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.
|Other names||Skin lightening, brightening, depigmentation, bleaching|
In a number of African countries, between 25 and 80% of women regularly use skin whitening products. In Asia this number is around 40%. In India over half of skin care products are sold to whiten skin.
Efforts to lighten the skin date back to at least the 1500s in Asia. 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. While some countries do not allow mercury compounds in cosmetics, others still do, and they can be purchased online.
- 1 Uses
- 2 Mechanisms of action
- 3 History
- 4 Society and culture
- 5 See also
- 6 Notes
- 7 References
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. Effective agents for specific areas include corticosteroids, tretinoin, and hydroquinone. These agents however are not allowed in cosmetics in Europe due to concerns of side effects.
Hydroquinone is a commonly used and effective as a skin whitening cream. It works by decreasing melanin production. Side effects may rarely include exogenous ochronosis. The European Union banned it from cosmetics in 2000.
Tretinoin, also known as all-trans retinoic acid, may be used to whiten specific areas. It may be used in combination with steroids and hydroquinone. Side effects may include redness and sun sensitivity. Use in pregnancy may harm the baby.
Alpha hydroxy acidsEdit
Glutathione is the most common agent taken by mouth in an attempt to whiten the skin. It may also be used as a cream. It is an antioxidant normally made by the body. Whether or not it actually works is unclear as of 2019. Due to side effects that may result with intravenous use, the government of the Philippines recommends against such use.
One 2017 review found tentative evidence of benefit of tranexamic acid in melasma. While another 2017 review found evidence to support its use was insufficient. Azelaic acid may a second line option for melasma.
Many skin whiteners contain a form of toxic mercury as the active ingredient. Their use however may harm a person's health and are illegal in many countries. In 2016 Viansilk's Crema Piel De Seda (Silky Skin Cream), in the United States was found to contain mercury.
Mechanisms of actionEdit
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).: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).:1164
Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanisms of action:
- Inhibition of the activity of tyrosinase: The catalytic action of tyrosinase is inhibited by the skin whitening agent.
- Inhibition of the expression or activation of tyrosinase: The antimelanogenic agent causes less tyrosinase to be generated or prevents tyrosinase from being activated to its functional form.
- Scavenging of the intermediate products of melanin synthesis.
- Preventing the transfer of melanosomes to keratinocytes.
- Directly destroying existing melanin.
- Destroying melanocytes.
Inhibition of tyrosinaseEdit
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.
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. Various signaling pathways and genetic mutations influence the expression of MITF.[notes 3]
MC1R receptor and cAMPEdit
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. 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] 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.: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.
Transfer of melanosomesEdit
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. Blocking this transfer is a mechanism of action of some skin whitening agents.
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]
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Melanogenesis inhibitors 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 with off-label use of previously known drugs or exploration of structural analogues of previously known tyrosinase inhibitors. 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 cultureEdit
In India, the sales of skin lightening creams in 2012 totaled around 258 tons, and in 2013 sales were about US$300 million. 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.
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.
Italics have been preserved whenever they appear in quotations. Text between square brackets are additional notes not present in the source.
- 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), and Slominski et al. (2004).
- "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]."
- 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). For a description with emphasis on physiology, see Yamaguchi, Hearing (2009) or Kondo (2011). An extensive and detailed review was written by Slominski et al. (2004).
- The assertion that ASIP is the only endogenous antagonist is found in Yamaguchi, Hearing (2009).
- "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."
"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]."
Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.
- Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).
- References about PAR2 and its role in skin pigmentation: Kim et al. (2016), Choi et al. (2014), Wu, Hammer (2014), Ando et al. (2012), Ando et al. (2010).
- "Mercury in skin lightening products" (PDF). WHO. Retrieved 15 July 2019.
- Ryle, Robyn (2016). Questioning Gender: A Sociological Exploration. SAGE Publications. p. PT412. ISBN 9781506325484.
- Desmedt, B; Courselle, P; De Beer, JO; Rogiers, V; Grosber, M; Deconinck, E; De Paepe, K (June 2016). "Overview of skin whitening agents with an insight into the illegal cosmetic market in Europe". Journal of the European Academy of Dermatology and Venereology : JEADV. 30 (6): 943–50. doi:10.1111/jdv.13595. PMID 26953335.
- "Skin lightening". nhs.uk. 2017-12-21.
- Tse, TW (September 2010). "Hydroquinone for skin lightening: safety profile, duration of use and when should we stop?". The Journal of Dermatological Treatment. 21 (5): 272–5. doi:10.3109/09546630903341945. PMID 20095963.
- Malathi, M; Thappa, DM (2013). "Systemic skin whitening/lightening agents: what is the evidence?". Indian Journal of Dermatology, Venereology and Leprology. 79 (6): 842–6. doi:10.4103/0378-6323.120752. PMID 24177629.
- Dilokthornsakul, W; Dhippayom, T; Dilokthornsakul, P (June 2019). "The clinical effect of glutathione on skin color and other related skin conditions: A systematic review". Journal of Cosmetic Dermatology. 18 (3): 728–737. doi:10.1111/jocd.12910. PMID 30895708.
