyl resorcinol, 4-butyl resorcinol, hexyl resorcinol, dimethoxytolyl-4-propyl resorcinol, and isobutylamidothiazolyl resorcinol. These ingredients with resorcinol as the name suffix have been widely used in whitening and spot-lighting products.
Figure: The marking is resorcinol structure, the picture source is Gaid Chemical Network
The famous "377"
"377" full name Symwhite®377, scientific name phenethyl resorcinol , is the research and development patent of international raw material company Dezhixin. It was once "out of the circle" among consumers because of a whitening and light spot essence from Doctor Tono Japan. In December last year, the Drug Administration clearly stipulated that products containing "377" cannot be registered as ordinary cosmetics, but should be registered as special cosmetics, so that "377" becomes even more popular.
Source: According to public information, Dezhixin chemically modified the natural whitening ingredient in European Chipine Pine Tower, thus developing this new raw material.
Mode of action: non-competitive inhibition of tyrosinase activity
Domestic relevant regulations: is limited to the use of special cosmetics, with a limit of 0.5%.
partial efficacy evaluation:
. In the colored 3D skin model MelanoDerm, 0.1% phenethyl resorcinol was used for 14 days. The treatment results showed that the melanin synthesis of cells was almost completely inhibited. . In vivo tests on 12 Asian subjects proved that 0.5% phenethylresorcinol can effectively whiten human skin. The whitening and lightening essence of Dr. Chengye, which has a loud voice, is said to have 1.8% added 377, and the significant "377" is directly stamped on the bottle on the packaging. In fact, many international brands such as Lancome , Elizabeth Arden, L'Oreal Paris and other whitening products have 377 added, and the added content varies.
domestic products, the skin's future 377 whitening and brightening essence has special symptoms of spot lightening and whitening. In addition to adding 377, whitening ingredients such as coagulation acid, nicotinamide, photoglyceridine, and two ascorbic acid derivatives are also added to take effect together.
Picture: Chengye Doctor Whitening and Lightening Essence (left), Skin Future 377 Whitening and Brightening Essence (right), Picture source: Tmall flagship store
4-butyl resorcinol, the effect is 6 times that of 377?
4-butyl resorcinol was once considered the strongest whitening agent among the four common resorcinol derivatives (the other three: phenethyl resorcinol, hexyl resorcinol, dimethoxytolyl-4-propyl resorcinol). A study has evaluated the human efficacy of the whitening effect of three molecules:
Researchers invited 14 elderly volunteers (55-60 years old, female) to treat age spots twice a day with 0.3% 4-butyl resorcinol, 0.3% hexyl resorcinol and 0.5% phenethyl resorcinol preparations. After 8 weeks, the results showed that 4-butyl resorcinol could significantly reduce age spots and significantly better than hexyl resorcinol and phenethyl resorcinol.
Source: In 1998, the Rucinol patent was launched by Japanese cosmetics brand POLA. (According to query, the term of invention patent is 20 years, and the patent has expired.)
mode of action: competitively inhibits tyrosinase activity
Domestic relevant regulations: currently has the maximum usage concentration of products on the market is 2%.The efficacy evaluation of
has been included in the "Catalogue of Cosmetics Materials" (2021 Edition):
Kolbe et al. [2] conducted a systematic comparison of the whitening properties of hydroquinone, arbutin, kojilic acid and 4-butyl resorcinol, and tested the inhibitory effect of four whitening agents on human tyrosinase activity and the effect of inhibiting melanin production in the artificial skin model MelanoDerm. The experimental results show that 4-butyl resorcinol is more than 6 times stronger than 377, 24 times stronger than kojilic acid, and 310 times stronger than arbutyl resorcinol.
In addition to POLA's own products, Uselin once (now the whitening ingredients in its whitening products have been replaced by their own patents) had a whitening essence, which is the main whitening ingredient of 4-butyl resorcinol. In addition, NOREVA, Italian brand Linas and other whitening products are also added. Among the domestic brands of
, Wuxiang's rejuvenation essence cream also adds 2% 4-butyl resorcinol. This product is called "Wuxiang Dabai Can" by netizens. Many netizens have also posted their evaluation results on social brands such as Xiaohongshu. When promoting products, it also focuses on 4-butyl resorcinol as the main whitening ingredient.
In addition, half acre flower field body lotion also has 4-butyl resorcinol added.
Picture: Wuxiang Dabai Can (left), Half acre flower field body lotion (right), the picture comes from Tmall flagship store
whitening agent originally used for "shrimp browning"
Hexyl resorcinol in terms of chemical structural formula should be accurately called 4-hexyl resorcinol , which is a whitening agent that crosses the border from "food additives".
