Skin whitening

Skin whitening, also known as skin lightening and skin bleaching, refer to the practice of using chemical substances in an attempt to lighten the skin or provide an even skin color by reducing the melanin concentration in the skin. Several chemicals have been shown to be effective in skin whitening, while some have proven to be toxic or have questionable safety profiles.

Skin whitening
Other namesSkin lightening, brightening, depigmentation, bleaching

In a number of African countries, between 25 and 80% of women regularly use skin whitening products.[1] In Asia this number is around 40%.[1] In India over half of skin care products are sold to whiten skin.[2][1]

Efforts to lighten the skin date back to at least the 1500s in Asia.[3] While a number of agents—such as kojic acid and alpha hydroxy acid—are allowed in cosmetics in Europe, a number of others such as hydroquinone and tretinoin are not.[3] While some countries do not allow mercury compounds in cosmetics, others still do, and they can be purchased online.[1]

Uses

Areas of increased pigmentation such as moles may be depigmented to match the surrounding skin. In cases of vitiligo, unaffected skin may be lightened to achieve a more uniform appearance.[4] Effective agents for specific areas include corticosteroids, tretinoin, and hydroquinone.[3] These agents however are not allowed in cosmetics in Europe due to concerns of side effects.[3]

Attempts to whiten large areas of skin may also be carried out by certain cultures.[3] This may be done for reasons of appearance, politics, or economics.[3]

Hydroquinone

Hydroquinone is a commonly used and effective as a skin whitening cream.[5] It works by decreasing melanin production.[5] Side effects may rarely include exogenous ochronosis.[5] The European Union banned it from cosmetics in 2000.[5]

Tretinoin

Tretinoin, also known as all-trans retinoic acid, may be used to whiten specific areas.[3] It may be used in combination with steroids and hydroquinone.[3] Side effects may include redness and sun sensitivity.[3] Use in pregnancy may harm the baby.[3]

Alpha hydroxy acids

How alpha hydroxy acid (AHA) works is unclear.[3] Side effects may include sun sensitivity, skin redness, thickening, or itching.[3] Low concentrations may be used in cosmetics.[3]

Kojic acid

Kojic acid has been found to be useful in a number of studies.[3] Side effects however include redness, and eczema.[3] It is allowed to be used in cosmetics.[3]

Glutathione

Glutathione is the most common agent taken by mouth in an attempt to whiten the skin.[6] It may also be used as a cream.[6] It is an antioxidant normally made by the body.[6] Whether or not it actually works is unclear as of 2019.[7] Due to side effects that may result with intravenous use, the government of the Philippines recommends against such use.[8]

Other

One 2017 review found tentative evidence of benefit of tranexamic acid in melasma.[9] While another 2017 review found evidence to support its use was insufficient.[10] Azelaic acid may a second line option for melasma.[11]

Laser

A number of types of laser treatments have been used in melasma with some evidence of benefit.[12] Reoccurrence however is common and certain types of lasers can result in more pigmentation.[12]

Mercury

Many skin whiteners contain a form of toxic mercury as the active ingredient.[1] Their use however may harm a person's health and are illegal in many countries.[1] In 2016 Viansilk's Crema Piel De Seda (Silky Skin Cream), in the United States was found to contain mercury.[13]

Mechanisms of action

Melanin is the main substance responsible for the color of the skin. Melanin is synthesized in melanosomes which are organelles produced in melanocytes, cells dedicated to this function that are present in the skin, hair follicles, and other structures of the body. The synthesis of melanin, also called "melanogenesis" and "melanization", involves a chain of enzyme-catalyzed chemical reactions and non-enzyme-catalyzed reactions.[notes 1] The main precursor to melanin is L-tyrosine. The first step of melanogenesis is the conversion of L-tyrosine to L-DOPA; this is the first and rate-limiting step and is catalyzed by the enzyme tyrosinase (TYR).[15]:1163 Other enzymes involved in the synthesis include tyrosinase-related protein 1 (TRP1) and tyrosinase-related protein 2 (TRP2), also known as "dopachrome tautomerase" (DCT). L-tyrosine is taken by the melanocytes from the intercellular medium, then transported to the melanosomes. L-tyrosine is also synthesized within the melanocytes from L-phenylalanine by the enzyme phenylalanine hydroxylase (PAH).[15]:1164

Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanisms of action:[16]

Inhibition of tyrosinase

Upregulation of tyrosinase caused by tyrosinase inhibitors. Several skin whitening agents, including tyrosinase inhibitors, have been found to cause an increase in the expression of tyrosinase, which by itself would increase melanin synthesis.[17]

Microphthalmia-associated transcription factor (MITF) is the master transcription factor that controls the expression of TYR, TRP1 and TRP2, MART1, PMEL17, and many other important proteins involved in the function of melanocytes.[notes 2] Downregulation of MITF decreases melanogenesis[notes 2] and is a mechanism of action of some skin whitening agents.[18] Various signaling pathways and genetic mutations influence the expression of MITF.[notes 3]

MC1R receptor and cAMP

The melanocortin 1 receptor (MC1R) is a transmembrane and G-protein coupled receptor expressed in melanocytes. MC1R is an important target for the regulation of melanogenesis.[20][21][19] Agonism of MC1R increases the ratio of eumelanin to pheomelanin and increases the generation of melanin overall.