- Sonthalia, Sidharth; Daulatabad, Deepashree; Sarkar, Rashmi (2016). "Glutathione as a skin whitening agent: Facts, myths, evidence and controversies". Indian J. Dermatol. Venereol. Leprol. 82 (3): 262–72. doi:10.4103/0378-6323.179088. PMID 27088927.
- Zhou, LL; Baibergenova, A (27 February 2017). "Melasma: systematic review of the systemic treatments". International Journal of Dermatology. 56 (9): 902–908. doi:10.1111/ijd.13578. PMID 28239840.
- Taraz, M; Niknam, S; Ehsani, AH (30 January 2017). "Tranexamic acid in treatment of melasma: A comprehensive review of clinical studies". Dermatologic Therapy. 30 (3): e12465. doi:10.1111/dth.12465. PMID 28133910.
- Rendon, Marta; Berneburg, Mark; Arellano, Ivonne; Picardo, Mauro (May 2006). "Treatment of melasma". Journal of the American Academy of Dermatology. Supplement 2. 54 (5): S272–S281. doi:10.1016/j.jaad.2005.12.039. PMID 16631968.
- Trivedi, MK; Yang, FC; Cho, BK (March 2017). "A review of laser and light therapy in melasma". International Journal of Women's Dermatology. 3 (1): 11–20. doi:10.1016/j.ijwd.2017.01.004. PMC 5418955. PMID 28492049.
- "FDA Warns Consumers Not to Use Viansilk's "Crema Piel De Seda" ("Silky Skin Cream")". Drugs: Drug Safety and Availability. USFDA. January 29, 2016. Retrieved January 30, 2016.
- Kondo, Taisuke; Hearing, Vincent J. (2011). "Update on the regulation of mammalian melanocyte function and skin pigmentation". Expert. Rev. Dermatol. 6 (1): 97–108. doi:10.1586/edm.10.70. PMC 3093193. PMID 21572549.
- Slominski, Andrzej; Tobin, Desmond J.; Shibahara, Shigeki; Wortsman, Jacobo (2004). "Melanin Pigmentation in Mammalian Skin and its Hormonal Regulation". Physiol. Rev. 84 (4): 1155–228. doi:10.1152/physrev.00044.2003. PMID 15383650.
- Ebanks, Jody P.; Wickett, R. Randall; Boissy, Raymond E. (2009). "Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration". Int. J. Mol. Sci. 10 (9): 4066–4087. doi:10.3390/ijms10094066. PMC 2769151. PMID 19865532.
- Gruber, James V.; Holtz, Robert (2013). "Examining the Impact of Skin Lighteners In Vitro". Oxidative Medicine and Cellular Longevity. 2013: 1–7. doi:10.1155/2013/702120. PMC 3655678. PMID 23738040.
- Smit, Nico; Vicanova, Jana; Pavel, Stan (2009). "The Hunt for Natural Skin Whitening Agents". Int. J. Mol. Sci. 10 (12): 5326–5349. doi:10.3390/ijms10125326. PMC 2801997. PMID 20054473.
- Yamaguchi, Yuji; Hearing, Vincent J. (2009). "Physiological factors that regulate skin pigmentation". BioFactors. 35 (2): 193–199. doi:10.1002/biof.29. PMC 2793097. PMID 19449448.
- Chen, Hongxiang; Weng, Qing Y.; Fisher, David E. (2014). "UV Signaling Pathways within the Skin". J. Invest. Dermatol. 134 (4): 2080–2085. doi:10.1038/jid.2014.161. PMC 4102648. PMID 24759085.
- Rodríguez, Carlos Iván; Setaluri, Vijayasaradhi (2014). "Cyclic AMP (cAMP) signaling in melanocytes and melanoma". Arch. Biochem. Biophys. 563: 22–7. doi:10.1016/j.abb.2014.07.003. PMID 25017568.
- Lee, Ai-Young; Noh, Minsoo (2013). "The regulation of epidermal melanogenesis via cAMP and/or PKC signaling pathways: insights for the development of hypopigmenting agents". Arch. Pharm. Res. 36 (7): 792–801. doi:10.1007/s12272-013-0130-6. PMID 23604723.
- Marzuka-Alcalá, Alexander; Gabree, Michele Jacobs; Tsao, Hensin (2014). Melanoma susceptibility genes and risk assessment. Methods Mol. Biol. Methods in Molecular Biology. 1102. pp. 381–93. doi:10.1007/978-1-62703-727-3_20. ISBN 978-1-62703-726-6. PMID 24258989.
- Law, Matthew H.; MacGregor, Stuart; Hayward, Nicholas K. (2012). "Melanoma Genetics: Recent Findings Take Us Beyond Well-Traveled Pathways". J. Invest. Dermatol. 132 (7): 1763–74. doi:10.1038/jid.2012.75. PMID 22475760.