Source: This substance was initially used to prevent shrimp browning. Since 1991, researchers have discovered that hexyl resorcinol is an effective inhibitor of tyrosinase in shrimps, which can inhibit the formation of black spots in shrimps and melanosis , and has strong inhibitory power and high safety. Later, it was gradually used as a whitening ingredient in cosmetics.
Mode of action: competitively inhibits tyrosinase activity
Domestic relevant regulations: currently has the maximum usage concentration of products on the market is 1%. It has been included in the "Catalogue of Used Cosmetics Raw Materials" (2021 Edition)
Partial efficacy evaluation:
has been reported. Through clinical tests of 15 subjects (using the experimental preparation every morning and evening for 8 weeks), it was found that the emulsion containing 0.5% hexyl resorcinol and the emulsion containing 2% hydroquinone had the same skin whitening effect. No adverse reactions were observed in both groups of preparations during the test.
A whitening essence milk from the American brand Replenix Luobeishi adds 2% hexyl resorcinol. It is said that the test data of an authoritative organization showed that the melanin content in the spot spots decreased by 13.6% after 4 weeks of use, and the color brightened by 30.19%.
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Picture: Replenix Luobeishi Whitening Essence (left), Baizhicuiying Skin Rejuvenation Essence (right), Source: Tmall flagship store
Estee Lauder whitening agent isolated from plant extracts
Dimethoxytolyl-4-propyl resorcinol is an exclusive patent of the Estee Lauder Group. It was originally discovered from plant extracts, but the current raw material production mainly relies on chemical organic synthesis.
Source: was isolated from the extract of the medicinal plant Dianella ensifolia. Since the relative molecular mass of this compound is 302, it is claimed to be CL-302 and the trade name is Nivitol™. At first, it was promoted to the name of Yamasuke Lan extract, and then it appeared in the ingredients list with the name of dimethoxytolyl-4-propyl resorcinol.
Mode of action: The information currently found in shows that it is related to the inhibition of dopa oxidase activity in tyrosinase activity.(There are fewer relevant information disclosed)
Domestic relevant regulations: The maximum usage concentration of products on the market is 0.2%, which has been included in the "Catalogue of Names of Cosmetic Materials Used" (2021 Edition)
Partial efficacy evaluation:
There have been studies that homogenate of mouse melanoma cells B16-F1 was treated with different concentrations of CL-302 and kojic acid. In terms of inhibiting tyrosinase activity, the inhibition result is 22 times stronger than kojic acid.
Since the raw material is the exclusive patent of Estee Lauder, only products of brands under the Estee Lauder Group are added, such as Clinique , Aquarium Mystery , TOM FORD, etc. Among them, Clinique's 302 laser bottle fade essence is well known to many consumers. The 302 in product promotion refers to this exclusive raw material patent.
Picture: Clinique 302 laser bottle, source: Tmall flagship store
is called "the strongest whitening agent on the surface"
peptide Amidol (THIAMIDOL) is the scientific name is isobutylamidylthiazolyl resorcinol. It is a new raw material developed by Byelsteuff in recent years. There are voices on the Internet to call it "the strongest whitening agent on the surface". This statement comes from a paper published by Byelsteuff [3]. The paper shows that the researchers compared the effects of commonly used whitening ingredients on the market such as 4-butyl resorcinol, 377, arbutin, hydroquinone, etc. to inhibit human tyrosinase.
single data on inhibiting tyrosinase, the inhibition of peptide Ammido is 20 times that of the second place 4-butyl resorcinol, 120 times that of the fourth place 377, and the third place is hexyl resorcinol. Konolic acid, hydroquinone, and nicotinamide do not perform well in inhibiting tyrosinase activity.
A prominent point in the experiment of Byersdorf is that human tyrosinase was used when molecular screening and comparison of the inhibition of tyrosinase activity by various whitening agents.
Since there are fewer tyrosinases in commercial production in humans, in many related experiments, researchers often used mushroom tyrosinase. However, the amino acid sequence of the mushroom tyrosinase activity center is not the same as that of human tyrosinase. Different structures may affect the binding of molecules, so the experimental results of the detection of mushroom tyrosinase may not be accurate.
Byersdorf uses genetic technology to produce recombinant human tyrosinase. The experiments conducted under recombinant human tyrosinase are more similar to those in the human body and are more convincing.
Source: Byersdorf used recombinant human tyrosinase to screen the ingredient
mode of action: According to current relevant information, it is only indicated as a tyrosinase activity inhibitor
Domestic relevant regulations: Currently, only one related information from June 2018 was found on the official website of the Drug Administration: Byersdorf's German headquarters health administrative license (imported) JHZYL1500003 isobutylamidylthiazolyl resorcinol has not been approved.
partial efficacy evaluation: researchers used 0.2% concentration of peptide Ammito to test the effect of fading color spots on human body, and evaluated the changes in color spots at weeks 4, 8 and 12 respectively, and found that the color spots could significantly fade.