The MC1R and cAMP signaling pathway[notes 3][20][21][22] starts with the activation of MC1R, which causes activation of adenylyl cyclase (AC), which produces cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which activates by protein phosphorylation cAMP response element-binding protein (CREB), which upregulates MITF, of which CREB is a transcription factor.

Alpha-melanocyte stimulating hormone (α-MSH), beta-melanocyte stimulating hormone (β-MSH), and adrenocorticotropic hormone are endogenous agonists of MC1R.[15]:1175 Agouti signaling protein (ASIP) appears to be the only endogenous antagonist of MC1R.[notes 4] Synthetic MC1R agonists have been designed, such as the peptides afamelanotide and melanotan II.[20]

Mutations of the MC1R gene correlate and are at least partially responsible for red hair, white skin, and an increased risk for skin cancer in some individuals.[20][23][21][24][25][26][15]:1175

Transfer of melanosomes
See also: human skin § Structure, and epidermis

Within the skin, melanocytes are present in the basal layer of the epidermis; from these melanocytes originate dendrites that reach keratinocytes.[notes 5]

Melanosomes along with the melanin they contain are transferred from melanocytes to keratinocytes when keratinocytes are low in the epidermis.[notes 6] Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation by holding the melanin originated in melanocytes and inducing melanogenesis through chemical signals directed at melanocytes.[notes 3] The transfer of melanosomes to keratinocytes is a necessary condition for the visible pigmentation of the skin.[27] Blocking this transfer is a mechanism of action of some skin whitening agents.[18][16]

The protease-activated receptor 2 (PAR2) is a transmembrane and G-protein coupled receptor expressed in keratinocytes and involved in melanocyte transfer.[notes 7] Antagonists of PAR2 inhibit the transfer of melanosomes and have skin whitening affects, while agonists of PAR2 have the opposite effect.[notes 7]

Destroying melanocytes

Some compounds are known to destroy melanocytes; this mechanism of action is often used to remove the remaining pigmentation in cases of vitiligo.[32]

History

Melanogenesis inhibitors[33] have been discovered and developed using several methods. One way is through the screening of synthetic chemical libraries. This method occasionally uses high throughput screening. Another way works by screening of plant extracts by computational search[34][35] with off-label use of previously known drugs[36][37][38] or exploration of structural analogues of previously known tyrosinase inhibitors.[39][40] These inhibitors are based on knowledge in varying degrees of their structure-activity relationship. The development and discovery of melanogenesis inhibitors illustrates many of the methods used in drug design. Some of the most potent competitive reversible tyrosinase inhibitors are synthetic compounds with a potency a hundreds times more than that of kojic acid.

Society and culture

In India, the sales of skin lightening creams in 2012 totaled around 258 tons, and in 2013 sales were about US$300 million.[41][42] As of 2013, the global market for skin lighteners was projected to reach $19.8 billion by 2018 based on sales growth primarily in Africa, Asia, and the Middle East.[43]

In the United Kingdom, many skin whiteners are illegal due to possible adverse effects. Such products are frequently still sold even after shops have been prosecuted. Trading standards departments lack resources to deal with the problem effectively.[44]

See also

Notes

Italics have been preserved whenever they appear in quotations. Text between square brackets are additional notes not present in the source.

  1. The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011),[14] and Slominski et al. (2004).[15]
  2. "The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [references omitted]."[16]
  3. Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost):
    Smit, Vicanova, Pavel (2009).[18] For a description with emphasis on physiology, see Yamaguchi, Hearing (2009)[19] or Kondo (2011).[14] An extensive and detailed review was written by Slominski et al. (2004).[15]
  4. The assertion that ASIP is the only endogenous antagonist is found in Yamaguchi, Hearing (2009).[19]
  5. "In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes."[18]

    "Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [reference omitted]."[16]

    Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.[27]
  6. Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).[27]
  7. References about PAR2 and its role in skin pigmentation: Kim et al. (2016),[28] Choi et al. (2014),[29] Wu, Hammer (2014),[27] Ando et al. (2012),[30] Ando et al. (2010).[31]

References
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