- Nelson, Andrew A.; Tsao, Hensin (2009). "Melanoma and genetics". Clin. Dermatol. 27 (1): 46–52. doi:10.1016/j.clindermatol.2008.09.005. PMID 19095153.
- Sturm, Richard A. (2009). "Molecular genetics of human pigmentation diversity". Hum. Mol. Genet. 18 (R1): R9–17. doi:10.1093/hmg/ddp003. PMID 19297406.
- Wu, Wufeng; Hammer, John A. (2014). "Melanosome transfer: It is best to give and receive". Curr. Opin. Cell Biol. 29: 1–7. doi:10.1016/j.ceb.2014.02.003. PMC 4130791. PMID 24662021.
- Kim, Ji Young; Kim, Dae Suk; Sohn, Hyojung; Lee, Eun Jung; Oh, Sang Ho (2016). "PAR-2 is involved in melanogenesis by mediating stem cell factor production in keratinocytes". Exp. Dermatol. 25 (6): 487–9. doi:10.1111/exd.12982. PMID 26909822.
- Choi, Hye-In; et al. (2014). "Melanosome uptake is associated with the proliferation and differentiation of keratinocytes". Arch. Dermatol. Res. 306 (1): 59–66. doi:10.1007/s00403-013-1422-x. PMID 24173125.
- Ando, Hideya; et al. (2012). "Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion". J. Invest. Dermatol. 132 (4): 1222–9. doi:10.1038/jid.2011.413. PMID 22189785.
- Ando, Hideya; et al. (2010). "Keratinocytes in culture accumulate phagocytosed melanosomes in the perinuclear area". Pigment Cell Melanoma Res. 23 (1): 129–33. doi:10.1111/j.1755-148X.2009.00640.x. PMID 19761520.
- van den Boorn, Jasper G.; Melief, Cornelis J.; Luiten, Rosalie M. (2011). "The Monobenzone-induced depigmentation: from enzymatic blockade to autoimmunity". Pigment Cell Melanoma Res. 24 (4): 673–9. doi:10.1111/j.1755-148X.2011.00878.x. PMID 21689385.
- Pillaiyar, Thanigaimalai (2018). "Inhibitors of Melanogenesis: An Updated Review". Journal of Medicinal Chemistry. 61 (17): 7395–7418. doi:10.1021/acs.jmedchem.7b00967. PMID 29763564.
- Choi, Joonhyeok; Choi, Kwang-Eun; Park, Sung Jean; Kim, Sun Yeou; Jee, Jun-Goo (2016). "Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors". J. Chem. Inf. Model. 56 (2): 354–67. doi:10.1021/acs.jcim.5b00484. PMID 26750991.
- Ai, Ni; Welsh, William J.; Santhanam, Uma; Hu, Hong; Lyga, John (2014). "Novel Virtual Screening Approach for the Discovery of Human Tyrosinase Inhibitors". PLoS ONE. 9 (11): e112788. Bibcode:2014PLoSO...9k2788A. doi:10.1371/journal.pone.0112788. PMC 4245091. PMID 25426625.
- Baek, Seung-Hwa; Lee, Sang-Han (2015). "Proton pump inhibitors decrease melanogenesis in melanocytes". Biomed. Rep. 3 (5): 726–730. doi:10.3892/br.2015.492. PMC 4535079. PMID 26405553.
- Choi, Joonhyeok; Jee, Jun-Goo (2015). "Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors". Int. J. Mol. Sci. 16 (12): 28534–28548. doi:10.3390/ijms161226114. PMC 4691061. PMID 26633377.
- Wang, Y.; et al. (2014). "Inhibitory effects of imatinib mesylate on human epidermal melanocytes". Clin. Exp. Dermatol. 39 (2): 202–8. doi:10.1111/ced.12261. PMID 24479586.
- Liu, Qing; Kim, Cheong Taek; Jo, Yang Hee; Kim, Seon Beom; Hwang, Bang Yeon; Lee, Mi Kyeong (2015). "Synthesis and Biological Evaluation of Resveratrol Derivatives as Melanogenesis Inhibitors". Molecules. 20 (9): 16933–45. doi:10.3390/molecules200916933. PMC 6332419. PMID 26393543.
- Jiang, Yongfu; et al. (2013). "Synthesis and Biological Evaluation of Unsymmetrical Curcumin Analogues as Tyrosinase Inhibitors". Molecules. 18 (4): 3948–61. doi:10.3390/molecules18043948. PMC 6269853. PMID 23552906.
- Narayan, A. Bloomberg Business Week, A Lucrative Promise for India's men: Whiter skin, Dec 5, 2013
- Narayan, Adi (5 December 2013). "A Lucrative Promise for India's Men: Whiter Skin". Bloomberg News.
- McDougall, Andrew (June 4, 2013). "Skin lightening trend in Asia boosts global market". Cosmetics Design Asia.
- "Skin-whitening creams: The battle against illegal products". BBC. 6 August 2018. Retrieved 15 September 2018.