Byersdorf's Nivea and some whitening products are added, such as Uselin Light Whitening Essence and Nivea 630 Light Whitening Essence.
Picture: Uselin Light Whitening Essence (left), Nivea 630 Light Whitening Essence (right), Picture source: Tmall flagship store
, these natural molecules also have "resorcinol"
The above ingredients are all displayed in the ingredients list under the name of resorcinol, and can be classified as resorcinol derivatives, and they all work by inhibiting tyrosinase activity. But in addition, some natural ingredients named after plants also have resorcinol structures in their molecular structural formulas, and experiments have shown that they can also inhibit tyrosinase activity.
is luminescent licorice , which was once known as "whitening gold" (for details, please click: "It has stronger whitening effect than vitamin C and nicotinamide. What are the application characteristics of luminescent licorice?丨Ingredient Special 7), and its molecule also has a resorcinol structure. Currently, the study found that the inhibition of tyrosinase by photolicordine is manifested as a reversible non-competitive inhibition.[4]
Figure: Structural form of light licorice, picture source Gaide Chemical Network
Now light licorice has been included in the "Catalogue of Names of Cosmetics Raw Materials" (2021 Edition), but there is no concentration requirement to display. In some in vitro experiments, its inhibitory effect on tyrosinase activity is stronger than that of nicotinamide and VC ethyl ether . Some scientists also compared it with kojic acid and arbutin in zebrafish experiments, which showed good spot-fading effects. In addition to
, in addition to lipidol, resorcinol structure also exists in the molecule of resveratrol. The effect of resveratrol is not limited to whitening, but from the perspective of the mechanism of whitening effect, resveratrol was found to reduce melanin production by inhibiting tyrosinase activity.
Figure: Resveratrol structural formula, source: Baidu Encyclopedia
Scientists have found that resveratrol is a non-peptide endothelin antagonist (the relationship between resveratrol and endothelin is manifested as one rises and another), and endothelin-1 can improve the tyrosinase (TYR) activity of melanocytes and increase the expression of tyrosinase (TYR) and tyrosinase-related protein-1 (TRP-1). This view holds that resveratrol "indirectly" inhibits tyrosinase.
Currently, resveratrol has also been included in the "Catalogue of Names of Cosmetics Raw Materials" (2021 Edition), and the maximum usage concentration of products on the market is 5%.
Regarding the evaluation of whitening efficacy of resveratrol, a project has recruited 40 female subjects with photoaging of facial expression, and randomly divided into treatment group and control group. 20 people in each group were applied to resveratrol or matrix for 12 consecutive weeks. The skin color and moisture content were measured at different time points before and after use. The results of
show that the mean melanin index of subjects in the resveratrol group decreased significantly compared with before the start of the trial, and the difference in melanin index was significantly lower than that in the control group. The physician evaluated that about 65% of the subjects had moderate to significant improvement in skin brightness, and about 60% of the subjects were satisfied with the efficacy.
The above mentioned Dr. Chengye's 377 whitening and spot-lighting essence, as well as a whitening essence from Replenix Luo Beishi, also have resveratrol added.
In addition, a research progress of rhodioside-pIus published on the official account not long ago showed that the structure of rhodioside-plus is still in the research stage (rhodioside has no resorcinol structure, and the modified plus version has). According to the article, such a molecular structure not only retains the transcriptional inhibitory effect on tyrosinase, but also enhances the inhibitory effect on tyrosinase activity.
Figure: Rhodiola-plus structural formula, source from this Meiji Classroom official account
From the perspective of biochemical , structure determines function. The structure of resorcinol may have a certain connection with the activity of tyrosinases. Substances with resorcinol structure have therefore become a major "family" of whitening agents. In the future, more effective and safe whitening ingredients may be found in this family - from the perspective of plant active ingredients or in the attempts of relevant structures.
References:
[1] Yu Chengqian, Xu Xuegang, Li Yuanhong. Research and application progress of phenethyl resorcinol[J]. Chinese Journal of Dermatology and Venereology, 2020, 34(6):4.
[2]Kolbe L, Mann T, Gerwat W, et al. 4-n-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyperpigmentation
[3]Mann T, Gerwat W, Batzer J, Eggers K, Scherner C, Wenck H, Stäb F, Hearing VJ, Röhm KH, Kolbe L. Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase. J Invest Dermatol. 2018 Jul;138(7):1601-1608.
[4] Luo Congyan, Mu Chunhai, Wang Yuanji, et al. Research on the inhibition of tyrosinase and in vitro antioxidant activity of photolicoricidine[J]. Chinese medicinal materials, 2010(11):5.
Information source: Tinglan Biological Official Account, to Benmeiji Classroom Official Account, National Medical Products Popularization Article "A Brief Discussion on Whitening Cosmetics and Whitening Agents", "Catalogue of Names of Cosmetics Materials Used" (2021 Edition)
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